Aging, and Early Neurodevelopmental Outcomes

Authors:

Sitara Mitragotri, Ayse Busra Iplikci, Karlen Lyons-Ruth

Date Created:

2025-01-01

Course Title:

Professor:

Not specified

About Paper:

Previous research has linked maternal childhood maltreatment whole brain volumes and total cortisol output, revealed significant (CM) to alterations in infant neurodevelopment, with infant associations only for hippocampal volumes (left, β=-.296, p=.023, epigenetic age acceleration (EAA) emerging as a potential 95%CI=[-1538.052, -121.586]; right, β=-.268, p=.034, 95%CI= mechanism. This study builds upon prior work by investigating [-1399.018,-57.246]...” it should be ”Following analyses testing whether infant EAA is associated with maternal CM and brain the predicting role of EAA on limbic volumes, controlling for volumes in regions critical for emotional regulation. The sample infant age, gender, whole brain volumes and total cortisol output, included57mother-infantdyads. MaternalCMwasassessedusing revealed significant associations only for hippocampal volumes the 75-item Maltreatment and Abuse Chronology of Exposure (right, β=-.296, p=.023, 95%CI=[-1538.052, -121.586]; left, β=- scale. Infant saliva samples were collected during the Still- .268, p=.034, 95%CI= [-1399.018,-57.246]; total β=-.298, p=.023, Face Paradigm at approximately four months of age, and DNA 95%CI= [-2396.035,-198.252]), but not for amygdala volumes methylation was quantified from these samples to calculate EAA (right, β=-.226, p=.087; left, β=-.209, p=.125; total, β=-.225, using the PedBE Clock. T1-weighted MRI scans for infant brain p = .093). These findings suggest that EAA reflects early volumes were acquired between the ages of 4 and 25 months. variation in infant brain development. Its negative association Regression analyses testing the predicting role of CM dimensions with hippocampal volume points to a potential stress-related and EAA revealed significant associations for maternal neglect neurodevelopmental mechanism. Although age deceleration was and EAA, while controlling for infant age and gender (neglect, more common, especially among infants of mothers with neglect bootstrapped B=-.019, SE= .007, p = .018, 95%CI [-.034, - histories, this may reflect alternative adaptations (e.g., early .004]; abuse, bootstrapped B=.016, SE=.017, p = .334, 95%CI limbic overgrowth) that signal increased vulnerability rather than [-.017, .050]). Following analyses testing the predicting role resilience. of EAA on limbic volumes, controlling for infant age, gender, Impact of Amyloid-β Oligomers on Somatic Mutation in Single iPSC-derived Neurons Yasmine Moussa, Michael Miller Harvard College | Leverett House | Neuroscience | 2026 Alzheimer’s disease (AD) is an age-related neurodegenerative performed fluorescence-activated nuclear sorting (FANS) to conditionmarkedbyaccumulationofmisfoldedproteinaggregates isolateneuronalnuclei, andsingle-cellgenomeamplificationusing in the form of amyloid-β (Aβ) plaques and tau neurofibrillary primary template-directed amplification (PTA), enabling single- tangles. Efforts to understand mechanisms of aging and age- cell whole-genome sequencing (scWGS). We then examined the related diseases have found that somatic mutations accumulate burden and signatures of somatic mutations. in neurons with age, and mutations are further elevated in AD. The pattern and genomic distribution suggests that these somatic We observed that somatic mutations accumulate in our AD iN cell model, with cells treated with AD brain extract showing a trend mutations may occur downstream of initiating mechanisms of AD. toward greater somatic single-nucleotide variants (sSNVs) per cell In AD pathogenesis, amyloid-β aggregation is thought to precede compared to media-treated cells. These findings suggest that downstream events, including tau misfolding. We sought to investigate how amyloid-β oligomers may affect somatic mutation componentsofamyloid-β-richADhumanbrainextractmayinduce accumulation, to provide insight into molecular mechanisms somatic mutations in neurons. Our findings also provide a basis for future studies directed towards understanding specific neuronal underlying AD. mutationalmechanismsbyanalyzingthemutationalspectra. These To assess this, we derived neurons (iNs) from induced pluripotent findings may also be further examined by introducing additional stem cells (iPSCs) and incubated with amyloid-β-rich AD human conditions, such as co-culturing neurons with other cell types, to brain extract, and compared with negative controls composed further validate these results. of media or immunodepleted human brain extract. We then

Abstract:

Previous research has linked maternal childhood maltreatment whole brain volumes and total cortisol output, revealed significant (CM) to alterations in infant neurodevelopment, with infant associations only for hippocampal volumes (left, β=-.296, p=.023, epigenetic age acceleration (EAA) emerging as a potential 95%CI=[-1538.052, -121.586]; right, β=-.268, p=.034, 95%CI= mechanism. This study builds upon prior work by investigating [-1399.018,-57.246]...” it should be ”Following analyses testing whether infant EAA is associated with maternal CM and brain the predicting role of EAA on limbic volumes, controlling for volumes in regions critical for emotional regulation. The sample infant age, gender, whole brain volumes and total cortisol output, included57mother-infantdyads. MaternalCMwasassessedusing revealed significant associations only for hippocampal volumes the 75-item Maltreatment and Abuse Chronology of Exposure (right, β=-.296, p=.023, 95%CI=[-1538.052, -121.586]; left, β=- scale. Infant saliva samples were collected during the Still- .268, p=.034, 95%CI= [-1399.018,-57.246]; total β=-.298, p=.023, Face Paradigm at approximately four months of age, and DNA 95%CI= [-2396.035,-198.252]), but not for amygdala volumes methylation was quantified from these samples to calculate EAA (right, β=-.226, p=.087; left, β=-.209, p=.125; total, β=-.225, using the PedBE Clock. T1-weighted MRI scans for infant brain p = .093). These findings suggest that EAA reflects early volumes were acquired between the ages of 4 and 25 months. variation in infant brain development. Its negative association Regression analyses testing the predicting role of CM dimensions with hippocampal volume points to a potential stress-related and EAA revealed significant associations for maternal neglect neurodevelopmental mechanism. Although age deceleration was and EAA, while controlling for infant age and gender (neglect, more common, especially among infants of mothers with neglect bootstrapped B=-.019, SE= .007, p = .018, 95%CI [-.034, - histories, this may reflect alternative adaptations (e.g., early .004]; abuse, bootstrapped B=.016, SE=.017, p = .334, 95%CI limbic overgrowth) that signal increased vulnerability rather than [-.017, .050]). Following analyses testing the predicting role resilience. of EAA on limbic volumes, controlling for infant age, gender, Impact of Amyloid-β Oligomers on Somatic Mutation in Single iPSC-derived Neurons Yasmine Moussa, Michael Miller Harvard College | Leverett House | Neuroscience | 2026 Alzheimer’s disease (AD) is an age-related neurodegenerative performed fluorescence-activated nuclear sorting (FANS) to conditionmarkedbyaccumulationofmisfoldedproteinaggregates isolateneuronalnuclei, andsingle-cellgenomeamplificationusing in the form of amyloid-β (Aβ) plaques and tau neurofibrillary primary template-directed amplification (PTA), enabling single- tangles. Efforts to understand mechanisms of aging and age- cell whole-genome sequencing (scWGS). We then examined the related diseases have found that somatic mutations accumulate burden and signatures of somatic mutations. in neurons with age, and mutations are further elevated in AD. The pattern and genomic distribution suggests that these somatic We observed that somatic mutations accumulate in our AD iN cell model, with cells treated with AD brain extract showing a trend mutations may occur downstream of initiating mechanisms of AD. toward greater somatic single-nucleotide variants (sSNVs) per cell In AD pathogenesis, amyloid-β aggregation is thought to precede compared to media-treated cells. These findings suggest that downstream events, including tau misfolding. We sought to investigate how amyloid-β oligomers may affect somatic mutation componentsofamyloid-β-richADhumanbrainextractmayinduce accumulation, to provide insight into molecular mechanisms somatic mutations in neurons. Our findings also provide a basis for future studies directed towards understanding specific neuronal underlying AD. mutationalmechanismsbyanalyzingthemutationalspectra. These To assess this, we derived neurons (iNs) from induced pluripotent findings may also be further examined by introducing additional stem cells (iPSCs) and incubated with amyloid-β-rich AD human conditions, such as co-culturing neurons with other cell types, to brain extract, and compared with negative controls composed further validate these results. of media or immunodepleted human brain extract. We then

Source:

Harvard / Associations Between Maternal Childhood Maltreatment, Infant Epigenetic / 2025

Topics:

infant, volume, age, brain, eaa, somatic, mutation, cell, association, mechanism, amyloid, neuron

Co-authors:

@sitaramitragotri333 , @aysebusraiplikci334 , @karlenlyonsruth335