# Early Life Brain Injury and Neurodegenerative Disorders of Aging

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2020 · $209,220

## Abstract

Hypoxic-ischemic (HI) encephalopathy (HIE) is the most frequent cause of acute acquired brain injury in
infants and imparts a life-long morbidity that is not well described. Long term clinical and behavioral follow-up
into adulthood is lacking, but recent MRI studies of former preterm infants with neonatal brain injury reveals
degeneration in the basal forebrain and marked symptoms of executive dysfunction similar to adult
neurodegenerative diseases. The acute mechanisms of injury in both HIE in infants and several other causes
of brain injury in children and teens involve excitotoxicity, oxidative injury, and neurotrophin abnormalities that
can cause plasma membrane alterations, mitochondrial, endoplasmic reticulum (ER), chromatin, and nuclear
dysfunction that instigate cell death. This is followed by astrocyte and microglial activation with prominent
neuroinflammation. The persistence of these mechanisms following the injury is not well described but ER
dysfunction, gliosis and ongoing neuroinflammation last well beyond the subacute phase in preclinical models
of neonatal HI. ER dysfunction, gliosis and ongoing neuroinflammation are well recognized as primary
etiologic mechanisms in adult neurodegenerative diseases including Alzheimer's Disease (AD). We have
identified ultrastructural abnormalities in the mouse basal forebrain nucleus basalis of Meynert caused by
neonatal HI that manifest in adulthood. Moreover, there are potential global abnormalities in tau
phosphorylation in brains of these mice reminiscent of AD. Blood serum immunoassays reveal abnormalities
in Aβ proteins as well as prolonged elevation of inflammatory biomarkers in these mice. Because neonatal HIE
and early life traumatic brain injury share multiple similar early and subacute pathogenic mechanisms and
early life traumatic brain injury unquestionably results in early AD and similar diseases, we question whether
neonatal HI results in long term neuropathology similar to adult onset neurodegenerative diseases
and whether neonatal HI in a genetically susceptible model, causes premature onset of manifestations
of adult neurodegeneration. We will explore these question with the following Aims. Aim 1: Determine
whether neonatal HI causes age-related neuropathology consistent with adult forms of neurodegeneration.
Aim 2: Determine whether neonatal HI causes neurobehavioural manifestations consistent with adult forms
of neurodegeneration.

## Key facts

- **NIH application ID:** 9867613
- **Project number:** 5R21AG061643-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** FRANCES J NORTHINGTON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $209,220
- **Award type:** 5
- **Project period:** 2019-02-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867613

## Citation

> US National Institutes of Health, RePORTER application 9867613, Early Life Brain Injury and Neurodegenerative Disorders of Aging (5R21AG061643-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9867613. Licensed CC0.

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