AGE-RELATED CHANGES IN ALERTNESS AND VISUAL PROCESSING

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.