Alzheimer’s and Epilepsy by Dean M. Hartley

Identifying “silent seizures” in Alzheimer’s patients and seeking novel ways to use anti-seizure

2009 Seed Grant
Dean M. Hartley, Ph.D.
Rush University

Alzheimer’s disease (AD) is an irreversible, progressive brain disorder. AD destroys neurons,
causing memory loss, confusion and impaired judgment. It is characterized by the formation of
two pathological features, plaques and tangles. Plaques are made from a fragment of the
protein called beta-amyloid and buildup between the neurons. Tangles form inside neurons and
consist of twisted bundles of fibers of a protein called tau.

Research has shown that over time, these two abnormal pathologies spread through the brain
in a very characteristic pattern and the Hartley lab is particularly interested in the progression of
the plaques. In the earliest stages, plaques are only present in the upper areas of the brain.
However, as the disease progresses the plaques moves to other specific areas lower in the
brain, as though they are following specific pathways. These cues suggest that the disease is
moving by electrical activity through specific neuronal pathways, connecting one area to the
next, driving new pathology. Understanding how this progression occurs is key in
understanding how to stop this disease.

Dr. Hartley is using his 2009 BRF Seed Grant to examine the possible role of seizure-like
activity in the progression of AD. Dr. Hartley’s working model is that brain cells become
“hyperactive,” similar to the activity measured during very mild seizures; this abnormal activity
then causes the characteristic AD pathology to develop in this area. Moreover, this hyperactivity
travels to other regions by specific connections causing a cascade of hyperexcitability and
subsequent AD pathology; this specific hyperactivity drives the progressive pathology in the

Studies have reported seizure-like activity in AD patients and animal models of AD. Recent
studies in animal models of AD have shown a type of “silent seizure,” suggesting there is an
undetected hyperactivity in the AD brain. Dr. Hartley is testing his hypothesis by placing
sensitive monitoring devices in a mouse model of AD to determine if the sequence of the
developing pathology is preceded by hyperactivity.

To further understand this problem, drugs that block this hyperactivity, including anti-seizure
medications, will be administered at different time periods. This will help in understanding if
hyperactivity is involved, and also determine if interrupting hyperactivity at a specific time may
block “downstream” areas from developing AD pathology. A better understanding of this
relationship is warranted and may be extremely valuable in identifying mechanisms responsible
for this devastating disease. Most importantly, this understanding may suggest that drugs
blocking or reducing hyperactivity in the brain may be able to stop the initiation or progression of
the disease; currently we are only able to treat the symptoms. The potential of this research is that antiepileptic drugs, which block neuronal hyperexcitability, may be useful in treating AD. Because these drugs are currently used to treat epilepsy, they could be rapidly transitioned to
the treatment of AD.

New research suggests that a healthy diet, exercise and social interaction can reduce the risk of
cognitive decline and AD.

Up to 5.1 million Americans are living with AD (NIH AD Fact Sheet). As the U.S population
ages, this number will significantly increase unless a treatment or cure can be found.

Other Grants

Rebekah C. Evans, Ph.D., Georgetown University
In Vivo and Ex Vivo Dissection of Midbrain Neuron Activity During Exercise
Exercise is important for the health of the body and the mind. Exercise promotes learning and reduces symptoms of brain-related diseases such as Parkinson’s disease and Alzheimer’s disease. However, it…
William J. Giardino, Ph.D. Stanford University
Deciphering the Neuropeptide Circuitry of Emotional Arousal in Narcolepsy
This research project aims to investigate the neural mechanisms of a specific type of brain cell called neuropeptide neurons within a region of the brain’s amygdala network called the bed…
Howard Gritton, Ph.D., University of Illinois
Attention Mechanisms Contributing to Auditory Spatial Processing.
Our world is composed of a rich mixture of sounds. We often process sounds including speech in the presence of many other competing auditory stimuli (e.g., voices in a crowded…
Nora Kory, Ph.D., Harvard University
Elucidating the Fates and Functions of Lactate in the Brain
The human brain requires significant energy to function. Despite accounting for only 2% of our body weight, the brain consumes a substantial 20% of the body’s energy, relying on a…