Hyperactive Hippocampal Formation

Dr. Sperling was surprised to see that some people in the study with mild memory problems had an extremely active hippocampal formation when they were trying to process a new memory. This suggested to her that, in these people, the hippocampal formation might have been trying to compensate for the damage done by the advancing Alzheimer's disease process. In people with mild cognitive impairment, thought to be a precursor stage of AD, the hippocampal formation may be going into overdrive. "It works harder to form a new memory. It's revving and driving as fast as it can." During that phase of hyperactivity, people are able to maintain memory. Unfortunately, hyperactivity doesn't continue, and Dr. Sperling hypothesizes that it may be a sign of impending failure of the hippocampal formation. "More and more, we've seen that hyperactivation is a strong predictor of who is going to decline over the next two years. Before the hippocampal formation fails, it seems to make a last-ditch effort to activate as much as it can, struggling to form memories."

Dr. Sperling has followed fifty people over time, including healthy people and those with MCI. The same face-name task was conducted during an fMRI session at two-year intervals. The healthy people showed no difference in the activity of their hippocampal formation. In some of those with MCI, this activity didn't decline much over the two years. But those individuals whose initial scans displayed hyperactivation of the hippocampal formation showed deterioration. "About half of the people in this third group had developed clinical Alzheimer's disease over these two years."

Dr. Sperling's team is now scanning older people every six months with fMRI to track brain function and using PET scans with PiB imaging to detect beta-amyloid plaque formation, as well as to see if there is a correlation between plaque formation and fMRI hyperactivation. Such a connection might have important implications for both diagnosis and drug development. If Dr. Sperling and other researchers are able to establish a definitive link between hippocampal hyperactivation and the impending onset of clinical Alzheimer's disease, fMRI scans of the hippocampal formation could be used as a predictive biomarker to aid physicians in diagnosing the disease and in selecting subjects for clinical trials who are well matched for the potential outcome of the trial. Ultimately, this type of information could be used to start treatment at an earlier stage of AD—a refinement that is much needed.

Previous: Watching the Brain Create Memories

Excerpted from THE ALZHEIMER'S PROJECT: MOMENTUM IN SCIENCE, published by Public Affairs, www.publicaffairsbooks.com.

Alzheimer's Disease (AD)

A progressive degenerative disease of the brain that causes impairment of memory and other cognitive abilities.

Amyloid Precursor Protein (APP)

The larger protein from which beta-amyloid is formed.

ApoE Gene

A gene that codes for a protein that carries cholesterol to and within cells; different forms of the ApoE gene are associated with differing risks for late-onset Alzheimer's disease. This gene may be referred to as a risk factor gene or a "susceptibility gene" because one form of the gene, called APOE4, is associated with the risk of developing late onset AD.

Beta-Amyloid

Derived from the amyloid precursor protein and found in plaques, the insoluble deposits outside neurons. May also be called A-beta.

Beta-Amyloid Plaque

A largely insoluble deposit found in the space between nerve cells in the brain. The plaques in Alzheimer's disease are made of beta-amyloid and other molecules, surrounded by non-nerve cells (glia) and damaged axons and dendrites from nearby neurons.

Cognitive Reserve

The brain's ability to operate effectively even when some damage to cells or brain cell communications has occurred.

Dementia

A broad term referring to a decline in cognitive function that interferes with daily life and activities. Alzheimer's disease is one form of dementia.

Functional MRI (fMRI)

An adaptation of an MRI (see magnetic resonance imaging) technique that measures brain activity during a mental task, such as one involving memory, language, or attention.

Hippocampal Formation

A structure in the brain that plays a major role in learning and memory and is involved in converting short-term to long-term memory. Also called the hippocampus.

Inflammation

The process by which the body responds to cellular injury by attempting to eliminate foreign matter and damaged tissue.

Insulin Resistance

A condition in which the pancreas makes enough insulin, but the cells do not respond properly to it; characterizes and precedes type 2 diabetes.

Magnetic Resonance Imaging (MRI)

A diagnostic and research technique that uses magnetic fields to generate a computer image of internal structures in the body.

Mild Cognitive Impairment (MCI)

A condition in which a person has cognitive problems greater than those expected for his or her age. Amnestic MCI includes memory problems, but not the personality or other cognitive problems that characterize AD.

Neurodegenerative Disease

A disease characterized by a progressive decline in the structure and function of brain tissue. These diseases include AD, Parkinson's disease, frontotemporal lobar degeneration, and dementia with Lewy bodies. They are usually more common in older people.

Oligomers

Clusters of a small number of beta-amyloid peptides.

Oxidative Damage

Damage that can occur to cells when they are exposed to too many free radicals.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.

Synapse

The tiny gap between nerve cells across which neurotransmitters and nerve signals pass.

Tau

A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.

Tangles

A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.

Memory

Normal Aging

Genetic Risk Factor

Dominant and Recessive Genes

Genes and Proteins

Protein-Misfolding Disease

Cholesterol

Biomarkers

Disease-Modifying Drug

Transgenic Mice

An animal that has had a gene (such as the human APP gene) inserted into its chromosomes for the purpose of research. Mice carrying a mutated human APP gene often develop plaques in their brains as they age.

Pathology

Microglia

Insulin & Insulin Resistance

Susceptibility Gene

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Susceptibility Genes

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Genome-Wide Association Study

Vascular Disease

Genetics

Genetics

Normal Aging