James Golomb

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.

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

HIPPOCAMPAL ATROPHY IN EARLY ALZHEIMER'S DISEASE: ANATOMIC SPECIFICITY AND VALIDATION

We evaluated three groups of elderly individuals who were carefully screened to rule out clinically significant diseases that could affect cognition. They were matched for age and education. The groups included normals (N=18), Alzheimers Disease (AD) patients (N=15), and minimally impaired individuals with memory complaints and impairments but who did not fulfill criteria for AD (N=17). Volumetric measurements of different regions of the temporal lobe on the coronal scan as well as ratings of the perihippocampal cerebrospinal fluid (CSF) accumulation (HCSF) on the negative angle axial MR were carried out. Volume reductions were found in AD relative to the normals for both medial and lateral temporal lobe volumes. Only hippocampal volume reductions were found in the minimal group. The minimally impaired individuals had equivalent hippocampal volume reductions and significantly larger parahippocampal and lateral temporal lobe gyri than the AD group. The axial HCSF was validated using the coronal volumes. The combination of coronal hippocampal and perihippocampal CSF was the best predictor of the axial HCSF rating. The parahippocampal volume did not add to the predictive ability of the hippocampal-perihippocampal CSF combination. Future work should validate these findings with longitudinal designs as well as assess the issue of normal aging of these structures and their relationship to cognitive function.

In Vivo Structural Studies of the Hippocampus in Normal Aging and in Incipient Alzheimer's Diseasea

Population trends indicate that in the near future the size of the elderly population will increase. This will result in a large increment in the numbers of persons suffering mild to severe levels of cognitive impairment. While considerable efforts continue to be made to explain brain changes associated with Alzheimer disease (AD), little is known of the brain changes in aging without dementia or so‐called normal aging. Pathologic studies suggest that the medial temporal lobe is informative in the examination of the early brain changes related to AD. However, pathologic studies only offer a single observation and considerable uncertainty exists regarding the likelihood of progression of disease and the development of dementia. Several structural neuroimaging studies have recently investigated this anatomy and recent reports are encouraging for a medial temporal lobe based diagnosis for age‐related cognitive impairments. We will present our findings on the MRI anatomy of the hippocampal formation as well as data bearing on the use of hippocampal formation imaging in the diagnosis of AD and as a predictive marker for future dementia. Our findings suggest an anatomically specific relationship between hippocampal volume and secondary memory performance. Because these observations apply to nondemented and normal elderly subjects, we are encouraged that the anatomy of age‐related cognitive impairments can be reliably recognized and possibly put to use in therapeutic studies.

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.

Hippocampal atrophy correlates with severe cognitive impairment in elderly patients with suspected normal pressure hydrocephalus.

Measurements of hippocampal formation atrophy using MRI have been useful in distinguishing demented patients with a diagnosis of probable Alzheimers disease from cognitively normal controls. To determine whether there is a similar relationship between hippocampal size and dementia in elderly patients suspected of normal pressure hydrocephalus (NPH), the authors obtained mini-mental status examination (MMSE) scores and MRI measurements of hippocampal size and CSF volume on 16 elderly patients whose severe ventriculomegaly and unexplained gait impairment made NPH a probable diagnosis. Hippocampal size correlated strongly with MMSE score (r = 0.75, p < 0.001); no significant MMSE correlation was found for ventricular CSF volume or extra-ventricular/ventricular CSF ratio. It was concluded that hippocampal atrophy is associated with severe cognitive dysfunction in many elderly patients with a diagnosis of NPH. As a hypothesis for further investigation, the detection of such atrophy may help identify cases where the presence of a pathology of Alzheimers disease complicates the diagnosis of NPH.

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 Alzheimers disease (AD). Hippocampal atrophy (HA) is also correlated with cognitive impairments, leading to the promise of behavioral markers for early AD. Prior theo retical 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 con current 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 per formance ; 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. (J Geriatr Psychiatry Neurol 2002; 15:82-90).

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.