Neurological phenotypes for Down syndrome across the life span

Area of Science:

• Neurology
• Genetics
• Developmental Biology

Background:

• Down syndrome (DS) presents with widespread neuroanatomic abnormalities impacting brain circuitry and cognitive function.
• Intellectual disability is common in DS, with significant variation in cognitive performance.
• Neuropathology consistent with Alzheimer's disease (AD) is nearly universal by age 40 in individuals with DS.

Purpose of the Study:

• To review the neurological phenotype of Down syndrome across the lifespan.
• To explore the relationship between brain abnormalities and cognitive outcomes in DS.
• To discuss the pathogenesis of Alzheimer's disease in the context of Down syndrome.

Main Methods:

• Review of neuroanatomic, neurodevelopmental, and neuropathological findings in Down syndrome.
• Analysis of genetic factors, including chromosome 21 gene overexpression, contributing to AD in DS.
• Examination of functional brain imaging data and mitochondrial dysfunction in AD pathogenesis.

Main Results:

• Neuroanatomic aberrations and impaired brain circuitry are characteristic of DS.
• Seizures exhibit a bimodal presentation, and cognitive decline is associated with later-life seizures.
• Amyloid-beta accumulation and mitochondrial dysfunction are key in AD development in DS.

Conclusions:

• All individuals with DS develop AD neuropathology, but dementia prevalence varies.
• Overexpression of genes on chromosome 21 contributes to AD risk in DS.
• Medical comorbidities and ongoing research using mouse models offer avenues for therapeutic interventions.