I spent several years as a postdoctoral researcher studying the specific vulnerability of inhibitory neurons in the brain to demise in dementia. We used some of the most advanced genetically targeted methods of activating and suppressing inhibitory activity in a mouse model of Alzheimer’s disease (AD) to determine whether this subdued or strengthened epileptiform discharges and seizures and changed the pathophysiological biomarkers and cognitive signs of dementia.
Dementia is a multifaceted and progressive neurodegenerative disorder that manifests in changes in memory, thinking, language, and behavior. For decades, we have also known in both mouse models and patients that dementia is correlated with a higher incidence of seizures, which is an imbalance of excitatory and inhibitory activity in the brain.
There are genetic factors that increase the risk for AD, as bred into mouse models of this condition. These mice have pathological and functional hallmarks of AD, including accumulation of beta-amyloid plaques, seizures, and cognitive deficits. Similarly, in humans, the four most common subtypes of dementia including AD, Vascular dementia, frontotemporal dementia, and Lewy body dementia all exhibit an elevated seizure risk. Seizures in dementia pose unique challenges, often mimicking other symptoms of cognitive decline. We think classically about convulsions, but seizures can also be mistaken for agitated behavior, attentional lapses, wandering, or hallucinations. The occurrence of seizures can also exacerbate cognitive decline, hasten functional impairment, and compromise the overall quality of life for both patients and caregivers. Individuals with dementia may have difficulty expressing their experiences during or after a seizure, making diagnosis and management more complex. This makes it particularly useful to screen and test for seizures in patients with dementia diagnoses.
The recent publication of a transcriptomic atlas of the aged human prefrontal cortex provides insight into the cellular and genetic landscape associated with AD progression and cognitive decline. This study not only advances our understanding of AD pathology but also underscores the urgent need for innovative approaches to monitoring and managing dementia. In this context, the routine integration of electroencephalography (EEG) emerges as a promising avenue for further exploration and development.
A particularly noteworthy revelation from the study is the significant decrease in the relative abundance of somatostatin inhibitory neurons in individuals with high AD pathology. This depletion emphasizes why we must understand the role of inhibitory neurons in cognitive function. Two distinct groups of inhibitory neurons are more abundant in individuals with preserved high cognitive function late in life, suggesting a connection between inhibitory neurons and cognitive resilience to AD pathology. This offers a critical insight that aligns with existing literature on the role of inhibitory neurons in controlling brain oscillations and enhancing information processing as well as in seizures.
While the transcriptomic atlas provides cell type-specific insights about inhibition in the brain that may help drive the development of therapeutic targets, complementary functional methodologies like EEG can help us address seizures in dementia now. Seizures might contribute causally to cognitive deficits in dementia and be especially impactful to identify and treat in its early stages. EEG stands out as a non-invasive and accessible tool that can capture epileptiform discharges and seizure activity. Furthermore, distinct quantitative EEG patterns associated with different stages of AD offer a potential biomarker for early detection. The real-time monitoring capabilities of EEG make it a promising tool for tracking changes in brain activity, which may correlate with the transcriptomic alterations identified in this study.
The transcriptomic atlas of the aged human prefrontal cortex continues to advance our understanding of inhibitory neuron pathology in aging cortex with varying degrees of AD progression. EEG, with its non-invasive nature and real-time monitoring capabilities, allows us to diagnose, monitor, and treat seizures. Integrating EEG into the multifaceted approach to dementia research and clinical care holds the potential to bridge the gap between genetic insights and functional outcomes, ultimately paving the way for more effective strategies in the battle against neurodegenerative diseases.
