The goal of this proposal is to establish the relevance of central nicotinic cholinergic lesions to the cognitive disorder and psychopathology of Alzheimer's disease and Parkinson's disease. Recent investigations into nature of cholinergic lesions in the brains of patients with dementia of the Alzheimer type (DAT) and Parkinson disease (PD), both demented and non-demented, have revealed a major loss of subcortical cholinergic cells and cortical nicotinic cholinergic receptors. This neurochemical deficit shared by the two disorders may represent the loss of presynaptic nicotinic receptors on ascending cortical projections from subcortical nuclei. Central nicotinic receptors have been shown to release several neurotransmitters including acetylcholine. The loss of these receptors may play an important role in the clinical symptomatology and psychopathology of both disorders by explaining the genesis of so-called """"""""subcortical"""""""" deficits in both disorders. Both disorders exhibit slowed processing, memory impairment, decisional impairment, and impaired ability to manipulate acquired knowledge. The effects nicotine on cognitive functioning parallel in large measure subcortical deficits, i.e. nicotine improves attention processing speed, reaction, time etc. Therapeutic studies with muscarinic agonists have not generally replicated the cognitive improvement seen in short-term anticholinesterase trials. Further, cholinergic drugs generally not improve the signs of cortical dementia: apraxia, agnosia, and aphasia. We conclude that previous studies with muscarinic stimulation or blockade have not led to either an adequate therapy or model of the cognitive pathology in DAT. Our preliminary studies administering nicotine to DAT patients have shown that acute nicotinic stimulation can briefly improve some of the above mentioned cardinal cognitive deficits seen in DAT and PD. This proposal will extend that work by validating a nicotinic model to explain subcortical-type cognitive deficits and other mental changes in both disorders. These studies will utilize a logical sequence of pharmacologic challenges with assessment of their cognitive and behavioral impact in several human populations. The first study will examine whether acute administration to DAT and non-demented PD patients and normal volunteers of the central nicotinic antagonist mecamylamine produces cognitive impairment and whether dose-response curves differ across young and old normals and DAT and non-demented PD patients. We will assess age- and disease-related sensitivity, especially whether PD patients have enhanced sensitivity to nicotinic blockade. The second study will examine whether repetitive acute nicotine administration improves subcortical cognitive deficits found in DA and PD and whether tolerance develops to this effect; this may explain why chronic anticholinesterase therapy in DAT has been disappointing. The third study will examine the specificity of the response to acute nicotine evaluating whether mecamylamine can prevent cognitive and behavioral changes produced by nicotine in DAT and PD patients and elderly normals. All studies will use state-of-the-art computerized testing with new developed testing paradigms that will enable precise assessment of the effects of these agents on the cognitive functions implicated in nicotinic dysfunction. These studies will provide important information relevant to the causes, mechanisms, and treatment of the dementia and psychopathology of Alzheimer's and Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH046625-04
Application #
3475465
Study Section
Treatment Development and Assessment Research Review Committee (TDA)
Project Start
1990-03-01
Project End
1995-02-28
Budget Start
1993-03-01
Budget End
1994-02-28
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405