Faculty Bibliography

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

In a series of multiple regression models predicting either duration or severity of Alzheimer disease (AD) patients, significant linear correlations were found consistently for the volume of CA1, the subiculum, and the entorhinal cortex. Similarly, the total number of neurons in CA1, CA4, and the subiculum was correlated significantly with both the duration and the severity of AD. A hierarchical multiple regression model was used to examine whether any of these intercorrelated measures had any unique relationship to disease duration or severity. The results showed that only CA1 demonstrated a unique contribution to the explained variance in predicting duration or severity of AD for volume and for neuronal numbers. These results indicate that in the hippocampal formation, volume and neuronal numbers of CA1 appear to show a unique relationship with clinical measures of AD.

We evaluated a strategy designed to improve useful activity of ciprofloxacin against Pseudomonas aeruginosa. Following changes in antimicrobial agent use made by the institutional Pharmacy and Therapeutic Drug Committee, monthly drug usage and microbial susceptibility records from June 1992 through October 1995 were reviewed. From July 1992 through October 1992 (Period 1), ciprofloxacin and ofloxacin usage represented 95 and 5% of total quinolone doses; from December 1992 to March 1993 (Period 2), ciprofloxacin represented 19%; from July 1993 to October 1993 (Period 3), ciprofloxacin usage represented 85%; from July 1994 to October 1994 (Period 4), ciprofloxacin represented 95%; and from July 1995 to October 1995 (Period 5), ciprofloxacin and ofloxacin respectively represented 98 and 2% of total quinolone doses. Comparison of the anti-pseudomonal activity of the two fluoroquinolones to ofloxacin use, ciprofloxacin use and total quinolone use during the entire observational period showed the highest (negative) correlation with ofloxacin use versus ofloxacin activity (y = -15.04x + 1367.99, r2 = 0.06, w = 0.126). Increased use of quinolones plus a change to primarily ofloxacin usage appeared to adversely affect the activity of both ofloxacin and ciprofloxacin against P. aeruginosa

The total number of neurons with and without neurofibrillary changes in sectors CA1 to CA4, subiculum, and dentate gyrus of 16 subjects with Alzheimer disease (AD) was estimated. The duration of neurofibrillary changes was calculated on the basis of regressions between the duration of AD and neuronal numbers. In the CA1 and subiculum, it takes 3.4 and 5.4 years, respectively, for an intact neuron affected by neurofibrillary pathology to become a ghost tangle.

Much has been learned about the clinical symptomatology of Alzheimer's disease (AD) and ontogenic reciprocal relationships in the past few decades. It is now possible to describe and verify inexorable symptomatic sequences and corresponding temporal relationships. It is also possible to identify more variable symptoms in AD. Ontogenic models can be useful in providing a clearer understanding of the nature of AD symptomatology in terms of both consistency and variability. These models can also be informative in explicating the management needs of AD patients and the treatment possibilities of AD symptoms as well as the etiology of variability in AD symptoms

We investigated the reliability, using a telephone interview procedure, of cognitive, functional, and behavioral scales in an elderly population with normal aging and dementia. Two clinicians performed the assessments: one performed the assessments in a telephone interview format and the other conducted the assessments at the clinic. The telephone interview always preceded the clinic evaluation (2-30 days apart), and both clinicians were blind to any previous evaluations of the patient. The intraclass correlation coefficients between the telephone interview and the ratings obtained by a different clinician on the clinic evaluation varied between 0.92 and 0.98 (P's < or = .001) for comprehensive test scores. These results indicate that a telephone interview format, although not a substitute for a face-to-face diagnostic evaluation, is a reliable procedure for obtaining the assessment modalities studied. These findings are particularly important in aged and dementia research populations where personal contact may not always be feasible

As a result of the neuropathologic process of Alzheimer's disease (AD), significant changes occur in neuromotor function (e.g., paratonia and compulsive grasping). These changes become manifest in the moderately severe stage of AD, when patients begin to require ongoing assistance with activities of daily life (ADL), and they are prominent in the severe stage of AD, when patients are continuously dependent on a caregiver. Patients in these stages often display behavioral disturbances during care activities. These disturbing behaviors result not only from cognitive impairment, but also from a patient's physical inability to cooperate with the caregiver. When care management strategies take into account the characteristic physical restrictions resulting from the neuromotor changes that accompany advanced AD, the caregiving process may be significantly facilitated

The total numbers of neurons with and without neurofibrillary changes in the hippocampal subdivisions were estimated in 16 subjects with Alzheimer disease (AD) and in 5 normal elderly controls. On the basis of clinical symptoms, AD patients were subdivided into relatively less (AD-1. Functional Assessment Staging [FAST] stages 7a to 7c) and more severely affected (AD-2, FAST stages 7e to 7f) patient groups. In the AD-1 group relative to controls, the total number of neurons was reduced only in CA1 and in the subiculum. In the AD-2 group, neuronal losses were found in all sectors of the cornu Ammonis and in the subiculum and ranged from 53% in CA3 to 86% in CA1. The dentate gyrus was the only hippocampal subdivision without significant neuronal loss. Within the combined AD patient groups, significant correlations were noted between both clinical stage and duration of AD and both the total number of neurons and the percentage of neurons with neurofibrillary changes in CA1, CA4, and the subiculum. Regression analyses predicted neuronal losses over the maximal observed duration of 22 years of 87% in CA1, 63% in CA4, and 77% in the subiculum. Our data suggest that over the course of AD, continuous neurofibrillary tangle formation and continuous neuronal loss occur in the hippocampal subdivisions. The rate of neuronal loss appears to be similar for CA1, CA4, and the subiculum

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