Evolving brain structural changes in PSEN1 mutation carriers

Sala‐Llonch, Roser; Lladó, Albert; Fortea, Juan; Bosch, Beatríz; Antonell, Anna; Balasa, Mircea; Bargalló, Núria; Bartrés‐Faz, David; Molinuevo, José Luís; Sánchez‐Valle, Raquel

doi:10.1016/j.neurobiolaging.2014.12.022

Cited by 31 publications

(35 citation statements)

References 59 publications

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“…18,19 The authors acknowledged that this was unexpected, and speculated that it may indicate a presymptomatic inflammatory process. Here, in a larger sample, we find no evidence to support an early cortical thickness rise.…”

Section: Discussionmentioning

confidence: 99%

Presymptomatic cortical thinning in familial Alzheimer disease

et al. 2016

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Objective:To identify a cortical signature pattern of cortical thinning in familial Alzheimer disease (FAD) and assess its utility in detecting and tracking presymptomatic neurodegeneration.Methods:We recruited 43 FAD mutation carriers—36 PSEN1, 7 APP (20 symptomatic, 23 presymptomatic)—and 42 healthy controls to a longitudinal clinical and MRI study. T1-weighted MRI scans were acquired at baseline in all participants; 55 individuals (33 mutation carriers; 22 controls) had multiple (mean 2.9) follow-up scans approximately annually. Cortical thickness was measured using FreeSurfer. A cortical thinning signature was identified from symptomatic FAD participants. We then examined cortical thickness changes in this signature region in presymptomatic carriers and assessed associations with cognitive performance.Results:The cortical signature included 6 regions: entorhinal cortex, inferior parietal cortex, precuneus, superior parietal cortex, superior frontal cortex, and supramarginal gyrus. There were significant differences in mean cortical signature thickness between mutation carriers and controls 3 years before predicted symptom onset. The earliest significant difference in a single region, detectable 4 years preonset, was in the precuneus. Rate of change in cortical thickness became significantly different in the cortical signature at 5 years before predicted onset, and in the precuneus at 8 years preonset. Baseline mean signature thickness predicted rate of subsequent thinning and correlated with presymptomatic cognitive change.Conclusions:The FAD cortical signature appears to be similar to that described for sporadic AD. All component regions showed significant presymptomatic thinning. A composite signature may provide more robust results than a single region and have utility as an outcome measure in presymptomatic trials.

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Section: Discussionmentioning

confidence: 99%

Presymptomatic cortical thinning in familial Alzheimer disease

et al. 2016

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“…At the structural-level, the brains of asymptomatic children with PSEN1 mutations display greater functional connectivity and increased grey matter volumes of several brain regions 20 . Interestingly, adult PSEN1 mutation carriers who are still asymptomatic retain these increased brain structure sizes, but upon developing AD symptoms, the affected brain structures rapidly decrease in size [50][51][52] . These changes are likely to be mirrored at the molecular level in the brain.…”

Section: Evidence Of Increased Stress Long Preceding Admentioning

confidence: 99%

Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease

Hin

Newman

Kaslin

et al. 2018

Preprint

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AbstractAlzheimer’s disease (AD) develops silently over decades. We cannot easily access and analyse pre-symptomatic brains, so the earliest molecular changes that initiate AD remain unclear. Previously, we demonstrated that the genes mutated in early-onset, dominantly-inherited familial forms of AD (fAD) are evolving particularly rapidly in mice and rats. Fortunately, some non-mammalian vertebrates such as the zebrafish preserve fAD-relevant transcript isoforms of the PRESENILIN (PSEN1 and PSEN2) genes that these rodents have lost. Zebrafish are powerful vertebrate genetic models for many human diseases, but no genetic model of fAD in zebrafish currently exists. We edited the zebrafish genome to model the unique, protein-truncating fAD mutation of human PSEN2, K115fs. Analysing the brain transcriptome and proteome of young (6-month-old) and aged, infertile (24-month-old) wild type and heterozygous fAD-like mutant female sibling zebrafish supports accelerated brain aging and increased glucocorticoid signalling in young fAD-like fish, leading to a transcriptional ‘inversion’ into glucocorticoid resistance and vast changes in biological pathways in aged, infertile fAD-like fish. Notably, one of these changes involving microglia-associated immune responses regulated by the ETS transcription factor family is preserved between our zebrafish fAD model and human early-onset AD. Importantly, these changes occur before obvious histopathology and likely in the absence of Aβ. Our results support the contributions of early metabolic and oxidative stresses to immune and stress responses favouring AD pathogenesis and highlight the value of our fAD-like zebrafish genetic model for elucidating early changes in the brain that promote AD pathogenesis. The success of our approach has important implications for future modelling of AD.

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“…Subjects underwent clinical and cognitive assessments, and a comprehensive neuropsychological battery was also administered, as described previously [13].…”

Section: Clinical and Neuropsychological Characterizationmentioning

confidence: 99%

“…In this sense, to date, morphometric GM or whole brain measures are the main neuroimaging biomarkers included in clinical trials, based on the extensive literature in mild cognitive impairment and dementia due to AD patients, both in sporadic [7] and ADAD [8][9][10]. However, there is some evidence that suggest that GM morphometric measures may suffer unexpected effects with anti-amyloid therapies [11] or present non-linear trajectories in different brain areas [12][13][14][15] that may lead to difficulty in their interpretation in clinical trials. On the other hand, thanks to the advances in MRI-related techniques, white-matter (WM) tract disruption is becoming a well described early event in AD, and although it is thought to be mainly secondary to GM damage, other hypotheses, that WM and GM loss are different effects of a common upstream pathological process, have been also proposed [16,17].…”

Section: Introductionmentioning

confidence: 99%

White Matter Abnormalities Track Disease Progression in PSEN1 Autosomal Dominant Alzheimer’s Disease

Sánchez‐Valle

Monté

Sala‐Llonch

et al. 2016

JAD

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Abstract. PSEN1 mutations are the most frequent cause of autosomal dominant Alzheimer's disease (ADAD), and show nearly full penetrance. There is presently increasing interest in the study of biomarkers that track disease progression in order to test therapeutic interventions in ADAD. We used white mater (WM) volumetric characteristics and diffusion tensor imaging (DTI) metrics to investigate correlations with the normalized time to expected symptoms onset (relative age ratio) and group differences in a cohort of 36 subjects from PSEN1 ADAD families: 22 mutation carriers, 10 symptomatic (SMC) and 12 asymptomatic (AMC), and 14 non-carriers (NC). Subjects underwent a 3T MRI. WM morphometric data and DTI metrics were analyzed. We found that PSEN1 MC showed significant negative correlation between fractional anisotropy (FA) and the relative age ratio in the genus and body of corpus callosum and corona radiate (p < 0.05 Family-wise error correction (FWE) at cluster level) and positive correlation with mean diffusivity (MD), axial diffusivity (AxD), and radial diffusivity (RD) in the splenium of corpus callosum. SMC presented WM volume loss, reduced FA and increased MD, AxD, and RD in the anterior and posterior corona radiate, corpus callosum (p < 0.05 FWE) compared with NC. No significant differences were observed between AMC and NC in WM volume or DTI measures. These findings suggest that the integrity of the WM deteriorates linearly in PSEN1 ADAD from the early phases of the disease; thus DTI metrics might be useful to monitor the disease progression. However, the lack of significant alterations at the preclinical stages suggests that these indexes might not be good candidates for early markers of the disease.

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Evolving brain structural changes in PSEN1 mutation carriers

Cited by 31 publications

References 59 publications

Presymptomatic cortical thinning in familial Alzheimer disease

Presymptomatic cortical thinning in familial Alzheimer disease

Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease

White Matter Abnormalities Track Disease Progression in PSEN1 Autosomal Dominant Alzheimer’s Disease

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