The goal of this study is to characterize the neurophysiologic mechanisms underlying the age-related decline in human visual cognitive function. This research will delineate specific neurophysiologic measures of subcortical functions that contribute to the age-related decline in cognitive function. It is hypothesized that the impairment of the sub, cortical function of alertness contributes to the age-related decrement in visual cognitive function and is related to right hemisphere dysfunction. Alertness is experimentally modulated in a double blind placebo-controlled drug study using a CNS depressant (diphenhydramine) and CNS stimulant (methylphenidate). Alertness is operationally defined using computerized EEG frequency analysis; slow later"""""""" al eye movements; blink rate; sympathetic nervous system activity (skin blood flow based, on laser Doppler velocimetry); parasympathetic nervous system activity (heart rate, variability). Visual cognitive function is assessed by performance on serial and parallel search tasks and a directed attention task. Measures of cognitive performance include: reaction time; accuracy; variability of reaction time. The hypothesis will be tested with 120 subjects, 60 in each of 2 age groups, 25-35 years and 65-75 years. Subjects will participate on 5 separate mornings. On each morning they will be given either a placebo, 0.5 mg/Kg diphenhydramine, 1 mg/Kg diphenhydramine: 0.1 mg/Kg methylphenidate or 0.2 mg/Kg methylphenidate. They will perform the cognitive tasks before and after administration of each drug condition. The research impacts clinical management of patients with cognitive deficits. Clinicians will be provided with measurement tools to document alertness deficits in cognitively impaired patients with subcortical lesions secondary to aging, focal lesions, neurodegenerative diseases and medications. If deficits in alertness can be measured and contribute to cognitive decline in the elderly, then strategies to increase alertness could be offered by clinicians. This may be particularly helpful in problem areas for the elderly such as driving and ambulation, where intermittent lapses in alertness or attention may produce significant injury. The normative data for cognitive function does not presently account for the subject's level of alertness. Since the level of alertness may account for a large amount of the variability in cognitive function, especially in the elderly and neurologically impaired population, the definition of a measurable state of alertness will improve the sensitivity and specificity of all clinical cognitive testing.?GRANT=R35AG09014 The aim of this LEAD application is to test the value of examining cellular and molecular abnormalities in extra-neural tissues from patients with Alzheimer's disease (DAT). It will test whether or not reported abnormalities relate to the presence of -the clinical syndrome of DAT or certain of its subgroups (familial vs sporadic, early vs.late onset, with vs without Parkinsonism, myoclonus, depression, or early aphasia). DAT patients and disease and intact controls of comparable age and sex will all receive detailed examination including neuropsychological testing; follow-up where possible will be to autopsy. Skin cell cultures including biopsy will be meticulously standardized to ensure that DAT and control cells are studied under identical conditions including identical biological age in culture. Parameters measured in the cultures will include two related to the materials which accumulate in DAT brain: amyloid precursor protein, and materials which react with antibodies to paired helical filaments (PHF). (Recent studies by the PI and co-workers indicate that skin cells accumulate anti-PHF reactive materials when grown under specified conditions, much more in DAT cells than in controls). Other parameters to be measured have been reported abnormal in DAT calls in at least two laboratories: isoproterenol-stimulated cyclic AMP synthesis, cellular calcium homeostasis, and [U-14C]glutamine oxidation. Data will be stored in a relational data base (SIR-software) and relations among clinical and laboratory findings analyzed in detail (SAS statistical software). Dr Ronald Black, an assistant professor of Neurology, will develop methods to quantitate anti-PHF reactive materials, compare the amounts of these materials in soluble and insoluble fractions of affected and unaffected areas of DAT and control brains, and then compare their amounts in cultured DAT and control cells. He will gain expertise in clinical as well as laboratory research in dementias by participating actively in the clinical evaluations. One pilot study will examine a possible increase in anti-APP reactive materials in DAT granulocytes, and a second possible abnormalities in phosphokinase activities in cultured DAT skin cells. Future pilots will also study other potential markers. The proposed investigations will extend the PI's ongoing mechanistic studies of abnormalities in cultured DAT cells. They will test directly whether or not the abnormalities studied relate closely to the clinical syndrome of DAT or to DAT subgroups.
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