Neurogenerative Diseases - 9

or therapeutically important that a given gene is
expressed differently specifically in neurons, and
not in astrocytes, oligodendrocytes, or microglia.
This is particularly true in neurodegeneration, where
the specific types and locations of neurons that are
the most vulnerable vary widely between different
diseases. Single-cell technology will give us more
insight into which cells are perturbed in which ways."

dementia studies currently underway in the United
States. Dr. Bennett has enrolled some 3,500 older
people into two ongoing studies-the Religious
Orders Study, which examines memory loss in nuns,
brothers, and priests from across the United States,
and the Rush Memory and Aging Project, a similar
study of laypersons in northeastern Illinois.
"After death, a detailed pathological exam is
performed, which gives us a sense of how the
person's cognitive performance compares to the
amount of pathology found," explained Dr. De Jager.
"Is this person performing better or worse based on
the known pathology?"

A leader in single-cell gene expression research in
neurodegenerative disease is Philip De Jager, M.D.,
Chief of the Division of Neuro-Immunology and
Weil-Granat professor of Neurology at Columbia
University Irving Medical Center. Dr. De Jager recently
began a study designed to create a reference map
of single-cell transcriptomes from the aging human
brain's frontal cortex and white matter.

So far, he and his team have done single-nucleus
sequencing on 24 postmortem brain samples from
these cohorts. "That's actually a moderately large
sample for this type of work, but to do powerful
statistical analyses, we need approximately 500
samples, which we will have by the end of next year,"
Dr. De Jager added.

"We've spent a lot of time on single-cell nucleus
sequencing from frozen brain material, which helps
to enumerate all of the cells found in the older brain
and to see which ones might be changing," said Dr.
De Jager. "About half of the amount of cognitive
decline in all forms of aging-related dementia
remains unexplained by known biology such as tau
and amyloid. To find the molecular pathways related
to the unknown component of clinical dementia,
we needed to plan ahead-to design studies that
measure how well the person was functioning
before death. With frozen brain tissue that has come
in randomly from the community, that information
is often relatively sparse."

Other new techniques are being developed to
facilitate single-cell gene expression studies in
neurodegenerative disease. "The postmortem
human brain typically needs to have been flash
frozen, and frozen tissue does not dissociate very
well, especially such complex tissue as the human
brain," said Dr. Labadorf. "One of my collaborators is
working on a technique to extract whole cells from
frozen brain tissue, which enables us to overcome
some of the difficulties involved in single-nuclear
RNA sequencing.

Dementia studies

About the author

So he is collaborating with David Bennett, M.D.,
director of the Rush Alzheimer's Disease Center
at Rush University Medical Center and the Robert
C. Borwell Professor of Neurological Science in
the Department of Neurological Sciences at Rush
Medical College, who leads two of the largest

Gina Shaw is a freelance health, science, and medical
writer. She has written extensively on neurology,
oncology, cardiology, orthopedics, audiology,
ophthalmology, emergency medicine, and pharmacy.

9
Neurogenerative Diseases

Table of Contents for the Digital Edition of Neurogenerative Diseases
