Longitudinal brain structural changes in preclinical Alzheimer's disease

Pegueroles, Jordi Malé i; Vilaplana, Eduard; Montal, Víctor; Sampedro, Frederic; Alcolea, Daniel; Carmona‐Iragui, María; Clarimón, Jordi; Blesa, Rafael; Lleó, Alberto; Fortea, Juan

doi:10.1016/j.jalz.2016.08.010

Cited by 79 publications

(80 citation statements)

References 49 publications

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“…Possibly, our present associations between betweenness centrality and language decline might be part of normal aging, or can be due to pathological processes unrelated to AD. In recent studies in cognitively normal individuals, we have demonstrated associations between amyloid abnormalities and path length in fronto‐temporo‐parietal regions (Tijms et al, ), and thinner temporal cortex to be related to memory decline and disease progression (Pegueroles et al, ; Verfaillie et al, ). We now show that lower path length values in fronto‐temporo‐occipital cortices and precuneus were associated with global cognitive decline.…”

Section: Discussionmentioning

confidence: 91%

“…Possibly, structural magnetic resonance imaging (MRI) might help identifying those at risk of decline (Dickerson et al, ; Tijms et al, ; Verfaillie et al, ). Evidence is accumulating that brain changes leading to cognitive decline and dementia are not restricted to specific regions such as the medial temporal lobe, but rather include widespread changes in structure, function and organization of the brain (Benzinger et al, ; Dickerson et al, ; Pegueroles et al, ). Patterns of grey matter morphology can be described as a network consisting of multiple small regions of grey matter (i.e., nodes) that are connected to each other when they show structural similarity within a cortex across subjects.…”

Section: Introductionmentioning

confidence: 99%

“…Possibly, structural magnetic resonance imaging (MRI) might help identifying those at risk of decline (Dickerson et al, 2009;Tijms et al, 2016;Verfaillie et al, 2016). Evidence is accumulating that brain changes leading to cognitive decline and dementia are not restricted to specific regions such as the medial temporal lobe, but rather include widespread changes in structure, function and organization of the brain (Benzinger et al, 2013;Dickerson et al, 2009;Pegueroles et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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A more randomly organized grey matter network is associated with deteriorating language and global cognition in individuals with subjective cognitive decline

Verfaillie

Slot

Dicks

et al. 2018

Human Brain Mapping

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ObjectivesGrey matter network disruptions in Alzheimer's disease (AD) are associated with worse cognitive impairment cross‐sectionally. Our aim was to investigate whether indications of a more random network organization are associated with longitudinal decline in specific cognitive functions in individuals with subjective cognitive decline (SCD). Experimental design: We included 231 individuals with SCD who had annually repeated neuropsychological assessment (3 ± 1 years; n = 646 neuropsychological investigations) available from the Amsterdam Dementia Cohort (54% male, age: 63 ± 9, MMSE: 28 ± 2). Single‐subject grey matter networks were extracted from baseline 3D‐T1 MRI scans and we computed basic network (size, degree, connectivity density) and higher‐order (path length, clustering, betweenness centrality, normalized path length [lambda] and normalized clustering [gamma]) parameters at whole brain and/or regional levels. We tested associations of network parameters with baseline and annual cognition (memory, attention, executive functioning, language composite scores, and global cognition [all domains with MMSE]) using linear mixed models, adjusted for age, sex, education, scanner and total gray matter volume. Principal observations: Lower network size was associated with steeper decline in language (β ± SE = 0.12 ± 0.05, p < 0.05FDR). Higher‐order network parameters showed no cross‐sectional associations. Lower gamma and lambda values were associated with steeper decline in global cognition (gamma: β ± SE = 0.06 ± 0.02); lambda: β ± SE = 0.06 ± 0.02), language (gamma: β ± SE = 0.11 ± 0.04; lambda: β ± SE = 0.12 ± 0.05; all p < 0.05FDR). Lower path length values in precuneus and fronto‐temporo‐occipital cortices were associated with a steeper decline in global cognition.ConclusionsA more randomly organized grey matter network was associated with a steeper decline of cognitive functioning, possibly indicating the start of cognitive impairment.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A more randomly organized grey matter network is associated with deteriorating language and global cognition in individuals with subjective cognitive decline

Verfaillie

Slot

Dicks

et al. 2018

Human Brain Mapping

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“…However, studying the influence of new biomarkers is more challenging as the trajectories have been poorly described and they might interact with those already reported, possibly giving nontrivial relationships. In this sense, how the different CSF biomarkers might explain or contribute to each disease atrophy pattern is still uncertain (Idland et al, ; Pegueroles, ).…”

Section: Introductionmentioning

confidence: 99%

Contribution of CSF biomarkers to early‐onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures

Falgàs

Ruiz‐Peris

Pérez‐Millan

et al. 2020

Human Brain Mapping

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Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early-onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid-long form of the amyloid-beta protein [Aβ42], total-tau protein [Ttau], neurofilament light chain [NfL], neurogranin [Ng], and 14-3-3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the "AD signature" and "FTLD signature." We tested multiple regression models to find which CSFbiomarkers better explained each disease neuroimaging signature. CTh and FA maps Neus Falgàs, Mariona Ruiz-Peris, Albert Lladó, and Raquel Sánchez-Valle authors contributed equally to this work.

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“…Only CSF markers significantly correlating with gray matter (GM) volume or brain amyloid load at a significance threshold of voxel-level uncorrected p < 0.001 combined with cluster-level family wise error (FWE)-corrected threshold p < 0.05 are listed in this table. AD (Whitwell et al 2007;Pegueroles et al 2017;Gordon et al 2018). Gray matter volume of the precuneus seems to be a robust early biomarker as it has been shown to predict subsequent whole-brain gray matter volume loss in cognitively healthy individuals over a 6-year follow-up period (Taki et al 2011).…”

Section: Csf Biomarkers Of Pathophysiological Pathways In Admentioning

confidence: 99%

Cerebrospinal fluid levels of synaptic and neuronal integrity correlate with gray matter volume and amyloid load in the precuneus of cognitively intact older adults

Schaeverbeke

Gille

Adamczuk

et al. 2019

Journal of Neurochemistry

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The main pathophysiological alterations of Alzheimer's disease (AD) include loss of neuronal and synaptic integrity, amyloidogenic processing, and neuroinflammation. Similar alterations can, however, also be observed in cognitively intact older subjects and may prelude the clinical manifestation of AD. The objectives of this prospective cross‐sectional study in a cohort of 38 cognitively intact older adults were twofold: (i) to investigate the latent relationship among cerebrospinal fluid (CSF) biomarkers reflecting the main pathophysiological processes of AD, and (ii) to assess the correlation between these biomarkers and gray matter volume as well as amyloid load. All subjects underwent extensive neuropsychological examinations, CSF sampling, [18F]‐flutemetamol amyloid positron emission tomography, and T1‐weighted magnetic resonance imaging. A factor analysis revealed one factor that explained most of the variance in the CSF biomarker dataset clustering t‐tau, α‐synuclein, p‐tau181, neurogranin, BACE1, visinin‐like protein 1, chitinase‐3‐like protein 1 (YKL‐40), Aβ1–40 and Aβ1–38. Higher scores on this factor correlated with lower gray matter volume and with higher amyloid load in the precuneus. At the level of individual CSF biomarkers, levels of visinin‐like protein 1, neurogranin, BACE1, Aβ1–40, Aβ1–38, and YKL‐40 all correlated inversely with gray matter volume of the precuneus. These findings demonstrate that in cognitively intact older subjects, CSF levels of synaptic and neuronal integrity biomarkers, amyloidogenic processing and measures of innate immunity (YKL‐40) display a latent structure of common variance, which is associated with loss of structural integrity of brain regions implicated in the earliest stages of AD. Open Science Badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript, and for *Preregistration* because the study was pre‐registered at https://osf.io/7qm9t/. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

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Longitudinal brain structural changes in preclinical Alzheimer's disease

Abstract: Our longitudinal data confirm a biphasic trajectory of changes in brain structure in preclinical AD. These have implications in AD trials, both in patient selection and the use of MRI as a surrogate marker of efficacy.

Cited by 79 publications

References 49 publications

A more randomly organized grey matter network is associated with deteriorating language and global cognition in individuals with subjective cognitive decline

A more randomly organized grey matter network is associated with deteriorating language and global cognition in individuals with subjective cognitive decline

Contribution of CSF biomarkers to early‐onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures

Cerebrospinal fluid levels of synaptic and neuronal integrity correlate with gray matter volume and amyloid load in the precuneus of cognitively intact older adults

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