Serum anticholinergic activity, white matter hyperintensities, and cognitive performance.

The authors investigated whether the cognitive impairments associated with white matter hyperintensities (WMH) in normal elderly subjects are exacerbated by any anticholinergic medications being taken by the subjects. Results showed serum anticholinergic activity (SAA) and WMH volume to have a synergistic interaction such that the cognitive decrements associated with increasing WMH volume were greatest in those older individuals in the highest quartile of the SAA distribution.

The relation of White Matter Hyperintensities to implicit learning in healthy older adults.

OBJECTIVE: This study examined whether MRI evidence of cerebrovascular disease in the form of white matter hyperintensities (WMH) was associated with decreased implicit sequence learning performance in a high-functioning group of normal elderly volunteers. METHOD: One hundred and eight community-dwelling elderly individuals received an MRI and performed an implicit sequence learning task, the serial reaction time (SRT) task. RESULTS: Hyperintensities present in the white matter were associated with a decreased learning effect. This association was found with both deep white matter and periventricular changes. Other factors affecting SRT performance (i.e., baseline reaction time and switch-cost) were not significantly related to the presence of WMH. CONCLUSIONS: The results indicate that in addition to previously identified generalized cognitive deficits, WMH are also associated with a specific decrease in the implicit learning of sequences.

A twelve-week, double-blind, randomized comparison of nortriptyline and paroxetine in older depressed inpatients and outpatients.

Selective serotonin reuptake inhibitors may be less efficacious than tricyclic antidepressants in the treatment of severe depression in older patients. The authors compared the 12-week clinical outcome of older depressed patients treated with nortriptyline or paroxetine in a double-blind randomized comparison in 116 psychiatric inpatients and outpatients (mean age: 72+/-8 years) who presented with a major depressive episode or melancholic depression. Discontinuation and response rates were compared in patients who began or who completed treatment. The discontinuation rate due to side effects was significantly higher with nortriptyline than with paroxetine (33% vs. 16%). There were no significant differences between the rates of response in the Intent-to-Treat analysis (nortriptyline: 57% vs. paroxetine: 55% ), or the Completer analysis (nortriptyline: 78% vs. paroxetine: 84%). Although paroxetine appears to be better tolerated than nortriptyline, the efficacy of these two drugs does not appear to differ in the acute treatment of older depressed patients, including hospitalized patients and those with melancholic features.

Relationship of deep white matter hyperintensities and apolipoprotein E genotype to depressive symptoms in older adults without clinical depression.

OBJECTIVE: This study examined whether evidence of cerebrovascular disease in the form of magnetic resonance imaging (MRI) signal hyperintensities in white matter was associated with depressive symptoms in a high-functioning group of normal elderly volunteers. METHOD: Ninety-two community-dwelling elderly individuals participating in a study of white matter hyperintensities (WMHs) in normal aging whose apolipoprotein E (APOE) genotype had been determined completed the Geriatric Depression Scale and received an MRI scan. Univariate analyses of variance were used to examine the relationship between depressive symptoms and the location of WMHs (in deep white matter versus in periventricular white matter) and to determine whether WMHs were more likely to be associated with symptoms of impaired motivation and concentration or with mood symptoms. The effect on depressive symptoms of the interaction between severity of cerebrovascular disease as evidenced by WMHs and APOE genotype was also examined. RESULTS: Hyperintensities in the deep white matter, but not in the periventricular white matter, were associated with depressive symptoms, especially symptoms of impaired motivation, concentration, and decision making. The relationship between deep WMHs and depressive symptoms was especially strong in individuals carrying the APOE-4 allele. CONCLUSIONS: The pattern of depressive symptoms associated with WMHs in this study was similar to the pattern described in the literature as characterizing "vascular" depression in older persons with major depression. The results suggest that cerebrovascular disease may also underlie the depressive symptoms often found in older individuals who are not clinically depressed.

Dual-task performance in depressed geriatric patients.

Older patients suffering from a major depression are often impaired on tasks that require executive control processes. However, a wide variety of executive abilities exist in humans, and it is not clear that all are impaired in depression or that such impairments persist beyond remission of the depression. One executive process that plays a central role in mental operations such as working memory is the ability to co-ordinate the simultaneous performance of multiple tasks. Dual-task performance has been extensively studied in normal subjects but there is little work with depressed patients. The present study examined the performance of depressed (M age=71.0, S.D.=7.1) and control subjects (M age=69.3, S.D.=7.0) on two tasks (visual tracking and backward digit span), both when each task was carried out by itself and when the two tasks were carried out simultaneously. Dual-task performance was impaired in depressed patients prior to antidepressant treatment and this impairment persisted even after remission of the depression. These results suggest that, like other executive abilities, the ability to schedule and co-ordinate the conflicting processing demands present in a dual-task situation is impaired in depressed geriatric patients and that this impairment may be a trait effect.

Hypothyroidism and cognition: preliminary evidence for a specific defect in memory.

The effect(s) of hypothyroidism on adult brain cognitive function are poorly understood. We performed a series of neuropsychological tests in 13 thyroid cancer patients while they continued to take their usual dose of levothyroxine (LT4) and again after discontinuing thyroid hormone. Three euthyroid subjects were also tested twice to assess the effect of repeated testing on performance. The tests assessed memory, mood, and attentional resources and controlled for the practice effects of repeated testing. The mean thyrotropin (TSH) on LT4 was 0.56 +/- 0.76 mU/L and while hypothyroid was 69 +/- 33 mU/L. While hypothyroid, the mean Beck depression score was significantly higher (15.31 +/- 9.41 hypothyroid vs. 7.31 +/- 4.82 on LT4) and the subjects rated themselves worse relative to functional memory, concentration, thinking, alertness, and motivation. Hypothyroidism was associated with a decrease in retrieval from memory (p = 0.0034), and this effect could not be attributed to depression or to practice effects. Thyroid state did not affect immediate recall, verbal learning, inhibitory efficiency, information processing speed, or attention switching. Athyrosis is associated with a decrement in delayed recall of verbal information but not in other objective measures of cognition, suggesting that the memory decrement of hypothyroidism is not caused by a generalized reduction in attentional resources.

Changes in cognitive functioning following treatment of late-life depression.

OBJECTIVE: Knowledge of the relationship between various clinical characteristics and cognitive functioning is advancing, but little is known about the cognitive response to treatment for geriatric depression. The purpose of this study was to examine the cognitive response to treatment for patients with late-life depression. METHOD: Subjects included 45 nondemented, elderly depressed patients who achieved remission after 12 weeks of antidepressant treatment and 20 elderly comparison subjects. All subjects were administered a battery of clinical measures, including cognitive screening instruments, before and after treatment. RESULTS: As a group, the elderly depressed patients showed a small improvement in overall cognitive functioning after treatment. Among depressed patients with concomitant cognitive impairment at baseline, performance on the Mattis Dementia Rating Scale domains of conceptualization and initiation/perseveration improved significantly relative to those of depressed patients with normal cognition. Despite the improvement following treatment, the overall level of cognitive functioning in the elderly depressed patients with cognitive impairment at baseline remained mildly impaired, especially in the memory and initiation/perseveration domains. CONCLUSIONS: Elderly depressed patients with cognitive impairment may experience improvement in specific domains following antidepressant treatment but may not necessarily reach normal levels of performance, particularly in memory and executive functions. This subgroup of late-life depression patients is likely at high risk of developing progressive dementia.

Decreased working memory and processing speed mediate cognitive impairment in geriatric depression.

BACKGROUND: While neuropsychological dysfunction is common in geriatric depression, not all aspects of cognition are equally affected. It has been suggested that depressed patients are impaired only in tasks that make heavy demands on processing resources and that a resource decrement therefore underlies the neuropsychological decrements seen in geriatric depression. The present study examined whether processing resources in the form of working memory and information processing speed are decreased in depression and whether a decrease in these resources actually mediates neuropsychological impairment. METHODS: Measures of processing resources were administered to elderly depressed patients prior to treatment and to age-matched controls. Patients whose depression remitted were retested as were the controls. Subjects also received neuropsychological tests of episodic memory and visuospatial performance. RESULTS: Depressed patients performed significantly worse on measures of both processing speed and working memory. While performance on these measures improved in patients whose depression remitted, the amount of improvement was no greater than that seen in the controls with repeat testing. Hierarchical regression analyses showed that depression explained a significant amount of variance on the neuropsychological tasks. However, if the variance associated with processing resources was removed first, depression no longer accounted for a significant amount of neuropsychological variance. CONCLUSIONS: Processing resources are decreased in elderly depressed patients and this decrease in resources appears to mediate impairments in several areas of neuropsychological functioning including episodic memory and visuospatial performance. The resource decrement persists after remission of the depression and thus may be a trait marker of geriatric depression.

Complementary category learning systems identified using event-related functional MRI.

Event-related fMRI was used to dissociate the neural systems involved in category learning with and without awareness. Ten subjects performed a speeded response category learning task. Functional MR images were acquired during both explicit and implicit learning conditions. Behavioral data showed evidence of learning in both conditions. Functional imaging data showed different activation patterns in implicit and explicit trials. Decreased activation in extrastriate region V3 was found with implicit learning, and increased activation in V3, the medial temporal lobe, and frontal regions were found with explicit learning. These results support the theory that implicit and explicit learning utilize dissociable neural systems. Moreover, in both the implicit and explicit conditions a similar pattern of decreased activation was found in parietal regions. This commonality suggests that these dissociable systems also operate in parallel.

A double-blind randomized comparison of nortriptyline and paroxetine in the treatment of late-life depression: 6-week outcome.

BACKGROUND: Some studies have suggested that selective serotonin reuptake inhibitors may be less efficacious than tricyclic antidepressants in the treatment of severe depression in older patients. The objective of this study was to compare the 6-week outcome of treatment with nortriptyline and paroxetine in older patients with a major depressive episode. METHOD: A double-blind randomized comparison of nortriptyline and paroxetine was conducted in 80 elderly (mean +/- SD age = 75.0 +/- 7.4 years) psychiatric inpatients and outpatients who presented with a major depressive episode. Dropout and response rates were compared in patients who began or completed treatment. Rates of response of inpatients and patients with melancholic depression were also compared. RESULTS: Over 6 weeks, there were no significant differences in dropout rates due to side effects (nortriptyline, 14% vs. paroxetine, 19%) or for any reason (27% vs. 33%). Similarly, there were no significant differences between the rates of favorable response to nortriptyline or paroxetine (intent-to-treat analysis, 57% vs. 44%; completer analysis, 78% vs. 66%). Analyses restricted to inpatients or to patients with melancholic depression yielded similar results. CONCLUSION: Nortriptyline and paroxetine appear to have similar efficacy and tolerability in the acute (6-week) treatment of older depressed patients, including hospitalized patients and those with melancholic features.

Cognitive effects of paroxetine in older depressed patients.

This study examined whether paroxetine produces cognitive toxicity in elderly patients suffering from a major depressive episode. Twenty-nine depressed patients with a wide range of cognitive functioning were treated with paroxetine. At baseline and during 6 weeks of treatment, patients were asked to complete various measures of cognitive function and had blood drawn to determine serum anticholinergicity. Measures of attention and cognitive speed showed significant improvement with treatment, while the memory performance remained unchanged. A similar pattern of results was found in both cognitively impaired and intact patients. The slight increase in serum anticholinergicity seen in some elderly patients did not significantly impair cognitive function, even in patients with a preexisting cognitive impairment.

Functional neuroanatomy of semantic memory: recognition of semantic associations.

In an effort to examine the functional neuroanatomy of semantic memory, we studied the relative cerebral blood flow of eight healthy young subjects using 15O-water positron emission tomography (PET). Relative to a visual baseline control condition, each of four visual matching-to-sample tasks activated components of the ventral visual processing stream, including the inferior occipital and temporal cortices. Contrasting the task with the highest semantic component, a variation on the Pyramids and Palm Trees paradigm, with a size discrimination task resulted in focal activation in the anterior inferior temporal lobe, focused in the parahippocampal gyrus. There was additional activation in BA47 of the inferior frontal cortex. These data replicate and extend previously reported results using similar paradigms, and are consistent with cognitive neuropsychological models that stress the executive role of BA47 in semantic processing tasks.

A positron emission tomography (PET) study of autobiographical memory retrieval.

Memory for the experiences of one's life, autobiographical memory (AM), is one of the most human types of memory, yet comparatively little is known of its neurobiology. A positron emission tomography (PET) study of AM retrieval revealed that the left frontal cortex was significantly active during retrieval (compared to memory control tasks), together with activation in the inferior temporal and occipital lobes in the left hemisphere. We propose that this left frontal lobe activation reflects the operation of control processes that modulate the construction of AMs in posterior neocortical networks.

Instantiation of semantic categories in sentence comprehension by Alzheimer patients.

This study examined whether Alzheimer patients can make elaborative inferences based on the semantic context provided by a sentence. More specifically, if presented with the name of a category in a sentence do they, like normals, infer (instantiate) the particular member of that category most appropriate to the meaning of the sentence (e.g., if a sentence mentions a container of juice, do they infer it is a bottle). Patients were presented with a sentence containing the name of a concrete category. The sense of the sentence was consistent with a low-dominant member of that category. Patients were then shown drawings of four members of that category and asked to select the one appropriate to the sentence. They were later asked to name the drawings. If semantic information is degraded in Alzheimer patients for those objects Alzheimer patients cannot name (as has been claimed), then AD patients should be unable to carry out the type of elaborative semantic inference required to instantiate. Results showed that Alzheimer patients were highly accurate at instantiating even objects they could not name. This is consistent with a relative preservation of semantic knowledge about concrete objects in Alzheimer patients.

Cognitive and motor slowing in Alzheimer's disease and geriatric depression.

While response slowing on psychological tasks is a symptom of both depression and Alzheimer's disease (AD), the underlying mechanisms may be quite different: a slowing of cognitive processing in AD and a motor retardation in depression. This hypothesis was tested by examining the rate at which participants performed a simple cognitive operation: subvocal pronunciation. Participants were shown words of between one and three syllables and were asked to decide whether each word ended in a particular sound. This task required participants to transform the written word into its phonological representation, an operation thought to involve subvocal pronunciation. Decision time rose linearly with the number of syllables in all three subject groups. The linear function of the AD patients had a significantly greater slope, indicating a slower rate of subvocal pronunciation, whereas the slope was the same for the normal old and depressed. Both the depressed and AD patients had a higher intercept than the normal old, suggesting a sensorimotor slowing. After treatment, the intercept of the linear function for depressed patients fell, but there was no change in the slope. Thus, this study suggests that AD produces a slowing in both cognitive and motor processes, whereas depression results solely in a motor retardation.

Serum anticholinergicity in elderly depressed patients treated with paroxetine or nortriptyline.

OBJECTIVE: The authors' goal was to compare serum anticholinergicity of 61 elderly depressed patients randomly assigned to double-blind treatment with paroxetine (N=31) or nortriptyline (N=30). METHOD: Both antidepressants were titrated in a standardized manner, and plasma was sampled weekly for measurement of paroxetine and nortriptyline and its hydroxy metabolite concentrations. Serum anticholinergicity was measured at baseline and after 1, 4, and 6 weeks of treatment. Side effects were assessed by using a validated scale. RESULTS: After correcting for pretreatment anticholinergicity, the authors found that mean serum anticholinergicity for the nortriptyline-treated patients was significantly greater than that for the paroxetine group at all weeks assessed. Serum anticholinergicity was significantly correlated with nortriptyline but not with paroxetine plasma levels. Complaints of dry mouth and tachycardia were significantly more frequent and severe in the nortriptyline group. CONCLUSIONS: These findings suggest that, at therapeutic plasma concentrations, paroxetine has approximately one-fifth the anticholinergic potential of nortriptyline in older patients.

An examination of regional cerebral blood flow during object naming tasks.

The purpose of this study was to examine regional cerebral blood flow using positron emission tomography (PET) during the performance of tasks related to visual confrontation naming. Ten healthy, young participants were scanned twice in each of 5 conditions; blood flow was measured using standard PET [15O]-water technology. Two major findings have replicated previous studies. First, the naming of visually presented objects, whether covert or overt, requires a region of the left inferior cortex including the fusiform gyrus. Second, during overt naming, there is an increase in activity in the inferior or frontal cortex and insula as a consequence of generating speech code. These data are consistent with other studies demonstrating the importance of the inferior temporal regions for semantic processing, and the frontal cortex for word form generation.

Low-level serum anticholinergicity as a source of baseline cognitive heterogeneity in geriatric depressed patients.

Depressed geriatric patients show substantial intersubject variability in cognitive performance, which complicates attempts to evaluate the cognitive effects of depression and of antidepressant therapy. This variability may reflect the multiple medications older patients take, many of which have anticholinergic effects. This study examined whether serum anticholinergicity (SA) explained some of the variability in depressed geriatric patients' memory performance. Before starting antidepressant treatment, 36 elderly depressed subjects were given a verbal learning test. At the same time, a blood sample was taken and analyzed by radioreceptor binding assay to determine their SA level. Nineteen of the subjects had detectable levels (mean = 0.28 pmole atropine equivalent). Subjects with an SA of zero showed significantly better delayed recall than did those with a positive SA level. Thus, even very low SA may produce subtle decrements in memory performance, an area of cognition known to be highly sensitive to anticholinergic effects.

Regional cerebral blood flow during word and nonword reading.

The purpose of this study was to examine changes in regional cerebral blood flow (rCBF) using positron emission tomography (PET) during overt word and nonword reading tasks to determine structures involved in semantic processing. Ten young, healthy, right-handed subjects were scanned 12 times, twice in each of six specific conditions. Blood flow was measured by 15O-water using standard PET imaging technology. The rCBFs during different cognitive conditions were compared by using analysis of covariance (SPM94), which resulted in three-dimensional maps of those brain regions more active in one condition relative to another. When the subjects read aloud words with difficult or unusual grapheme-phoneme translations (i.e., third-order approximation to English or irregularly spelled real words), increases in activation were seen in the inferior frontal cortex. When subjects were reading aloud regular and irregular words (which had important semantic components relative to nonwords), activation of the fusiform gyrus was seen. These data are broadly consistent with brain regions generally associated with reading based on other neuropsychological paradigms, and they emphasize the multicomponent aspects of this complex cognitive process.

Sentence context influences the interpretation of word meaning by Alzheimer patients.

This study examined whether, in Alzheimer patients, verbal context selectively activates elements of a word's meaning that are relevant to the context. Subjects were shown a sentence ending in a target noun, followed by a question about an attribute of that target. The sentence primed either the attribute in the question, a different attribute, or no attribute. Both normals and AD patients answered the question faster when the target had appeared in a context priming that particular attribute. These results suggest that Alzheimer patients retain knowledge of semantic attributes and that these attributes are susceptible to contextual activation.