Robert D. Nebes

Frequent Amyloid Deposition Without Significant Cognitive Impairment Among the Elderly

OBJECTIVE To characterize the prevalence of amyloid deposition in a clinically unimpaired elderly population, as assessed by Pittsburgh Compound B (PiB) positron emission tomography (PET) imaging, and its relationship to cognitive function, measured with a battery of neuropsychological tests. DESIGN Subjects underwent cognitive testing and PiB PET imaging (15 mCi for 90 minutes with an ECAT HR+ scanner). Logan graphical analysis was applied to estimate regional PiB retention distribution volume, normalized to a cerebellar reference region volume, to yield distribution volume ratios (DVRs). SETTING University medical center. PARTICIPANTS From a community-based sample of volunteers, 43 participants aged 65 to 88 years who did not meet diagnostic criteria for Alzheimer disease or mild cognitive impairment were included. MAIN OUTCOME MEASURES Regional PiB retention and cognitive test performance. RESULTS Of 43 clinically unimpaired elderly persons imaged, 9 (21%) showed evidence of early amyloid deposition in at least 1 brain area using an objectively determined DVR cutoff. Demographic characteristics did not differ significantly between amyloid-positive and amyloid-negative participants, and neurocognitive performance was not significantly worse among amyloid-positive compared with amyloid-negative participants. CONCLUSIONS Amyloid deposition can be identified among cognitively normal elderly persons during life, and the prevalence of asymptomatic amyloid deposition may be similar to that of symptomatic amyloid deposition. In this group of participants without clinically significant impairment, amyloid deposition was not associated with worse cognitive function, suggesting that an elderly person with a significant amyloid burden can remain cognitively normal. However, this finding is based on relatively small numbers and needs to be replicated in larger cohorts. Longitudinal follow-up of these subjects will be required to support the potential of PiB imaging to identify preclinical Alzheimer disease, or, alternatively, to show that amyloid deposition is not sufficient to cause Alzheimer disease within some specified period.

Reliability and validity of some handedness questionnaire items.

Abstract A group of college students filled out a handedness questionnaire; a month later they were asked to perform the tasks mentioned on the questionnaire and then to fill out the questionnaire again. Twenty-three items have been scaled for reliability and validity and for the frequency of right hand preference by predominantly left handed people. On these bases, certain items are recommended for inclusion on future handedness questionnaires.

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. Hum. Brain Mapping 5:84–92, 1997.

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.

A Positron Emission Tomography (PET) Study of Autobiographical Memory Retrieval

Memory for the experiences of ones 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.

Self-Reported Sleep Quality Predicts Poor Cognitive Performance in Healthy Older Adults

This study examined the relation between sleep quality and cognitive performance in older adults, controlling for common medical comorbidities. Participants were community volunteers who, while not selected on the basis of their sleep, did report substantial variability in sleep quality. Good and poor sleepers differed on tests of working memory, attentional set shifting, and abstract problem solving but not on processing speed, inhibitory function, or episodic memory. Poor sleep was also associated with increased depressive symptomatology but only for functional symptoms (e.g., decreased concentration) and not for mood (e.g., sadness). The relationships between sleep quality and cognition were not explained by confound factors such as cerebrovascular disease, depression, or medication usage. Sleep problems may contribute to performance variability between elderly individuals but only in certain cognitive domains.

Basal Cerebral Metabolism May Modulate the Cognitive Effects of Aβ in Mild Cognitive Impairment: An Example of Brain Reserve

Inverse correlations between amyloid-β (Aβ) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [18F]fluoro-2-deoxy-d-glucose (FDG) in Alzheimers disease (AD) patients, suggest local Aβ-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Aβ deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Aβ deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Aβ deposition or increasing the level of Aβ necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Aβ deposition has been present for longer periods of time does Aβ become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

Use of semantic context by patients with Alzheimer's disease.

In this study we used semantic-priming procedures to examine limitations in the use of semantic context by patients with Alzheimers disease. We also tried to determine whether any such contextual effects were mediated solely through automatic processes or whether attentional processes were also involved. Three tasks were applied to examine the effect of semantic context on the performance of 18 normal elderly and 18 normal young subjects, and on 18 patients with Alzheimers disease. When normal and demented subjects were asked to decide whether a given item was a member of a certain category, results showed that their response times were equally affected by the items dominance in the category. The time that demented patients took to recognize a word was actually affected more by the semantic context provided by a priming sentence than was that of normal subjects. When asked to generate the final word of an incomplete sentence, demented subjects performed very poorly unless potential responses were highly constrained by sentence context.

Automatic and attentional mechanisms of semantic priming in alzheimer's disease

Previous studies using a word-naming task have suggested that in demented patients, semantic priming results only from automatic spreading activation and not from attention-dependent processes. If this is true, then on a lexical-decision task where attention-dependent processes are a major source of the semantic-priming effect, demented patients should show little or no priming. To test this prediction, three groups of 16 subjects (young and normal-old individuals and patients with Alzheimers disease) were given a Word-Naming and a Lexical-Decision task. In both tasks, the amount of semantic priming (the difference in response time to a word preceded by a semantically unassociated vs. a semantically associated word) was determined. Demented patients showed significantly greater semantic priming than either normal group on both tasks. This result argues against the hypothesis that the semantic priming found in demented patients is due solely to automatic processes.

Cognitive deficits and clinical diagnosis of Alzheimer's disease

We used cognitive deficits detected by neuropsychological testing to evaluate clinical diagnosis of Alzheimers disease. Deficits were defined with respect to performance of control subjects according to procedural guidelines set by a NINCDS-ADRDA Work Group. The most frequent deficits were in recent memory and lexical-semantic language abilities. Clinical diagnosis of Alzheimers disease was compared with diagnosis based on a criterion of two or more cognitive deficits both on initial neuropsychological testing and on testing repeated a year later in some subjects. Initial clinical diagnosis identified 96% of cases who met the criterion when first tested and 100% of those with multiple deficits at follow-up. Specificity with respect to the criterion was 86% on initial testing and 89% at follow-up. These findings support the validity of clinical diagnosis of Alzheimers disease using the NINCDS-ADRDA criteria.