Psychometric Cognitive Decline Precedes the Advent of Subjective Cognitive Decline in the Evolution of Alzheimer's Disease.

BACKGROUND: We have described the clinical stages of the brain aging and Alzheimer's disease (AD) continuum. In terms of the pre-dementia stages of AD, we introduced the terminology "mild cognitive impairment" (MCI) for the first pre-dementia stage and "subjective cognitive decline" (SCD) for the pre-MCI stage. We now report the characteristics of a pre-SCD condition eventuating in likely AD. OBJECTIVE: The aim of this study was to characterize a pre-SCD condition eventuating in AD. METHOD: Sixty healthy persons with "no cognitive decline" (NCD) were recruited and 47 were followed (mean baseline age, 64.1 ± 8.9 years; mean follow-up time, 6.7 ± 3.1 years). Outcome was determined at the final assessment prior to 2002 as "decliner," if SCD or worse, or "nondecliner" if NCD. RESULTS: After controlling for age, gender, years of education, and follow-up time, there was a between-group difference in the decline rate (p < 0.001). Also, after controlling for demographic variables and follow-up time, the combinatorial psychometric score was lower at baseline in the future decliners (p = 0.035). Of the 9 psychometric variables, after controlling for demographic variables and follow-up time, 3 were significantly lower at baseline in future decliners. Since AD is known to be age related and all subjects in this study were otherwise healthy, we also did an analysis without controlling for age. The combinatorial psychometric score was highly significantly better at baseline in the future nondecliners than in the future decliners (p = 0.008). CONCLUSION: This is ostensibly the first study to link psychometric cognitive decline to the subsequent SCD stage of eventual AD.

Neuropsychological and neuropsychiatric prediction of global cognitive status among older Spanish-speaking Hispanics and English-speaking whites.

BACKGROUND: Neuropsychological and depression measures have been found to predict cognitive functioning. We compared these associations among whites and Spanish-speaking Hispanics. METHODS: Fifty-two pairs of whites and Hispanics were matched demographically and clinically in a cross-sectional study. Hierarchical regression analyses predicted Global Deterioration Scale (GDS) rating by baseline neuropsychological tests and depression symptoms. RESULTS: Neuropsychological tests predicted GDS better in whites; depression symptoms--specifically retardation--predicted well in Hispanics but not whites. Immediate recall of the New York University (NYU)-Paragraph Test and the Retardation item of the Hamilton Depression Rating Scale were associated with GDS in Hispanics and delayed recall of the NYU-Paragraph Test and Wechsler Adult Intelligence Scale-Digit Symbol in whites. Neuropsychological tests and depression symptoms predicted GDS differently in Hispanics and whites. DISCUSSION: These results suggest that other measures should be considered to increase the predictive accuracy of neuropsychological tests when assessing cognitive status in Spanish-speaking Hispanics. Additional studies of specific ethnic/racial and sociodemographic subgroups are warranted.

Two Year Outcomes, Cognitive and Behavioral Markers of Decline in Healthy, Cognitively Normal Older Persons with Global Deterioration Scale Stage 2 (Subjective Cognitive Decline with Impairment).

BACKGROUND: Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2. OBJECTIVE: Two-year interval behavioral markers were investigated herein. METHODS: Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years. RESULTS: Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p < 0.001), with component declines in Remote memory (p < 0.01), and Functioning/self-care (p = 0.01). CONCLUSION: SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.

Learning and generalization tasks predict short-term cognitive outcome in nondemented elderly.

This study examines whether behavioral measures obtained in nondemented elderly can predict cognitive status at 2-year follow-up. Prior studies have established that delayed paragraph recall can help predict short-term risk for decline to mild cognitive impairment and Alzheimer disease. It was examined whether prediction accuracy can be improved by adding a discrimination-and-generalization task that has previously been shown to be disrupted in nondemented elderly with hippocampal atrophy, a risk factor for Alzheimer disease. Fifty nondemented, medically healthy elderly patients received baseline clinical diagnosis and cognitive testing; 2 years later, patients received a follow-up clinical diagnosis of normal, mild cognitive impairment, or probable Alzheimer disease. In all, 2 baseline variables, delayed paragraph recall and generalization performance, were predictive of follow-up outcome with sensitivity of 81% and specificity of 91%-better than the classification accuracy based on either of these measures alone. These preliminary results suggest that these behavioral tasks may be useful tools in predicting short-term cognitive outcome in nondemented elderly.

The effects of Alzheimer's disease on item output in verbal fluency tasks.

We collected category fluency data from several moderate-to-large samples of participants at three different sites: the New York University Aging and Dementia Center, the Oregon Health Services Aging and Dementia Research Center, and the Einstein Aging Study at the Albert Einstein College of Medicine. These data were analyzed by calculating the average relative frequency (e.g., typicality) of the category members generated by each participant. Alzheimer's disease (AD) patients recalled fewer atypical members of common taxonomic categories than did the elderly control group. In addition, the probability of producing an item declined at a greater rate for AD patients than for the elderly control group over the duration of the task. According to sequential sampling models, this latter result implies that the rate at which AD patients search memory must be slower than the search rate of the elderly controls.

Hippocampal atrophy disrupts transfer generalization in nondemented elderly.

Specific reductions in hippocampal volume in nondemented elderly individuals with mild cognitive impairment have been shown to correlate with future development of Alzheimer's disease (AD). Hippocampal atrophy (HA) is also correlated with cognitive impairments, leading to the promise of behavioral markers for early AD. Prior theoretical work has suggested that hippocampal dysfunction may selectively impair generalization involving novel recombinations of familiar stimuli. In this study, nondemented elderly individuals were trained on a series of concurrent visual discriminations and were then tested for transfer when stimulus features were recombined in new ways. Presence or absence of HA, revealed by neuroimaging, was not correlated with concurrent discrimination performance; however, individuals with mild HA showed significant decreases in transfer performance relative to nonatrophied participants. These preliminary results suggest that even very mild degrees of hippocampal atrophy may be associated with subtle behavioral impairments.

Mild cognitive impairment: historical development and summary of research.

This review article broadly traces the historical development, diagnostic criteria, clinical and neuropathological characteristics, and treatment strategies related to mild cognitive impairment (MCI), The concept of MCI is considered in the context of other terms that have been developed to characterize the elderly with varying degrees of cognitive impairment Criteria based on clinical global scale ratings, cognitive test performance, and performance on other domains of functioning are discussed. Approaches employing clinical, neuropsychological, neuroimaging, biological, and molecular genetic methodology used in the validation of MCI are considered, including results from cross-sectional, longitudinal, and postmortem investigations. Results of recent drug treatment studies of MCI and related methodological issues are also addressed.

Neural substrates of verbal memory impairments in adults with type 2 diabetes mellitus.

BACKGROUND: Verbal memory impairment is well documented in type 2 diabetes mellitus (T2DM) but, to date, the neural substrates remain unclear. The present study evaluated verbal memory and ascertained the degree of frontal and temporal lobe involvement in the anticipated verbal memory impairment among adults with T2DM. METHOD: Forty-six late-middle-aged and elderly adults with T2DM and 50 age-, sex-, and education-matched adults without T2DM underwent medical evaluation, verbal memory assessment, and brain magnetic resonance imaging (MRI) evaluations. RESULTS: As anticipated, participants with T2DM had clear verbal memory impairments. Consistent with prior reports, we found volume reductions restricted to the hippocampus. Our diffusion tensor imaging analysis revealed that participants with T2DM had extensive cerebral gray and white matter microstructural abnormalities predominantly in the left hemisphere, with a larger concentration present in the temporal lobe. In contrast, we uncovered mostly nonspecific microstructural abnormalities in the absence of tissue loss in the frontal lobe. Of great importance, we present the first evidence among participants with T2DM linking verbal memory impairment and compromised microstructural integrity of the left parahippocampal gyrus, a key memory-relevant structure. CONCLUSIONS: Our results suggest that the hippocampus and parahippocampal gyrus may be particularly vulnerable to the deleterious effects of T2DM. The parahippocampal gyrus in particular may play a crucial role in the verbal memory impairments frequently reported in T2DM. Future studies should employ methods such as resting state functional magnetic resonance imaging and diffusion tensor imaging tractography to better characterize network connectivity, which may help further characterize the verbal memory impairment frequently reported in T2DM.

Clinical features of MCI: motor changes.

Mild cognitive impairment (MCI) is a classification reserved for nondemented elderly individuals at increased risk for future decline to dementia, compared to those with normal cognition. Cognitive tests, particularly those assessing verbal recall, have been found to be useful in the identification of elderly people with MCI. We argue that a variety of motor/psychomotor evaluations are also sensitive to MCI. Motor assessments described as complex correctly categorize normal versus MCI elderly with comparable accuracies to those obtained by cognitive tests. Unlike performance on verbally based cognitive measures, motor-test scores appear to be relatively independent of educational attainment, indicating that the use of certain motor tests may be particularly valuable in the identification of MCI among elderly with widely varying educational backgrounds.

Mild cognitive impairment (MCI): a historical perspective.

Descriptions of dementia can be traced to antiquity. Prichard (1837) described four dementia stages and Kral (1962) described a "benign senescent forgetfulness" condition. The American Psychiatric Association's DSM-III (1980) identified an early dementia stage. In 1982, the Clinical Dementia Rating (CDR) and the Global Deterioration Scale (GDS) were published, which identified dementia antecedents. The CDR 0.5 "questionable dementia" stage encompasses both mild dementia and earlier antecedents. GDS stage 3 described a predementia condition termed "mild cognitive decline" or, alternatively, beginning in 1988, "mild cognitive impairment" (MCI). This GDS stage 3 MCI condition is differentiated from both a preceding GDS stage 2, "subjective cognitive impairment" (SCI) stage and a subsequent GDS 4 stage of mild dementia.GDS stage 3 MCI has been well characterized. For example, specific clinical concomitants, mental status and psychological assessment score ranges, behavioral and emotional changes, neuroimaging concomitants, neurological reflex changes, electrophysiological changes, motor and coordination changes, and changes in activities, accompanying GDS stage 3 MCI have been described.Petersen and associates proposed a definition of MCI in 2001 which has been widely used (hereafter referred to as "Petersen's MCI"). Important differences between GDS stage 3 MCI and Petersen's MCI are that, because of denial, GDS stage 3 MCI does not require memory complaints. Also, GDS stage 3 MCI recognizes the occurrence of executive level functional deficits, which Petersen's MCI did not. Nevertheless, longitudinal and other studies indicate essential compatibility between GDS stage 3 MCI and Petersen's MCI duration and outcomes.

Dissociating hippocampal versus basal ganglia contributions to learning and transfer.

Based on prior animal and computational models, we propose a double dissociation between the associative learning deficits observed in patients with medial temporal (hippocampal) damage versus patients with Parkinson's disease (basal ganglia dysfunction). Specifically, we expect that basal ganglia dysfunction may result in slowed learning, while individuals with hippocampal damage may learn at normal speed. However, when challenged with a transfer task where previously learned information is presented in novel recombinations, we expect that hippocampal damage will impair generalization but basal ganglia dysfunction will not. We tested this prediction in a group of healthy elderly with mild-to-moderate hippocampal atrophy, a group of patients with mild Parkinson's disease, and healthy controls, using an "acquired equivalence" associative learning task. As predicted, Parkinson's patients were slower on the initial learning but then transferred well, while the hippocampal atrophy group showed the opposite pattern: good initial learning with impaired transfer. To our knowledge, this is the first time that a single task has been used to demonstrate a double dissociation between the associative learning impairments caused by hippocampal versus basal ganglia damage/dysfunction. This finding has implications for understanding the distinct contributions of the medial temporal lobe and basal ganglia to learning and memory.