ALZHEIMER'S DISEASE AND ATTENTION: AN INVESTIGATION INTO THE INITIAL STAGE OF INFORMATION PROCESSING DISSERTATION Presented to the Graduate Council of the University of North Texas in Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY By

thought, and other higher cortical functions, and changes in personality and behavior (pp. 119-120). 10 Thus, according to DSM III-R, Alzheimer dementia can be conceptualized as consisting of three components: l) cognitive impairment, memory in particular—the essential feature of dementia, 2) functional and structural impairment of the brain, and 3) behavioral manifestations which impair the individual's capacity for self-care, interpersonal relationships, and social adjustment (Wang, 1981). Although deficits in orientation, memory, intellectual functioning, judgment, and affectivity are stressed as the classic features of dementia, these symptoms emphasize the advanced stages of the dementing process and fail to incorporate the clinical picture in earlier stages of the disease before such gross malfunction is evident (Wells, 1977) . Early Detection and Structural Changes of Alzheimer's Disease The accurate, early detection of Alzheimer's disease (AD) has become an urgent health care concern. Joynt and Shoulson (1979) and Damasio and Van Allen (1979) discussed the importance of accurately differentiating AD from the increasing number of identified biological and psychosocial causes of dementia which are amenable to treatment. Early detection of dementia may also have a drastic impact on the choice of medication prescribed, since some drugs are known to have a negative impact on cognitive performance ("Drugs and Memory," 1982). Furthermore, Henderson and Huppert (1984) suggest that early detection of AD is an important 11 objective in order to avoid crises, plan appropriate patient management, and provide pharmacological treatment when it is most likely to be beneficial to the patient. Jolles (1984) suggested that treatment in the earlier stages of the disease can be expected to be more successful than in later stages because structural brain changes are less pronounced. And, finally, the behavioral, emotional, and cognitive profile displayed by the patient may provide a clue to the cause of the disease and its pathogenesis (Jolles, 1984). At the present time, a peripheral biochemical marker for the detection of AD has not been identified. Thus, the definitive diagnosis of this disorder can only be accomplished by histological confirmation through brain biopsy or autopsy (Katzman, 1986). The most characteristic morphological changes in the brains of patients with AD are neuritic plaques and neurofibrillary tangles (Moss & Albert, 1988). The density and distribution of these abnormal structures are considered to be the most salient neuropathological marker for the diagnosis of AD. Other structural alterations in the brain associated with Alzheimer's include cortical atrophy (Gurtzman, Klimitz & Avdaloff, 1982), loss of neurons in cortical and subcortical regions (Ball et al., 1985; Corkin, 1982), granulovacuolar degeneration (Reitan & Wolfson, 1985), and loss of myelin in the cerebral cortex (Tomlinson, Blessed & Roth, 1970). Biochemical studies have consistently found a decrease in 12 the cholinergic enzymes acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) in patients suffering from AD (Bartus, Dean, & Beer, 1982). Noradrenergic and serotoninergic systems (Rossor & Iverson, 1986) and neurotransmitter peptides (somatostatin and corticotropin-releasing factor) have also been found to be affected by AD (Davies, Katzman & Terry, 1980; Rossor, Emson, & Mountjoy, 1980). Of particular interest for the present study are the structural and biochemical changes which occur in the frontal neocortex, specifically in the nucleus basilis of Meynert (nbM), which is located in the substantia innominata. This structure contains clusters of neurons that are recognizable by their large size, abundant Nissl material, AChE activity, and physiological properties (Whitehouse, Price, Struble, Clark, Coyle, & DeLong, 1982). The nbM is a major source of cholinergic innervation throughout the cerebral cortex. It receives afferents from the amygdala, hypothalamus, peripeduncular nucleus, midbrain, and other brain stem nuclei, and sends projections to the amygdala, thalamus, hypothalamus, brain stem, olfactory bulbs, hippocampus, entorhinal cortex, and neocortex. Thus, the nbM is in a critical position for the integration of information from a wide variety of subcortical sources and for direct influence upon the cerebral cortex (Whitehouse et al., 1982) and focused 13 arousal (Sheer, 1984; Sheer & Schrock, 1986). It may also contribute to reward, learning, and attentional mechanisms (Coyle, Price & DeLong, 1983). Carlson (1986) stated that, during the early stages of AD, cortical degeneration primarily involves presynaptic terminal buttons, but as the disease progresses additional degeneration of cortical gray matter occurs. Recent research suggests that neurons of the nbM experience a profound (greater than 75%) and selective degeneration in patients with AD (Whitehouse et al., 1982). This degeneration provides a pathological substrate for the cholinergic deficiency evidenced in the brains of individuals suffering from AD. Since the nbM undergoes considerable change during the course of Alzheimer's disease, the cognitive functions mediated by this structure should also evidence significant decline. Therefore, the detection and measurement of such deficits may provide an early neuropsychological marker for the presence of AD. Bondareff, Mountjoy, and Roth (1982) and Iverson et al. (1983) have identified significant degeneration of the locus Coeruleus (LC) in some patients diagnosed as suffering from AD. The LC is located in the dorsal pons and contains cell bodies of the noradrenergic system. The LC sends neurons to the neocortex, hippocampus, thalamus, cerebellar cortex, and medulla; thus, the LC could potentially affect numerous widespread and important regions in the brain. 14 Corkin et al. (1986) implicated the LC in the mediation of attention, arousal, and spatial memory. These authors also suggest that noradrenaline (NA) is involved in the regulation of attention, arousal, mood, memory, and spatial abilities. Arai, Kosaka, and Iizuka (1984) report low NA concentrations in individuals diagnosed with AD. Palmer et al. (1987) similarly reported reduced levels of noradrenergic marker concentrations in AD patients, in a sample of AD patients studied by Freed et al. (1988), a significant association was found between deficits in attentional focusing and reduced levels of an NA metabolite. These studies suggest that degeneration of the LC may occur in AD and that the behaviors mediated by this structure may be compromised as a result of the degeneration. Again, measurement of the specific behavioral deficits secondary to LC degeneration may provide an early marker for the presence of AD. Laboratory Models of Alzheimer's Disease Over the past decade, several laboratories have used animal models to investigate the neurobiological changes that accompany age-related cognitive decline (Dean & Bartus, 1985). These laboratories have also attempted to develop animal models which reflect the neural and cognitive changes associated with dementia in humans (Kolb & Nonneman, 1978; Pepeu, Casamenti, Bracco, Ladinsky, & Consolo, 1985). Kelly and Moore (1978) report that lesions of the nbM in rats 15 resulted in a diminution in ChAT activity in the cerebral cortex. Lesions of the nbM in rats have also been implicated in a marked decrease in AChE activity in the cerebral cortex (Wenk, Bigl, & Meyer, 1980). Lo Cante, Casamenti, Bigl, Milaneschi, and Pepeu (1982) reported that rats with unilateral electrolytic lesions of the nbM exhibited several changes in behavior, including impairments in the acquisition of a two-way active avoidance response and an increase in spontaneous motility. Bilateral excitotoxic lesions of the nbM have been found to result in impairment in the acquisition of a one-way active avoidance response and severe deficits in the retention of a passive avoidance response (Flicker, Dean, Watkins, Fisher, & Bartus, 1983). Beninger, Jhamandas, Boegman, and El-Defrawy (1984) suggest that nbM lesions impair working memory (recall of recent events of transient importance) but not reference memory (information stored over the long term). These studies indicate that lesions of the nbM result in significant impairment of the cortical cholinergic system, which is associated with deficits in cognitive functioning. Several studies have used animal models to investigate the role of cortical NA in attention and arousal. Robbins (1984) reported that lesions to the dorsal noradrenergic ascending bundle (DNAB) result in NA depletion in several cortical areas, including the neocortex and the hippocampus. Mason and Iversen (1979) suggest that rats with lesions to 16 the DNAB exhibit an attentional inability to screen out irrelevant stimuli. Robbins, Everitt, Fray, Gaskin, Carli, and de la Riva (1982) report that DNAB-lesioned animals displayed deficits in the acquisition of new tasks but not in performance. These studies suggest that depletions in cortical NA may result in attentional dysfunction. One of the major limitations of animal models is that cerebral structures are poorly defined in many subprimate species, thus preventing direct correlation between animal and human lesions, in experimental investigations of humans with localized lesions, it has been reported that frontal lesions impair performance on tasks which require sustained attention (Milner, 1974; Milner, 1982; Shallice, 1982). Wilkins, Shallice, & McCarthy (1987) report that patients with lesions involving the right frontal lobe were impaired on tasks requiring sustained voluntary attention. This study suggests that when the rate of stimulus presentation is slow, requiring individuals to impose attention voluntarily on an uninteresting task, anterior lesions result in deficits in the ability to maintain optimum levels of alertness over prolonged periods of time, since AD involves anterior structures (nbM), the present investigation may represent a human model for some of the deficits exhibited by individuals with AD. 17 Clinical Stages of Alzheimer's Disease As a result of the pathological structural changes and the dissolution of large numbers of neurons associated with Alzheimer's disease, drastic mental deterioration accompanies this disorder and eventually interferes with social and occupational functioning. Although memory failures are the most prominent and often first observed liil symptom, cognitive disturbances occur in additional areas such as language usage, visuospatial abilities, apraxia, the ability to learn new problem-solving skills, abstract thinking, and the ability to make judgments (Katzman, 1986). Reisberg (1983) stated that the symptomatology of cognitive decline is fairly consistent across individuals with AD. He conceptualized the intellectual deterioration within three broad clinical phases. The initial phase of the disease process has been termed the "forgetfulness phase." During this phase, the cognitive deficit is primarily subjective and may be evidenced as an increased difficulty in recalling the formerly familiar names of places and objects, and as an increased tendency on the part of the individual to forget where objects have been placed. The deficits are not severe enough to disrupt social and occupational functioning, but the onset of these symptoms may result in minor disruptions within the individual's family system. 18 During the second phase, termed the "confusional phase," symptoms become increasingly apparent. Difficulty in recalling the names of persons and objects becomes more manifest, and the inability to remember where items have been placed results in increasing inaccessibility of valuables. Recall of recent events and activities in which the individual participated are disrupted, and the person is no longer capable of functioning in demanding social or occupational situations. Deficits in concentration are readily elicited, and the individual may become lost when traveling to a location which should have been reached without undue difficulty. The "dementia phase" is defined as beginning at the point at which the individual is no longer capable of independent survival. The inability successfully to complete basic activities of daily living is the hallmark of this phase of cognitive impairment. Gross disturbances in orientation, memory, and psychomotor abilities eventually result in the need for total health care and/or institutionalization. From this description of symptomatology, it is apparent that during the advanced stages of this condition there is not likely to be a diagnostic dilemma, but that during the initial stages differential diagnosis becomes more difficult. The Global Deterioration Scale, developed by Reisberg, Ferris, de Leon, and Crook (1982), identifies 19 seven distinct clinical stages of Alzheimer's disease. The first stage reflects no cognitive decline, and memory deficits are not evident in clinical interviews. The second stage, very mild cognitive decline, is comparable with the 11 forget fulness phase." Complaints of memory deficits are primarily subjective, and objective evidence of memory deficits in clinical interviews is lacking. The third stage is that of mild cognitive decline, which occurs during the early part of the "confusional phase." The earliest clinically identifiable deficits become apparent at this stage. Intensive interviewing may identify objective evidence of memory deficits, although frequently there are no errors on mental status questionnaires (Kahn, Goldfarb, Pollack, & Peck, i960). it is during this stage that deficits in concentration can be detected by clinical testing. Alzheimer's Disease and Attention Several studies have explored the relationship between AD and attention; unfortunately, their results have been equivocal. In a preliminary investigation of the early stages of information processing by Miller (1977), it was reported that individuals with AD were much less efficient at extracting information from brief stimulus displays than were normal subjects. Miller (1977) hypothesized that defective attentional processing could account for these findings. Zarit, Miller, and Kahn (1978) reported that the 20 immediate repetition of a simple stimulus was a response which remained intact, regardless of the condition of brain functioning. Weingartner, Kaye, Smallberg, Ebert, Gillin and Sitaram (1981) reported that the psychometric performance of patients with progressive idiopathic dementia (PID) indicated that attentional mechanisms were largely unaffected by the disease process. Corkin (1982); Crook, Ferris, McCarthy, and Rae (1980); Kaszniak, Garron, and Fox (1979); and Larner (1977) have stated that patients with AD performed significantly worse on tests of immediate recall of digits than did normals. The severity of the dementing illness apparently has drastic affects on these findings, since Danziger and Storandt (1982) reported that mildly demented patients do not consistently exhibit this impairment on the immediate recall of digits. In a study conducted by Vitaliano, Breen, Albert, Russo, and Prinz (1984), the relationship among cognitive performance, functional competence, and severity of dementing illness was examined. The results of this study indicate that measures of attention were useful in differentiating severity of functional impairment in demented individuals but not in distinguishing controls from mildly demented patients. The authors concluded that measures of attention may not be useful for the identification of individuals with subtle signs of cerebral dysfunction, but may be appropriate for gualitative 21 assessment of the severity of impairment after a diagnosis of dementia has been established. Furthermore, the authors concluded that changes in attention may not occur until late in the course of the degenerative process. This conclusion has received additional support from Albert (1984) and Moss and Albert (1988), who reported that in the early stages of AD attention remains relatively intact. Corkin (1982) and Berg et al. (1984) have suggested that, as the disease progresses, attentional mechanisms are relatively compromised and that significant impairment on tests of attention become apparent in moderately to severely demented patients. Largen (1980) used four measures of focused arousal and found consistently large and significant differences between Alzheimer patients and matched geriatric controls, in a more recent study, Loring and Largen (1985) reported that, when controlled for normal age differences, patients who developed a degenerative dementia with an earlier age of onset tended to perform significantly worse on tests of concentration than did individuals with a later age of onset. These results also indicated that patients who developed a degenerative dementia during the presenile period were more impaired than their senile counterparts on age-adjusted measures of sustained concentration. Attentional processing dysfunctions have also been related to severity of electroencephalograph^ (EEG) slowing 22 (Kaszniak, Garron, Fox, Bergen, & Huckman, 1979). Loring (1982) and Sheer (1984) replicated Largen's (1980) study but also incorporated measures of 40-Hz EEG, a central measure of focused arousal. These studies reported that the mean absolute levels of 40-Hz EEG in AD groups were significantly different from those of geriatric control groups. Spydell and Sheer (1983) reported not only that 40-Hz EEG was significantly different between Alzheimer and geriatric control groups, but that the 40-Hz EEG activity was markedly lower in the AD group. From these studies, it has been postulated that individuals with AD are unable to maintain focused arousal. This inability disrupts normal short-term processing and results in impaired problem-solving performance. Sheer (1984) noted that the Alzheimer samples used m the Spydell and Sheer (1983) and Loring (1982) studies were cases representative of the earlier stages of the degenerative process, suggesting that impairments in focused arousal may occur relatively early in the disease. The lack of consistency in the findings of these studies may be the result of the instruments used to assess attention. Albert (1984) recommended the use of digit span forward as a test of attention. Digit span has been used by numerous investigators studying memory functions (Berg et al., 1984; Corkin, 1982; Crook, Ferris, McCarthy, & Rae, 1980; Danziger & Storandt, 1982; Eslinger, Damasio, Benton, & Van Allen, 1985; Kaszniak, Garron, & Fox, 1979; Larner, 23 1977). Digit span tasks have also been incorporated into many mental status questionnaires, such as the Cognitive Capacity Screening Examination (Jacobs, Bernhard, Delgado, & Strain, 1977), the Mini-Mental State Exam (Folstein, Folstein, & McHugh, 1975), the Dementia Rating Scale (Coblentz, Mattis, Zingesser, Kasoff, Wisniewski, & Katzman, 1973), and the Mental State Questionnaire (Kahn et al., 1960). Zarit et al. (1978) reported that digit span tasks were clearly not sufficiently sensitive to detect even massive degrees of general intellectual impairment. Talland (1965) has repeatedly demonstrated that performance on digit span tasks can be within normal limits even in severely amnesic patients, and Weingartner et al. (1981) stated that it is unfortunate that digit span tasks have been used so frequently in the construction of mental status examinations. These studies suggest that digit recall tasks represent a particularly poor technique for assessing memory dysfunction. Kaszniak, Poon, and Riege (1986) report that digit span tasks incorporate both primary and secondary memory components, indicating that these recall tasks are not specific to a particular component of information processing. An additional criticism of digit span tasks is the paucity of clinical information they yield. Digit span tasks fail to provide the clinician with any qualitative information which could be used in the assessment of dementia.