Dr. Thal's Research Interest:

My current research interests focus on three areas: the effects of basal forebrain lesion-induced memory loss, clinical pathological correlations in Alzheimer's disease (AD), and the conduct of clinical drug trials in AD.

In the laboratory, we are studying destruction of the basal forebrain in the rat which results in a marked decrease in cortical cholinergic markers as well as a multiplicity of learning and behavioral deficits secondary to impaired attention and acquisition. The model serves as an excellent neurobehavioral example of cortical and hippocampal cholinergic deafferentation. My laboratory focuses on the characterization of the cognitive deficits following lesioning. We are currently using an immunotoxin that targets cells with nerve growth factor (NGF) receptors on the surface to selectively lesion cholinergic forebrain neurons. Cognitive deficits are characterized using the Morris water maze task, passive avoidance, acoustic startle reflex, visual discrimination tasks and T-mazes. We are also studying the effects of augmenting cholinergic neurotransmission. This is accomplished by infusing NGF protein (or other growth factors), utilizing NGF releasing agents and direct acting agonists. In addition, transplantation experiments are carried out using regulatable genetically engineered cell lines that release NGF or acetylcholine. Histological evaluation uses both conventional stains and immunohistochemistry to evaluate the effects of the lesion and/or degree of recovery. Biochemical measurements of choline acetyltransferase, amino acids, aminergic neurotransmitters, and cholinergic receptors are also carried out. In vivo microdialysis is also used to examine neurotransmitter release.

At the Alzheimer's Disease Research Center, we are longitudinally following almost 600 individuals who are either normal or demented with in-depth annual evaluations from the earliest stages of AD to death. The majority of our research subjects undergo brain examination allowing us to perform detailed clinical pathological correlations. Early in the course of the disease, we focus on the rate and predictors of cognitive decline, early identification of patients with AD, and on early predictors of outcome.

At the Alzheimer's Disease Cooperative Study Unit, we are carrying out clinical drug trials for new and promising agents to improve symptoms, slow the decline, halt disease progression, or delay appearance of disease. Clinical drug trials are also being carried out to treat the troublesome behavioral symptoms. The development of new instruments for use in clinical psychopharmacological trials is also a high priority. Clinical drug trials are carried out at over forty centers nationally; the administrative and data coordinating center for the consortium is located in San Diego.