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The investigation of resting-state functional connectivity (rsFC) in asymptomatic individuals at genetic risk for Alzheimer's disease (AD) enables discovering the earliest brain alterations in preclinical stages of the disease. The APOE-ε4 variant is the major genetic risk factor for AD, and previous studies have reported rsFC abnormalities in carriers of the ε4 allele. Yet, no study has assessed APOE-ε4 gene-dose effects on rsFC measures, and only a few studies included measures of cognitive performance to aid a clinical interpretation. We assessed the impact of APOE-ε4 on rsFC in a sample of 429 cognitively unimpaired individuals hosting a high number of ε4 homozygotes (n = 58), which enabled testing different models of genetic penetrance. We used independent component analysis and found a reduced rsFC as a function of the APOE-ε4 allelic load in the temporal default-mode and the medial temporal networks, while recessive effects were found in the extrastriate and limbic networks. Some of these results were replicated in a subsample with negative amyloid markers. Interaction with cognitive data suggests that such a network reorganization may support cognitive performance in the ε4-homozygotes. Our data indicate that APOE-ε4 shapes the functional architecture of the resting brain and favor the idea of a network-based functional compensation.
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Doença de Alzheimer , Apolipoproteína E4 , Mapeamento Encefálico , Encéfalo , Cognição , Rede Nervosa , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Cognição/fisiologia , Predisposição Genética para Doença/genética , Genótipo , Imageamento por Ressonância Magnética , Rede Nervosa/fisiologia , Vias Neurais/fisiologiaRESUMO
Amyloid (Aß) pathology is the earliest detectable pathophysiological event along the Alzheimer's continuum, which can be measured both in the cerebrospinal fluid (CSF) and by Positron Emission Tomography (PET). Yet, these biomarkers identify two distinct Aß pools, reflecting the clearance of soluble Aß as opposed to the presence of Aß fibrils in the brain. An open question is whether risk factors known to increase Alzheimer's' disease (AD) prevalence may promote an imbalance between soluble and deposited Aß. Unveiling such interactions shall aid our understanding of the biological pathways underlying Aß deposition and foster the design of effective prevention strategies. We assessed the impact of three major AD risk factors, such as age, APOE-ε4 and female sex, on the association between CSF and PET Aß, in two independent samples of non-demented individuals (ALFA: n = 320, ADNI: n = 682). We tested our hypotheses both in candidate regions of interest and in the whole brain using voxel-wise non-parametric permutations. All of the assessed risk factors induced a higher Aß deposition for any given level of CSF Aß42/40, although in distinct cerebral topologies. While age and sex mapped onto neocortical areas, the effect of APOE-ε4 was prominent in the medial temporal lobe, which represents a target of early tau deposition. Further, we found that the effects of age and APOE-ε4 was stronger in women than in men. Our data indicate that specific AD risk factors affect the spatial patterns of cerebral Aß aggregation, with APOE-ε4 possibly facilitating a co-localization between Aß and tau along the disease continuum.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Apolipoproteínas E/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Biomarcadores/metabolismo , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/metabolismoRESUMO
INTRODUCTION: Poor sleep quality is associated with cognitive outcomes in Alzheimer's disease (AD). We analyzed the associations between self-reported sleep quality and brain structure and function in cognitively unimpaired (CU) individuals. METHODS: CU adults (N = 339) underwent structural magnetic resonance imaging, lumbar puncture, and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. A subset (N = 295) performed [18F] fluorodeoxyglucose positron emission tomography scans. Voxel-wise associations with gray matter volumes (GMv) and cerebral glucose metabolism (CMRGlu) were performed including interactions with cerebrospinal fluid (CSF) AD biomarkers status. RESULTS: Poorer sleep quality was associated with lower GMv and CMRGlu in the orbitofrontal and cingulate cortices independently of AD pathology. Self-reported sleep quality interacted with altered core AD CSF biomarkers in brain areas known to be affected in preclinical AD stages. DISCUSSION: Poor sleep quality may impact brain structure and function independently from AD pathology. Alternatively, AD-related neurodegeneration in areas involved in sleep-wake regulation may induce or worsen sleep disturbances. Highlights Poor sleep impacts brain structure and function independent of Alzheimer's disease (AD) pathology. Poor sleep exacerbates brain changes observed in preclinical AD. Sleep is an appealing therapeutic strategy for preventing AD.
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Doença de Alzheimer , Disfunção Cognitiva , Adulto , Humanos , Doença de Alzheimer/patologia , Encéfalo/patologia , Substância Cinzenta/patologia , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons/métodos , Sono , Biomarcadores/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/metabolismoRESUMO
PURPOSE: Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([18F]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants. METHODS: We included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-ß (Aß) positive. Associations between GFAP markers and [18F]FDG uptake were studied. We also investigated whether these associations were modified by Aß and tau status (AT stages). RESULTS: Plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aß pathology but became negative in Aß-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism. CONCLUSIONS: Higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Gliose/diagnóstico por imagem , Gliose/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Fluordesoxiglucose F18/metabolismo , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Inflamação , Glucose/metabolismoRESUMO
INTRODUCTION: Harboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described. METHODS: Multicenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3). RESULTS: Carrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging. DISCUSSION: In addition to the known resistance against amyloid-ß deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD-related cognitive decline.
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Doença de Alzheimer , Apolipoproteína E2 , Disfunção Cognitiva , Dosagem de Genes , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E2/genética , Disfunção Cognitiva/genética , Genótipo , Substância Cinzenta/patologia , HumanosRESUMO
The ε4 allele of the gene Apolipoprotein E is the major genetic risk factor for Alzheimer's Disease. APOE ε4 has been associated with changes in brain structure in cognitively impaired and unimpaired subjects, including atrophy of the hippocampus, which is one of the brain structures that is early affected by AD. In this work we analyzed the impact of APOE ε4 gene dose and its association with age, on hippocampal shape assessed with multivariate surface analysis, in a ε4-enriched cohort of n = 479 cognitively healthy individuals. Furthermore, we sought to replicate our findings on an independent dataset of n = 969 individuals covering the entire AD spectrum. We segmented the hippocampus of the subjects with a multi-atlas-based approach, obtaining high-dimensional meshes that can be analyzed in a multivariate way. We analyzed the effects of different factors including APOE, sex, and age (in both cohorts) as well as clinical diagnosis on the local 3D hippocampal surface changes. We found specific regions on the hippocampal surface where the effect is modulated by significant APOE ε4 linear and quadratic interactions with age. We compared between APOE and diagnosis effects from both cohorts, finding similarities between APOE ε4 and AD effects on specific regions, and suggesting that age may modulate the effect of APOE ε4 and AD in a similar way.
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Doença de Alzheimer , Apolipoproteína E4/genética , Predisposição Genética para Doença , Hipocampo/anatomia & histologia , Neuroimagem/métodos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Atlas como Assunto , Estudos de Coortes , Feminino , Heterozigoto , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
Gray matter networks (GMn) provide essential information on the intrinsic organization of the brain and appear to be disrupted in Alzheimer's disease (AD). Apolipoprotein E (APOE)-ε4 represents the major genetic risk factor for AD, yet the association between APOE-ε4 and GMn has remained unexplored. Here, we determine the impact of APOE-ε4 on GMn in a large sample of cognitively unimpaired individuals, which was enriched for the genetic risk of AD. We used independent component analysis to retrieve sources of structural covariance and analyzed APOE group differences within and between networks. Analyses were repeated in a subsample of amyloid-negative subjects. Compared with noncarriers and heterozygotes, APOE-ε4 homozygotes showed increased covariance in one network including primarily right-lateralized, parietal, inferior frontal, as well as inferior and middle temporal regions, which mirrored the formerly described AD-signature. This result was confirmed in a subsample of amyloid-negative individuals. APOE-ε4 carriers showed reduced covariance between two networks encompassing frontal and temporal regions, which constitute preferential target of amyloid deposition. Our data indicate that, in asymptomatic individuals, APOE-ε4 shapes the cerebral organization in a way that recapitulates focal morphometric alterations observed in AD patients, even in absence of amyloid pathology. This suggests that structural vulnerability in neuronal networks associated with APOE-ε4 may be an early event in AD pathogenesis, possibly upstream of amyloid deposition.
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Apolipoproteína E4/genética , Substância Cinzenta/diagnóstico por imagem , Feminino , Genótipo , Substância Cinzenta/fisiologia , Voluntários Saudáveis , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologiaRESUMO
White matter hyperintensities (WMH) have been extensively associated with cognitive impairment and reductions in gray matter volume (GMv) independently. This study explored whether WMH lesion volume mediates the relationship between cerebral patterns of GMv and cognition in 521 (mean age 57.7 years) cognitively unimpaired middle-aged individuals. Episodic memory (EM) was measured with the Memory Binding Test and executive functions (EF) using five WAIS-IV subtests. WMH were automatically determined from T2 and FLAIR sequences and characterized using diffusion-weighted imaging (DWI) parameters. WMH volume was entered as a mediator in a voxel-wise mediation analysis relating GMv and cognitive performance (with both EM and EF composites and the individual tests independently). The mediation model was corrected by age, sex, education, number of Apolipoprotein E (APOE)-ε4 alleles and total intracranial volume. We found that even at very low levels of WMH burden in the cohort (median volume of 3.2 mL), higher WMH lesion volume was significantly associated with a widespread pattern of lower GMv in temporal, frontal, and cerebellar areas. WMH mediated the relationship between GMv and EF, mainly driven by processing speed, but not EM. DWI parameters in these lesions were compatible with incipient demyelination and axonal loss. These findings lead to the reflection on the relevance of the control of cardiovascular risk factors in middle-aged individuals as a valuable preventive strategy to reduce or delay cognitive decline.
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Substância Cinzenta/diagnóstico por imagem , Tempo de Reação/fisiologia , Substância Branca/diagnóstico por imagem , Adulto , Idoso , Apolipoproteínas E/genética , Axônios/patologia , Mapeamento Encefálico , Cognição , Doenças Desmielinizantes/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Função Executiva , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Masculino , Memória Episódica , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de WechslerRESUMO
Perception is a highly active process relying on the continuous formulation of predictive inferences using short-term sensory memory templates, which are recursively adjusted based on new input. According to this idea, earlier studies have shown that novel stimuli preceded by a higher number of repetitions yield greater novelty responses, indexed by larger mismatch negativity (MMN). However, it is not clear whether this MMN memory trace effect is driven by more adapted responses to prior stimulation or rather by a heightened processing of the unexpected deviant, and only few studies have so far attempted to characterize the functional neuroanatomy of these effects. Here we implemented a modified version of the auditory frequency oddball paradigm that enables modeling the responses to both repeated standard and deviant stimuli. Fifteen subjects underwent functional magnetic resonance imaging (fMRI) while their attention was diverted from auditory stimulation. We found that deviants with longer stimulus history of standard repetitions yielded a more robust and widespread activation in the bilateral auditory cortex. Standard tones repetition yielded a pattern of response entangling both suppression and enhancement effects depending on the predictability of upcoming stimuli. We also observed that regularity encoding and deviance detection mapped onto spatially segregated cortical subfields. Our data provide a better understanding of the neural representations underlying auditory repetition and deviance detection effects, and further support that perception operates through the principles of Bayesian predictive coding.
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Atenção/fisiologia , Córtex Auditivo/fisiologia , Percepção Auditiva/fisiologia , Discriminação Psicológica/fisiologia , Adulto , Córtex Auditivo/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Adulto JovemRESUMO
The neuroanatomical bases of episodic memory (EM) and executive functions (EFs) have been widely addressed in patients with brain damage and in individuals with neurologic disorders. These studies reported that larger brain structures support better outcomes in both cognitive domains, thereby supporting the "bigger is better" account. However, relatively few studies have explored the cerebral morphological properties underlying EM and EFs in cognitively healthy individuals and current findings indicate no unitary theoretical explanation for the structure-function relationship. Moreover, existing studies have typically restricted the analyses to a priori defined regions of interest. Here we conducted unbiased voxel-wise analysis of the associations between regional gray as well as white matter volumes (GMv; WMv) and performance in both cognitive domains in a sample of 463 cognitively intact individuals. We found that efficiency in EM was predicted by lower GMv in brain areas belonging to the default-mode network (DMN). By contrast, EFs performance was predicted by larger GMv in a distributed set of regions, which overlapped with the executive control network (ECN). Volume of white matter bundles supporting both cross-cortical and interhemispheric connections was positively related to processing speed. Furthermore, aging modulated the relationship between regional volumes and cognitive performance in several areas including the hippocampus and frontal cortex. Our data extend the critical role of the DMN and ECN by showing that variability in their morphological properties, and not only their activation patterns, affects EM and EFs, respectively. Moreover, our finding that aging reverts these associations supports previously advanced theories of cognitive neurodevelopment.
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Envelhecimento/patologia , Envelhecimento/psicologia , Encéfalo/anatomia & histologia , Encéfalo/diagnóstico por imagem , Função Executiva , Memória Episódica , Encéfalo/fisiologia , Estudos Transversais , Função Executiva/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do ÓrgãoRESUMO
INTRODUCTION: Apolipoprotein E (APOE)-ε4 is the major genetic risk factor for Alzheimer's disease. However, the dose-dependent impact of this allele on brain morphology of healthy individuals remains unclear. METHODS: We analyzed gray matter volumes (GMvs) in a sample of 533 healthy middle-aged individuals with a substantial representation of ε4-carriers (207 heterozygotes and 65 homozygotes). RESULTS: We found APOE-ε4 additive GMv reductions in the right hippocampus, caudate, precentral gyrus, and cerebellar crus. In these regions, the APOE genotype interacted with age, with homozygotes displaying lower GMv after the fifth decade of life. APOE-ε4 was also associated to greater GMv in the right thalamus, left occipital gyrus, and right frontal cortex. DISCUSSION: Our data indicate that APOE-ε4 exerts additive effects on GMv in regions relevant for Alzheimer's disease pathophysiology already in healthy individuals. These findings elucidate the mechanisms underlying the increased Alzheimer's disease risk in ε4-carriers, suggesting a dose-dependent disease vulnerability on the brain structure level.
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Envelhecimento , Córtex Cerebral/fisiologia , Genótipo , Substância Cinzenta/fisiologia , Voluntários Saudáveis , Idoso , Envelhecimento/genética , Alelos , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Estudos de Coortes , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de RiscoRESUMO
INTRODUCTION: Traditional brain imaging genetics studies have primarily focused on how genetic factors influence the volume of specific brain regions, often neglecting the overall complexity of brain architecture and its genetic underpinnings. METHODS: This study analyzed data from participants across the Alzheimer's disease (AD) continuum from the ALFA and ADNI studies. We exploited compositional data analysis to examine relative brain volumetric variations that (i) differentiate cognitively unimpaired (CU) individuals, defined as amyloid-negative (A-) based on CSF profiling, from those at different AD stages, and (ii) associated with increased genetic susceptibility to AD, assessed using polygenic risk scores. RESULTS: Distinct brain signatures differentiated CU A-individuals from amyloid-positive MCI and AD. Moreover, disease stage-specific signatures were associated with higher genetic risk of AD. DISCUSSION: The findings underscore the complex interplay between genetics and disease stages in shaping brain structure, which could inform targeted preventive strategies and interventions in preclinical AD.
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BACKGROUND: Neuroimaging-based brain-age delta has been shown to be a mediator linking cardiovascular risk factors to cognitive function. We aimed to assess the mediating role of brain-age delta in the association between modifiable risk factors of dementia and longitudinal cognitive decline in middle-aged and older individuals who are asymptomatic, stratified by Alzheimer's disease pathology. We also explored whether the mediation effect is specific to cognitive domain. METHODS: In this cohort study, we included participants from the ALFA+ cohort aged between 45 years and 65 years who were cognitively unimpaired and who had available structural MRI, cerebrospinal fluid ß-amyloid (Aß)42 and Aß40 measurements obtained within 1 year of each other, modifiable risk factors assessment, and cognitive evaluation over 3 years. Participants were recruited from the Barcelonaßeta Brain Research Center (Barcelona, Spain). Included individuals underwent a first assessment between Oct 25, 2016, and Jan 28, 2020, and a follow-up cognitive assessment 3·28 (SD 0·27) years later. We computed brain-age delta and composites of different cognitive function domains (preclinical Alzheimer's cognitive composite [PACC], attention, executive function, episodic memory, visual processing, and language). We used partial least squares path modelling to explore mediation effects in the associations between modifiable risk factors (including cardiovascular, mental health, mood, metabolic or endocrine history, and alcohol use) and changes in cognitive composites. To assess the role of Alzheimer's disease pathology, we computed separate models for Aß-negative and Aß-positive individuals. FINDINGS: Of the 419 participants enrolled in ALFA+, 302 met our inclusion criteria, of which 108 participants were classified as Aß-positive and 194 as Aß-negative. In Aß-positive individuals, brain-age delta partially mediated (percent mediation proportion 15·73% [95% CI 14·22-16·66]) the association between modifiable risk factors and decline in overall cognition (across cognitive domains). Brain-age delta fully mediated (mediation proportion 28·03% [26·25-29·21]) the effect of modifiable risk factors on the PACC, wherein increased values for risk factors correlated with an older brain-age delta, and, consequently, an older brain-age delta was linked to greater PACC decline. This effect appears to be primarily driven by memory decline. Mediation was not significant in Aß-negative individuals (3·52% [0·072-4·17]) on PACC, although path coefficients were not significantly different from those in the Aß-positive group. INTERPRETATION: Our findings suggest that brain-age delta captures the association between modifiable risk factors and longitudinal cognitive decline in middle-aged and older people. In asymptomatic middle-aged and older individuals who are Aß-positive, the pathology might be the strongest driver of cognitive decline, whereas the effect of risk factors is smaller. Our results highlight the potential of brain-age delta as an objective outcome measure for preventive lifestyle interventions targeting cognitive decline. FUNDING: La Caixa Foundation, the TriBEKa Imaging Platform, and the Universities and Research Secretariat of the Catalan Government. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Pessoa de Meia-Idade , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/epidemiologia , Estudos de Coortes , Estudos Longitudinais , Tomografia por Emissão de Pósitrons , Testes Neuropsicológicos , Neuroimagem , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/epidemiologia , Fatores de RiscoRESUMO
PURPOSE: To determine whether the APOE-ε4 allele modulates the relationship between regional ß-amyloid (Aß) accumulation and cognitive change in middle-aged cognitively unimpaired (CU) participants. METHODS: The 352 CU participants (mean aged 61.1 [4.7] years) included completed two cognitive assessments (average interval 3.34 years), underwent [18F]flutemetamol Aß positron emission tomography (PET), T1w magnetic resonance imaging (MRI), as well as APOE genotyping. Global and regional Aß PET positivity was assessed across five regions-of-interest by visual reading (VR) and regional Centiloids. Linear regression models were developed to examine the interaction between regional and global Aß PET positivity and APOE-ε4 status on longitudinal cognitive change assessed with the Preclinical Alzheimer's Cognitive Composite (PACC), episodic memory, and executive function, after controlling for age, sex, education, cognitive baseline scores, and hippocampal volume. RESULTS: In total, 57 participants (16.2%) were VR+ of whom 41 (71.9%) were APOE-ε4 carriers. No significant APOE-ε4*global Aß PET interactions were associated with cognitive change for any cognitive test. However, APOE-ε4 carriers who were VR+ in temporal areas (n = 19 [9.81%], p = 0.04) and in the striatum (n = 8 [4.14%], p = 0.01) exhibited a higher decline in the PACC. The temporal areas findings were replicated when regional PET positivity was determined with Centiloid values. Regionally, VR+ in the striatum was associated with higher memory decline. As for executive function, interactions between APOE-ε4 and regional VR+ were found in temporal and parietal regions, and in the striatum. CONCLUSION: CU APOE-ε4 carriers with a positive Aß PET VR in regions known to accumulate amyloid at later stages of the Alzheimer's disease (AD) continuum exhibited a steeper cognitive decline. This work supports the contention that regional VR of Aß PET might convey prognostic information about future cognitive decline in individuals at higher risk of developing AD. CLINICALTRIALS: gov Identifier: NCT02485730. Registered 20 June 2015 https://clinicaltrials.gov/ct2/show/NCT02485730 and ClinicalTrials.gov Identifier:NCT02685969. Registered 19 February 2016 https://clinicaltrials.gov/ct2/show/NCT02685969 .
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Brain-age can be inferred from structural neuroimaging and compared to chronological age (brain-age delta) as a marker of biological brain aging. Accelerated aging has been found in neurodegenerative disorders like Alzheimer's disease (AD), but its validation against markers of neurodegeneration and AD is lacking. Here, imaging-derived measures from the UK Biobank dataset (N=22,661) were used to predict brain-age in 2,314 cognitively unimpaired (CU) individuals at higher risk of AD and mild cognitive impaired (MCI) patients from four independent cohorts with available biomarker data: ALFA+, ADNI, EPAD, and OASIS. Brain-age delta was associated with abnormal amyloid-ß, more advanced stages (AT) of AD pathology and APOE-ε4 status. Brain-age delta was positively associated with plasma neurofilament light, a marker of neurodegeneration, and sex differences in the brain effects of this marker were found. These results validate brain-age delta as a non-invasive marker of biological brain aging in non-demented individuals with abnormal levels of biomarkers of AD and axonal injury.
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Doença de Alzheimer , Humanos , Masculino , Feminino , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Peptídeos beta-Amiloides/metabolismo , Neuroimagem/métodos , Biomarcadores , Aprendizado de MáquinaRESUMO
Both animal and human studies have identified a critical role of the hippocampus in contextual fear conditioning. In humans mainly functional magnetic resonance imaging has been used. To extend these findings to volumetric properties, 58 healthy participants underwent structural magnetic resonance imaging and participated in a differential fear conditioning paradigm with contextual stimuli. Ratings of emotional valence, arousal, and contingency as well as skin conductance responses (SCRs) were used as indicators of conditioning. Twenty-nine participants with the smallest hippocampal volumes were compared with 29 persons with the largest hippocampal volumes. Persons with larger hippocampal volume (especially on the right side) learned to discriminate between two conditioned contexts, whereas those with small hippocampal volumes did not, as indicated by SCRs. Further analyses showed that these results could not be explained by amygdalar volumes. In contrast, the participant answers on the self-report measures were not significantly influenced by hippocampal or amygdalar, but by total brain volume, suggesting a role of cortical structures in these more cognitive evaluation processes. Reanalysis of the self-report data using partial hippocampal volumes revealed a significant influence of the posterior but not anterior subvolumes, which is in accordance with theories and empirical findings on hippocampal functioning. This study shows the relevance of hippocampal volume for contextual fear conditioning in healthy volunteers and may have important implications for anxiety disorders.
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Tonsila do Cerebelo/anatomia & histologia , Tonsila do Cerebelo/fisiologia , Medo/fisiologia , Hipocampo/anatomia & histologia , Hipocampo/fisiologia , Ansiedade/psicologia , Condicionamento Psicológico/fisiologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Testes NeuropsicológicosRESUMO
Most people have a soundtrack of life, a set of special musical pieces closely linked to certain biographical experiences. Autobiographical memories (AM) and music listening (ML) involve complex mental processes ruled by differentiate brain networks. The aim of the paper was to determine the way both networks interact in linked occurrences. We performed an fMRI experiment on 31 healthy participants (age: 32.4 ± 7.6, 11 men, 4 left-handers). Participants had to recall AMs prompted by music they reported to be associated with personal biographical events (LMM: linked AM-ML events). In the main control task, participants were prompted to recall emotional AMs while listening known tracks from a pool of popular music (UMM: unlinked AM-ML events). We wanted to investigate to what extent LMM network exceeded the overlap of AM and ML networks by contrasting the activation obtained in LMM versus UMM. The contrast LMM>UMM showed the areas (at P < 0.05 FWE corrected at voxel level and cluster size>20): right frontal inferior operculum, frontal middle gyrus, pars triangularis of inferior frontal gyrus, occipital superior gyrus and bilateral basal ganglia (caudate, putamen and pallidum), occipital (middle and inferior), parietal (inferior and superior), precentral and cerebellum (6, 7 L, 8 and vermis 6 and 7). Complementary results were obtained from additional control tasks. Provided part of tLMM>UMM areas might not be related to ML-AM linkage, we assessed LMM brain network by an independent component analysis (ICA) on contrast images. Results from ICA suggest the existence of a cortico-ponto-cerebellar network including left precuneus, bilateral anterior cingulum, parahippocampal gyri, frontal inferior operculum, ventral anterior part of the insula, frontal medial orbital gyri, caudate nuclei, cerebellum 6 and vermis, which might rule the ML-induced retrieval of AM in closely linked AM-ML events. This topography may suggest that the pathway by which ML is linked to AM is attentional and directly related to perceptual processing, involving salience network, instead of the natural way of remembering typically associated with default mode network.
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Encéfalo/fisiologia , Emoções/fisiologia , Imageamento por Ressonância Magnética , Memória Episódica , Música/psicologia , Rede Nervosa/fisiologia , Gânglios da Base , Cerebelo , Feminino , Lobo Frontal , Humanos , Masculino , Rememoração Mental/fisiologia , Lobo ParietalRESUMO
Higher grey matter volumes/cortical thickness and fluorodeoxyglucose uptake have been consistently found in cognitively unimpaired individuals with abnormal Alzheimer's disease biomarkers compared with those with normal biomarkers. It has been hypothesized that such transient increases may be associated with neuroinflammatory mechanisms triggered in response to early Alzheimer's pathology. Here, we evaluated, in the earliest stages of the Alzheimer's continuum, associations between grey matter volume and fluorodeoxyglucose uptake with CSF biomarkers of several pathophysiological mechanisms known to be altered in preclinical Alzheimer's disease stages. We included 319 cognitively unimpaired participants from the ALFA+ cohort with available structural MRI, fluorodeoxyglucose PET and CSF biomarkers of amyloid-ß and tau pathology (phosphorylated tau and total tau), synaptic dysfunction (neurogranin), neuronal and axonal injury (neurofilament light), glial activation (soluble triggering receptor on myeloid cells 2, YKL40, GFAP, interleukin-6 and S100b) and α-synuclein using the Roche NeuroToolKit. We first used the amyloid-ß/tau framework to investigate differences in the neuroimaging biomarkers between preclinical Alzheimer's disease stages. Then, we looked for associations between the neuroimaging markers and all the CSF markers. Given the non-negative nature of the concentrations of CSF biomarkers and their high collinearity, we clustered them using non-negative matrix factorization approach (components) and sought associations with the imaging markers. By groups, higher grey matter volumes were found in the amyloid-ß-positive tau-negative participants with respect to the reference amyloid-ß-negative tau-negative group. Both amyloid-ß and tau-positive participants showed higher fluorodeoxyglucose uptake than tau-negative individuals. Using the obtained components, we observed that tau pathology accompanied by YKL-40 (astrocytic marker) was associated with higher grey matter volumes and fluorodeoxyglucose uptake in extensive brain areas. Higher grey matter volumes in key Alzheimer-related regions were also found in association with two other components characterized by a higher expression of amyloid-ß in combination with different glial markers: one with higher GFAP and S100b levels (astrocytic markers) and the other one with interleukin-6 (pro-inflammatory). Notably, these components' expression had different behaviours across amyloid-ß/tau stages. Taken together, our results show that CSF amyloid-ß and phosphorylated tau, in combination with different aspects of glial response, have distinctive associations with higher grey matter volumes and increased glucose metabolism in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and fluorodeoxyglucose uptake at the earliest stages of the Alzheimer's continuum, which may revert later on the course of the disease when neurodegeneration drives structural and metabolic cerebral changes.
RESUMO
BACKGROUND: The number of APOE-ε4 alleles is a major nonmodifiable risk factor for sporadic Alzheimer disease (AD). There is increasing evidence on the benefits of dietary DHA (22:6n-3) before the onset of AD symptoms, particularly in APOE-ε4 carriers. Brain alterations in the preclinical stage can be detected by structural MRI. OBJECTIVES: We aimed, in middle-aged cognitively unimpaired individuals at increased risk of AD, to cross-sectionally investigate whether dietary DHA intake relates to cognitive performance and to MRI-based markers of cerebral small vessel disease and AD-related neurodegeneration, exploring the effect modification by APOE-ε4 status. METHODS: In 340 participants of the ALFA (ALzheimer and FAmilies) study, which is enriched for APOE-ε4 carriership (n = 122, noncarriers; n = 157, 1 allele; n = 61, 2 alleles), we assessed self-reported DHA intake through an FFQ. We measured cognitive performance by administering episodic memory and executive function tests. We performed high-resolution structural MRI to assess cerebral small vessel disease [white matter hyperintensities (WMHs) and cerebral microbleeds (CMBs)] and AD-related brain atrophy (cortical thickness in an AD signature). We constructed regression models adjusted for potential confounders, exploring the interaction DHA × APOE-ε4. RESULTS: We observed no significant associations between DHA and cognitive performance or WMH burden. We observed a nonsignificant inverse association between DHA and prevalence of lobar CMBs (OR: 0.446; 95% CI: 0.195, 1.018; P = 0.055). DHA was found to be significantly related to greater cortical thickness in the AD signature in homozygotes but not in nonhomozygotes (P-interaction = 0.045). The association strengthened when analyzing homozygotes and nonhomozygotes matched for risk factors. CONCLUSIONS: In cognitively unimpaired APOE-ε4 homozygotes, dietary DHA intake related to structural patterns that may result in greater resilience to AD pathology. This is consistent with the current hypothesis that those subjects at highest risk would obtain the largest benefits from DHA supplementation in the preclinical stage.This trial was registered at clinicaltrials.gov as NCT01835717.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/prevenção & controle , Apolipoproteína E4/genética , Encéfalo/diagnóstico por imagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Estudos Transversais , Predisposição Genética para Doença , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Mounting evidence links poor sleep quality with a higher risk of late-life dementia. However, the structural and cognitive correlates of insomnia are still not well understood. The study aims were to characterize the cognitive performance and brain structural pattern of cognitively unimpaired adults at increased risk for Alzheimer's disease (AD) with insomnia. METHODS: This cross-sectional study included 1683 cognitively unimpaired middle/late-middle-aged adults from the ALFA (ALzheimer and FAmilies) study who underwent neuropsychological assessment, T1-weighted structural imaging (n = 366), and diffusion-weighted imaging (n = 334). The World Health Organization's World Mental Health Survey Initiative version of the Composite International Diagnostic Interview was used to define the presence or absence of insomnia. Multivariable regression models were used to evaluate differences in cognitive performance between individuals with and without insomnia, as well as potential interactions between insomnia and the APOE genotype. Voxel-based morphometry and tract-based spatial statistics were used to assess between-group differences and potential interactions between insomnia and the APOE genotype in gray matter volume and white matter diffusion metrics. RESULTS: Insomnia was reported by 615 out of 1683 participants (36.5%), including 137 out of 366 (37.4%) with T1-weighted structural imaging available and 119 out of 334 (35.6%) with diffusion-weighted imaging. Individuals with insomnia (n = 615) performed worse in executive function tests than non-insomniacs and displayed lower gray matter volume in left orbitofrontal and right middle temporal cortex, bilateral precuneus, posterior cingulate cortex and thalamus, higher gray matter volume in the left caudate nucleus, and widespread reduction of mean and axial diffusivity in right hemisphere white matter tracts. Insomnia interacted with the APOE genotype, with APOE-ε4 carriers displaying lower gray matter volumes when insomnia was present, but higher volumes when insomnia was not present, in several gray matter regions, including the left angular gyrus, the bilateral superior frontal gyri, the thalami, and the right hippocampus. CONCLUSIONS: Insomnia in cognitively unimpaired adults at increased risk for AD is associated to poorer performance in some executive functions and volume changes in cortical and subcortical gray matter, including key areas involved in Alzheimer's disease, as well as decreased white matter diffusivity.