Faculty Bibliography

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

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

BACKGROUND: Activities of daily living (ADL) deficits are integral components of dementia disorders, and ADL measures are among the most robust markers of the course of Alzheimer's disease (AD). Despite this acknowledged importance, no clearly useful ADL instrument for cross-cultural application in pharmacologic trials in the early stages of AD had been available. METHOD: An international effort was launched to develop an ADL scale for pharmacologic trials in early AD. Steps taken from 1990 to the present included: (1) international scientific working group meetings and reviews, (2) reviews of existing measures, (3) collating of existent, nonredundant items, (4) querying experts for new items, (5) interviews with informants and subjects in the USA, France, and Germany, toward the identification of potential new items, (6) identification of an item pool based upon these procedures, (7) creation of a trial instrument, (8) piloting of this instrument, and (9) refinement of the scale based upon statistical analysis of the pilot data. Final item selection was based upon: (1) relevance for > or = 80% of subjects in severity-stratified USA and German samples; (2) absence of gender and national biases; (3) significant (p <.05) discrimination between (a) normal versus mildly impaired and (b) mildly impaired versus moderately to moderately severely impaired subjects; and (4) Global Deterioration Scale (GDS) scores accounting for > or = 12% of variance in the item after controlling for age and gender. RESULTS: An ADL scale consisting of 40 items that correlate with the global and cognitive progress of AD is developed for international usage in pharmacologic trials in incipient, mild, moderate, and moderately severe AD. The scale contains 40 items falling within 13 ADL categories. The 40-item scale is shown to have .81 correlation with GDS staging, .81 with mental status assessment (Mini-Mental State Examination), and .81 with a psychometric test (the SKT) (p values < .001). CONCLUSION: This scale can be used to measure therapeutic response in AD

The clinical impact of Alzheimer's disease pathology at biopsy was investigated in 56 cognitively impaired patients undergoing shunt surgery for idiopathic normal pressure hydrocephalus (NPH). Cognition was measured by means of the global deterioration scale (GDS), the mini mental status examination (MMSE) and a battery of six psychometric tests. Gait was assessed using objective measurements of velocity and the ambulatory index (AI). The prevalence of cases exhibiting neuritic plaques (positive biopsies) increased in parallel with dementia severity from 18% for patients with GDS 3 to 75% for patients with GDS scores > or =6. Patients with positive biopsies were more cognitively impaired (higher GDS and lower MMSE scores) as well as more gait impaired (higher AI scores and slower velocities) than patients with negative biopsies. After surgery, gait velocity and AI scores improved significantly and to a comparable degree for patients with and without positive biopsies. Similar proportions of positive and negative biopsy patients also had improved gait as assessed by means of subjective video tape comparisons. There were no significant differences between the biopsy groups in the magnitude of postoperative psychometric change or in the proportion of cases exhibiting improved urinary control. Alzheimer's disease pathology is a common source of comorbidity in older patients with idiopathic NPH where it contributes to the clinical impairment associated with this disorder. For patients accurately diagnosed with NPH, concomitant Alzheimer's disease pathology does not strongly influence the clinical response to shunt surgery

Data from clinical, electrophysiologic, neurophysiologic, neuroimaging and neuropathologic sources indicates that the progression of brain aging and Alzheimer's disease (AD) deterioration proceeds inversely to human ontogenic acquisition patterns. A word for this process of degenerative developmental recapitulation, 'retrogenesis', has been proposed. These retrogenic processes provide new insights into the pathologic mechanism of AD deterioration. An understanding of retrogenic phenonmena can also result in insights into the applicability of retrogenic pathologic mechanisms for non-AD dementing disorders. Management strategies based upon retrogenesis have recently been proposed. Retrogenic pathophysiology also points to previously unexplored pharmacologic approaches to dementia prevention and treatment

This study examined whether baseline neuropsychological performance in elderly assessed at a research clinic could accurately predict subsequent decline to dementia. Logistic regression analyses were applied to (1) 213 nondemented elderly with a Global Deterioration Scale (GDS) score of 1, 2, or 3, of whom 74 (35%) subsequently declined to any diagnosis of dementia, and (2) a diagnostically more restricted subset of this sample (N = 179), of whom 56 (31%) declined to a diagnosis of probable Alzheimer's disease (AD). The mean follow-up intervals were 3.8 and 3.7 years, respectively. A small set of baseline neuropsychological measures (especially a Paragraph Delayed Recall Test) significantly differentiated decliners from nondecliners to dementia or AD, after accounting for the contribution of age, sex, education, follow-up interval, and the rating of global clinical status. When examined in combination with the other factors or alone, the cognitive tests produced reasonably high specificities (91%-97%) and sensitivities (73%-89%). Using the obtained regression model, a similar level of classification accuracy was replicated on an independent sample of 119 nondemented elderly. A subanalysis of the high-risk GDS 3 subgroup indicated that cut scores from the paragraph test distinguished nondecliners from decliners (overall accuracies 87%-91%), implying that this assessment may accurately predict future cognitive status in elderly with mild cognitive impairment

We used CT and MR to examine the frequency of occurrence of hippocampal formation atrophy (HA) in a research clinic population of 130 normal elderly, 72 nondemented patients with very mild memory and cognitive impairments (MCI), 73 mild Alzheimer's disease (AD) patients, and 130 patients with moderate to severe AD. HA was found in 29% of the normal elderly group and its frequency of occurrence was strongly related to increasing age. For normal elderly 60-75 years of age, 15% had HA: the proportion rose to 48% in subjects 76-90 years of age. Among the three groups of impaired patients, the frequencies of HA ranged from 78% in the MCI patients to 96% in the advanced AD group. Unlike the normal elderly group, the percentages were not related to age. In both the normal elderly group and MCI group disproportionately more males than females had HA. After controlling for learning and the effects of generalized brain changes as reflected in ventricular size, only in the normal group was HA associated with reduced delayed verbal recall performance. Follow-up examinations for 15 individuals with baseline HA. 4 who at entry were MCI and 11 probable AD, yielded clinical and neuropathologic diagnoses of AD in all cases. The results of the present study indicate that hippocampal formation atrophy is associated with memory and cognitive impairments. Further longitudinal and neuropathologic work is required to validate the relationship between hippocampal formation atrophy and AD