Alan Kluger

Frequency of hippocampal formation atrophy in normal aging and Alzheimer's disease

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 Alzheimers 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.

Efficacy of donepezil in mild cognitive impairment A randomized placebo-controlled trial

Objective: To evaluate the efficacy and safety of the acetylcholinesterase inhibitor donepezil in a placebo-controlled trial in patients with mild cognitive impairment (MCI). Methods: A total of 270 patients with MCI were enrolled in a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Patients were randomized to receive donepezil (n = 133; 5 mg/day for 42 days, followed by forced dose escalation to 10 mg/day) or placebo (n = 137). Primary efficacy measures were the New York University (NYU) Paragraph Delayed Recall test and the Alzheimer disease (AD) Cooperative Study Clinician’s Global Impression of Change for MCI (ADCS CGIC-MCI). Secondary efficacy measures included the modified AD Assessment Scale-cognitive subscale (ADAS-cog), the Patient Global Assessment (PGA), and additional neuropsychologic measures. Efficacy analyses were performed on intent-to-treat (ITT) and fully evaluable (FE) populations. Results: Primary efficacy measures of the NYU Paragraph Recall test and the ADCS CGIC-MCI did not show significant treatment effects in the ITT population. Some secondary measures showed effects favoring donepezil. More donepezil-treated patients showed improvements in ADAS-cog total scores, in tests of attention and psychomotor speed, and in PGA scores. More donepezil-treated than placebo-treated patients experienced adverse events, most of which were mild to moderate and transient. Conclusion: Although significant treatment effects were not seen in the primary efficacy measures, outcomes on secondary measures suggest promising directions for further evaluation of donepezil treatment in patients with MCI.

Neuropsychological prediction of decline to dementia in nondemented elderly.

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 Alzheimers 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. (J Geriatr Psychiatry Neurol 1999; 12:168-179).

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 Parkinsons 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 Parkinsons disease, and healthy controls, using an acquired equivalence associative learning task. As predicted, Parkinsons 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.

Hippocampal formation size predicts declining memory performance in normal aging

Hippocampal formation (HF) atrophy, although common in normal aging, has unknown clinical consequences.We used MRI to derive HF size measurements at baseline on 44 cognitively normal older adults entering a longitudinal study of memory function (mean age = 68.4 years, mean follow-up = 3.8 years). Only one subject became demented at follow-up. Multiple regression analyses controlling for age, gender, education, and diffuse cerebral atrophy revealed that HF size significantly predicted longitudinal change on memory tests previously found sensitive to decline in normal aging. These results indicate HF atrophy may be a risk factor for accelerated memory dysfunction in normal aging. NEUROLOGY 1996;47: 810-813

Retrogenesis: clinical, physiologic, and pathologic mechanisms in brain aging, Alzheimer's and other dementing processes.

Abstract 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.

The Alzheimer's Disease Activities of Daily Living International Scale (ADL-IS)

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 Alzheimers 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.

Assessing patterns of agitation in Alzheimer's disease patients with the cohen-mansfield agitation inventory

As part of the effort of the NIA Alzheimers disease cooperative study to develop improved instruments for quantifying effects in Alzheimers disease (AD) clinical trials, patterns of agitated behaviors were evaluated with the Cohen-Mansfield Agitation Inventory (CMAI) in 241 AD patients and 64 healthy elderly controls with valid baseline assessment on the CMAI. The test-retest reliability of the CMAI over 1 month was good (r = 0.74 to 0.92). Physically and verbally nonaggressive behaviors were most often reported, whereas physically aggressive behaviors were rare. Frequency of agitated behaviors increased with dementia severity, especially for patients with a Mini-Mental Status Exam score of 0–4. Agitation tended to increase in the evening with dementia severity for the more impaired patients. Amount of agitation did increase after 12 months in all but controls and mildly demented patients. The CMAI shows promise for evaluating a unique aspect of behavior and may be useful in assessing the effects of cognitive enhancers and other types of psychotropic drugs on behavior in dementia patients.

Positron emission tomography studies of normal aging: a replication of PET III and 18-FDG using PET VI and 11-CDG

Using PET VI and 11-CDG we replicated our earlier PET III and 18-FDG normal aging findings. Examination of young and old normal volunteers revealed the absence of any absolute regional age-related changes in glucose utilization. For the combined sample (N = 81) we did find evidence to suggest a relative hypofrontal change with increasing age. A strong relationship between age and ventricular size (CT) was also found. These findings suggest the preserved glucose metabolism of the resting aging brain in the presence of structural atrophic changes.

Motor/Psychomotor Dysfunction in Normal Aging, Mild Cognitive Decline, and Early Alzheimer's Disease: Diagnostic and Differential Diagnostic Features

To determine the association between cognitive dysfunction and motor behavior in older adults, 41 cognitively normal elderly (NL), 25 nondemented patients exhibiting mild cognitive impairment (MI) and at risk for future decline to dementia, and 25 patients with mild (early) Alzheimers disease (AD) were examined using a wide array of motor/psychomotor and cognitive assessments. The three groups were recruited from an aging and dementia research center and were composed of well-characterized physically healthy volunteers, with similar ages and gender distributions. The outcome measures included 16 motor/psychomotor tests categorized a priori into gross, fine, and complex, as well as eight cognitive tests of memory and language. Relative to the NL group, MI individuals performed poorly on cognitive, fine, and complex motor measures but not on gross motor tests; AD patients performed worse on cognitive and all motor domains. Differences in complex motor function persisted after adjustment for performance on cognitive and on less complex motor tests. Classification analyses showed similar accuracies in discriminating NL from MI and NL from AD cases for both complex motor (79% and 92% accuracy, respectively) and cognitive tests (80% and 93% accuracy, respectively). Less complex motor tests produced poorer accuracies. Among nondemented subjects, education correlated with several cognitive scores but no motor scores. These results indicate that motor impairment is an important aspect of cognitive decline in older adults. Motor/psychomotor assessments were found to be comparably sensitive to traditional tests of cognitive function in identifying persons affected by the earliest stages of AD pathology and may improve identification of at-risk nondemented elderly, especially among diversely educated individuals.