Raja Parasuraman - US grants

Recent neuroradiological findings suggest that altered patterns of brain metabolism may precede cortically-mediated neuropsychological deficits in senile dementia of the Alzheimer's type (SDAT). These metabolic changes may be associated with patterns of attentional loss that are not detectable by standard neuropsychological tests. The principal aims of the proposed project are (a) to evaluate two systems of attention in early stages of SDAT in comparison to the normal elderly, and (b) to explore the contribution to early diagnosis of SDAT of assessment of patterns of attentional loss and altered brain metabolism. A unified neuropsychological model of attention in SDAT is proposed. The model links two aspects of attention, "attentional cost", and sustained attention capacity, with a corticocortical system and a subcortical thalamic projection system, respectively. Three interrelated experiments designed to evaluate these two attentional systems will be carried out. In Experiments 1 and 2 a probe-reaction time task will be used to evaluate the attentional cost of mental operations (e.g., stimulus encoding, response selection) in patients in the early stages of SDAT. The cost of processing will be examined as a function of processing type, cortical hemisphere subserving processing, and intensity of processing demands. In Experiment 3 sustained attentional capacity will be evaluated by a degraded letter-detection task. The results of these studies will provide valuable pilot data for carrying out more extensive investigations of the utility of assessment of attentional loss in early diagnosis of SDAT, particularly in combination with measures of brain metabolism. The attention data obtained from SDAT patients will be related to data on brain metabolic patterns being collected from the same patients at the Laboratory of Neurosciences. This unique neuroradiological/neuropsychological approach will provide valuable information relevant to early diagnosis of SDAT that would not otherwise be available at low cost. Findings from this study may also indicate that a subtle attentional loss in the early stages of the disease predicts subsequent rate of decline. Such a result would potentially help in the development of appropriate management and treatment modalities for patients with SDAT.

The diagnosis of dementia of the Alzheimer type (DAT) is uncertain in life partly because of difficulties in discriminating the physiological and cognitive changes accompanying normal aging from those associated with the early stages of DAT. Recently, however, alterations in patterns of regional cerebral glucose metabolism have been reported to be present in early DAT. These metabolic changes may reflect compensatory brain mechanisms that are operative in both normal aging and in early DAT, but which break down as the disease progresses. The strength of such compensatory processes may depend upon the efficiency of attentional mechanisms, particularly in response to increased information-processing demands. A neuropsychological model is proposed that integrates these findings with the results of preliminary studies indicating that simple cognitive operations are preserved at greater "attentional cost" in early DAT. The model proposes that inefficient attentional mechanisms represent an early functional impairment in DAT and are underlying factors in the memory and cognitive deficits of DAT. Furthermore, the magnitude of attention-related compensation mechanisms in the early stages of DAT may predict the rate of subsequent cognitive decline. The major aim of the proposed research is to evaluate this model in a series of six studies in four groups of subjects: young adults, older adults, older adults rigorously screened for health status, and DAT patients. Two methods for manipulating attention- -reaction time to a "probe" stimulus, and covert shifts of attention--will be used to evaluate the attentional demands of cognitive operations in aging and early DAT. Studies 1 and 3 will examine two aspects of attention--(i) the attentional demands of simple cognitive operations and (ii) the switching of attention from one spatial location to another--in all four groups of subjects. Studies 2 and 4 will examine more complex features of these attentional mechanisms in young and older adults. Study 5 will examine interrelationships between the attentional mechanisms investigated in Studies 1 and 3 and cerebral metabolic rates for glucose as assessed by 18-FDG positron emission tomography (PET). In study 6 healthy elderly and DAT subjects will be given yearly follow-up evaluations on PET and the Study 1 attention tests for a period of four years. The proposed research will identify changes in attentional and physiological function in the early stages of DAT which have not been investigated extensively, and also advance understanding of attentional changes accompanying normal aging. The results should contribute to the development of cognitive and physiological markers for early diagnosis of DAT.

DESCRIPTION (Adapted from Investigator's Abstract): In order to further examine spatial attention across a broad range of visual and auditory tasks, a neuroanatomical model is proposed, postulating dysfunction of interacting corticocortical circuits associated with different aspects of selective attention in DAT. A series of eight studies in patients with dementia of the Alzheimer's type (DAT), age-matched controls, and young, "young-old" and "old-old" adults will be conducted, with the following aims: (1) To examine the functional characteristics of spatial attention in mildly demented DAT patients across a broad range of visual, auditory, and cross-modal tasks; (2) To examine the neural mechanisms underlying spatial attention deficits in early DAT; (3) To examine age-related changes in these attentional functions, particularly in the old-old. For the second aim, positron emission tomography (PET) and event-related brain potentials (ERPs) will be used to disclose spatial and temporal properties, respectively, of spatial attention in the human brain. PET will aid in identifying affected brain regions in DAT. ERPs will be used to investigate the temporal locus of spatial attention changes in DAT.

New methods for preventing, slowing the progression of, and treating Alzheimer's disease (AD) are urgently needed given the dramatic growth in the number of people afflicted with AD. Such efforts would be helped if AD could be detected in its preclinical stage, before irreversible brain changes occur. One approach, followed in the proposed research, is to examine individuals who are not demented but are at increased risk for developing AD due to inheritance of the epsilon4 allele of the apolipoprotein E gene (APOE) on chromosome 19. Nondemented persons with the APOE-epsilon4 genotype exhibit regional cerebral metabolic changes in association temporal, parietal, and frontal cortical areas that mirror those seen in mildly demented AD patients. These brain regions include distributed networks that mediate visuospatial attention and spatial working memory. The proposed research will therefore investigate the hypothesis that nondemented APOE-epsilon4 carriers have selective deficits in specific component processing operations underlying attention and memory. The goal is to investigate changes over time in preclinical AD in component operations of attention, working memory, and their neurobiological correlates, using information-processing tests, event-related brain potentials (ERPs), and biological markers (beta-amyloid and tau). These measures will be obtained in middle-aged nondemented adults genotyped for APOE, AD patients, and age-matched controls. A unique aspect of the research is the comprehensive approach to assessment of longitudinal changes, including behavioral, electrophysiological, and biological measures. Five studies are proposed, one large-scale study and four additional experiments. These studies will ascertain the cognitive impact of APOE in otherwise asymptomatic adults and will establish the relationship between changes in attention and working memory in preclinical and early AD. The results will have significant implications for the early detection of AD as well as for an understanding of the genetic basis of normal cognitive operations underlying attention and memory.

DESCRIPTION (provided by applicant): The early detection of Alzheimer's disease (AD) continues to be an important goal, given the staggering medical costs associated with this disease. A major approach has been to examine individuals who are not demented but are at increased genetic risk for AD due to inheritance of the e4 allele of the Apolipoprotein E (APOE) gene. The proposed research addresses several acute unresolved issues concerning the role of APOE-E4 in the development of cognitive deficits leading to AD. To achieve the goal of early detection of AD, individuals should be studied in midlife and not in old age. Also, information-processing tests should be used, so that the cognitive processes underlying a particular deficit can be isolated and linked to brain networks. Finally, to better understand when and how APOE-related cognitive changes lead to the cognitive deficits of AD, longitudinal studies in middle-aged adults are needed. The proposed research will advance the goal of early detection by identifying cognitive and neurobiological markers sensitive to APOE-E4 genotype and showing how those markers in midlife predict the development of subsequent deficits leading to mild cognitive impairment (MCI) and to AD. The longitudinal studies will examine effects of APOE on attention and memory in two cohorts of healthy adults, one in midlife (40-59) and the other older (60-75), as well as in MCI patients. Both US and Norwegian samples of middle-aged and older adults will be assessed, because of the greater frequency of the relatively rare e4 allele among Northern Europeans. For increased sensitivity, behavioral assays of cognitive brain processes will be supplemented with event-related brain potential (ERP) measures. The research will also test the hypothesis that APOE has both a fundamental, modulatory effect as well as domain-specific effects on cognition many years before the onset of AD symptoms. The basic modulatory effect of APOE on cognition may be mediated by axonal pathways, whose integrity will be assessed using magnetic resonance imaging (MRI). Domain-specific effects will be studied by examining the interaction between APOE and neurotransmission genes recently linked to individual differences in attention and memory. The results will have significant implications for the early detection of AD as well as for an improved understanding of the neurocognitive effects of APOE. This in turn may allow for the development of prevention therapies to be provided to those at greatest risk for AD at the earliest possible time.