WASHINGTON — Scientists have created a detailed map of gene activity in a crucial part of the brain called the prefrontal cortex, gaining insight into normal development and major brain disorders such as Alzheimer’s disease, Parkinson’s disease and schizophrenia.
In nine separate studies, researchers examined changes in certain types of brain cells that occur over time and made progress toward deciphering the molecular processes that underlie some of the most devastating brain disorders, a step toward possible new treatments.
The prefrontal cortex is “the front part of the outer layer of the brain, located behind the forehead.” It helps a person plan, make decisions, regulate emotions, and adapt behavior. It is also susceptible to age-related decline and its functions are affected in many psychiatric and neurodegenerative disorders.
Gene activity was examined in the nuclei of more than 6.3 million brain cells – neurons, immune cells, blood vessel-associated cells – and supporting cells that help maintain brain function – from 1,494 deceased donors, ranging in age from infancy to 108 years old, and with diverse genetic ancestry.
Donors included “people without a diagnosed brain disorder as well as” people with conditions such as Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, vascular dementia, schizophrenia and bipolar disorder.
Research has identified patterns common to certain diseases as well as others specific to individual disorders.
“Together, these studies help to explain where disease-related changes occur and which biological processes merit further investigation,” said Dr. Panos Roussos, director of the Center for Disease Neurogenomics at the Icahn School of Medicine at Mount Sinai in New York and leader of the research published Wednesday in Nature and other journals.
“A useful treatment must influence the right biological process in the right cells. This map helps refine this research. It can identify vulnerable cell populations, reveal processes associated with preserved brain function, and help researchers decide which potential treatment targets to test,” Roussos said.
The work was conducted as part of the PsychAD research consortium, with support from the National Institute on Aging, part of the US government’s National Institutes of Health.
Strong similarities
Alzheimer’s disease, Lewy body disease, vascular dementia, and Parkinson’s disease have shown particularly strong similarities in the activity of genes involved in nerve cell development, neuronal communication, and blood vessel biology. Researchers also identified pathways common to Alzheimer’s and Parkinson’s diseases in microglia, the brain’s resident immune cells.
By comparing brain samples from donors of different ages, researchers found significant molecular changes during development into adulthood, relative stability through much of adulthood, and then further changes later in life, particularly in immune and support cells.
“This provides a benchmark for distinguishing typical aging from changes associated with disease,” Roussos said.
The researchers identified about 24 years as a transition point after which the bulk of most cell types in this region become more stable.
“This does not mean that the brain suddenly stops developing on a person’s 24th birthday, or that its decline begins at that age. Other aspects of brain biology continue to change throughout life,” Roussos said.
Researchers have discovered cellular patterns associated with differences in cognition and depression accompanying Alzheimer’s disease. For example, people who retained cognitive function despite significant Alzheimer’s disease pathology showed differences in energy-related processes in brain cells.
“These provide clues to possible protective mechanisms that require further testing,” Roussos said.
Hereditary genetic risk
Researchers have linked inherited genetic risk of disorders to particular genes and cell types, and mapped genetic influences on the activity of more than 14,000 genes.
They also reconstructed daily patterns of genetic activity using brain samples from people who died at different times of the day. In younger and middle-aged adults, daily clock genes showed coordinated patterns in neurons. In older people, these patterns were weaker and less synchronized.
“This suggests that aging changes the way daily biological rhythms are organized in the brain. Whether reestablishing these rhythms could improve brain health is an important question for future research,” Roussos said.
Researchers also constructed molecular profiles for individual donors with Alzheimer’s disease, identified differences in gene regulation, and predicted interactions between cell types between individuals.
“This helps explain biological variations between people with the same diagnosis and provides a basis for studying more individualized treatment strategies,” Roussos said.
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