Robert J. Ivnik

Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment

Objective: To test the hypothesis that MRI-based measurements of hippocampal volume are related to the risk of future conversion to Alzheimer’s disease (AD) in older patients with a mild cognitive impairment (MCI). Background: Patients who develop AD pass through a transitional state, which can be characterized as MCI. In some patients, however, MCI is a more benign condition, which may not progress to AD or may do so slowly.Patients:— Eighty consecutive patients who met criteria for the diagnosis of MCI were recruited from the Mayo Clinic Alzheimer’s Disease Center/Alzheimer’s Disease Patient Registry. Methods: At entry into the study, each patient received an MRI examination of the head, from which the volumes of both hippocampi were measured. Patients were followed longitudinally with approximately annual clinical/cognitive assessments. The primary endpoint was the crossover of individual MCI patients to the clinical diagnosis of AD during longitudinal clinical follow-up. Results: During the period of longitudinal observation, which averaged 32.6 months, 27 of the 80 MCI patients became demented. Hippocampal atrophy at baseline was associated with crossover from MCI to AD (relative risk [RR], 0.69, p = 0.015). When hippocampal volume was entered into bivariate models—using age, postmenopausal estrogen replacement, standard neuropsychological tests, apolipoprotein E (APOE) genotype, history of ischemic heart disease, and hypertension—the RRs were not substantially different from that found univariately, and the associations between hippocampal volume and crossover remained significant. Conclusion: In older patients with MCI, hippocampal atrophy determined by premorbid MRI-based volume measurements is predictive of subsequent conversion to AD.

Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease.

Magnetic resonance imaging (MRI)-based volumetric measurements of medial temporal lobe (MTL) structures can discriminate between normal elderly control subjects and patients with Alzheimers disease (AD) of moderate to advanced severity. In terms of clinical utility, however, a more important issue concerns the ability of the technique to differentiate between normal elderly control subjects and AD patients with the very mildest form of the disease. We performed MRI-based volumetric measurements of the hippocampus, parahippocampal gyrus, and amygdala in 126 cognitively normal elderly control subjects and 94 patients with probable AD. The diagnosis of AD was made according to NINDS/ADRDA criteria, and disease severity was categorized by Clinical Dementia Rating (CDR) scores. Patients with CDR 0.5 were classified as very mild, CDR 1 as mild, and CDR 2 as moderate disease severity. Volumes of each structure declined with increasing age in control subjects and did so in parallel for men and women. The volume of each measured MTL structure also declined with age in patients with AD. The volume of each MTL structure was significantly smaller in AD patients than control subjects (p < 0.001). Of the several MTL measures, the total hippocampal volumetric measurements were best at discriminating control subjects from AD patients. The mean hippocampal volumes for AD patients relative to control subjects by severity of disease were as follows: very mild AD (CDR 0.5) -1.75 SD below the control mean, mild AD (CDR 1) -1.99 SD, and moderate AD (CDR 2) -2.22 SD. Age- and gender-adjusted, normalized MRI-based hippocampal volumetric measurements provide a sensitive marker of the MTL neuroanatomic degeneration in AD early in the disease process.

Mild Cognitive Impairment: Ten Years Later

In the past 10 years, there has been a virtual explosion in the literature concerning the construct of mild cognitive impairment. The interest in this topic demonstrates the increasing emphasis on the identification of the earliest features of cognitive disorders such as Alzheimer disease and other dementias. Mild cognitive impairment represents the earliest clinical features of these conditions and, hence, has become a focus of clinical, epidemiologic, neuroimaging, biomarker, neuropathological, disease mechanism, and clinical trials research. This review summarizes the progress that has been made while also recognizing the challenges that remain.

Aging, memory, and mild cognitive impairment

In recent years, patients who are at high risk for developing Alzheimers disease (AD) have become a focus of study. Several research groups have identified these patients, developed diagnostic criteria, and followed the patients longitudinally. These patients therefore constitute a clinical entity that is suitable for therapeutic interventions. In this article, we report our 5-year experience at the Mayo Clinic in characterizing a group of patients with mild cognitive impairment. These subjects were recruited from community-dwelling individuals who were receiving general medical care in the Department of Internal Medicine. They received the diagnosis of mild cognitive impairment if they met the following criteria: (a) complaint of defective memory, (b) normal activities of daily living, (c) normal general cognitive function, (d) abnormal memory function for age, and (e) absence of dementia. In following more than 75 of these patients, some of whom have been studied for as long as 5 years, it appears that approximately 10% to 15% of the subjects evolve to AD each year. We therefore evaluated the cognitive profiles of these patients at the time of their initial diagnosis in an attempt to predict who would remain stable and who would evolve to AD. Certain features of learning and memory performance indicated patients who were more likely to progress, but the strongest predictor was their apolipoprotein E status. The patients who possessed an epsilon 4 allele were more likely to convert to AD at a more rapid rate then those who were not carriers. Our results and similar data from other study groups indicate that diagnostic criteria can be defined for patients who are likely to convert to AD; the natural history of these patients is becoming apparent, and variables that predict ultimate conversion can be defined. Consequently, patients with mild cognitive impairment constitute an important group for study, particularly form the aspect of therapeutic interventions.

Rate of medial temporal lobe atrophy in typical aging and Alzheimer's disease

Objectives: To determine the annual rates of volumetric change of the hippocampus and temporal horn in cognitively normal elderly control subjects and individually matched patients with AD, and to test the hypothesis that these rates were different. Background: Cross-sectional studies consistently reveal cerebral atrophy in elderly nondemented subjects compared with healthy young adults, and greater atrophy in patients with AD relative to elderly control subjects. However, rates of atrophy are estimated most accurately by performing serial measurements in the same individuals. Methods: MRI-based volumetric measurements of the hippocampi and temporal horns were performed in 24 cognitively normal subjects aged 70 to 89 years who were individually matched with respect to gender and age with 24 patients with AD. Each subject underwent an MRI protocol twice, separated by 12 months or more. Results: The mean annual rate of hippocampal volume loss among control subjects was -1.55 ± 1.38% and the temporal horns increased in volume by 6.15 ± 7.69% per year. These rates were significantly greater among AD patients: hippocampus, -3.98 ± 1.92% per year, p < 0.001; temporal horn, 14.16 ± 8.47% per year, p = 0.002. Conclusion: A statistically significant yearly decline in hippocampal volume and an increase in temporal horn volume was identified in elderly control subjects who represent typical aging individuals. These rates were approximately 2.5 times greater in patients with AD than in individually age- and gender-matched control subjects.

An operational approach to National Institute on Aging–Alzheimer's Association criteria for preclinical Alzheimer disease

A workgroup commissioned by the Alzheimers Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines.

Mayo's older americans normative studies: WAIS-R norms for ages 56 to 97

Abstract Data obtained in Mayos Older Americans Normative Studies (MOANS) provide age-specific norms for the Wechsler Adult Intelligence Scale-Revised (WAIS-R) on a sample of 512 cognitively normal persons age 56 to 97. IQ scores derived from these norms are termed “MAYO Verbal, Performance and Full Scale IQs” to differentiate them from traditional WAIS-R IQs. MAYO IQs are, by design, estimates of WAIS-R IQs. A normative procedure that adjusts both for age and also for differences between the WAIS-Rs national normative sample and this projects sample is described. The tables needed to convert WAIS-R raw scores to MAYO IQs are presented for ages 56 through 97. The assumptions that underlie the development of MAYO IQs are discussed. Concordance rates are presented which suggest that MAYO IQs are very similar to traditional WAIS-R IQs at ages where both can be validly calculated. The availability of MAYO IQs should enhance the use of the WAIS-R beyond age 74 and should also assist future research designed...

Neuropsychological tests' norms above age 55: COWAT, BNT, MAE token, WRAT-R reading, AMNART, STROOP, TMT, and JLO

Abstract Age- (> 55 years) and education-based norms are presented for eight neuropsychological tests: COWAT, BNT, MAE Token, WRAT-R Reading, AMNART, STROOP, TMT, and JLO. These data were obtained via several research projects that are known collectively as Mayos Older Americans Normative Studies (MOANS). While this normative information should prove useful for each test, the fact that these norms were simultaneously obtained from the same reference group should promote accuracy in the comparison of any persons performance on one test against his or her functioning on any other tests with MOANS norms. Finally, the unique features of this MOANS sample are reviewed. These features must be kept in mind when these norms are applied in any specific clinical or research setting.

MRI hippocampal volumes and memory function before and after temporal lobectomy

We investigated the relationship between preoperative MRI hippocampal volumes and clinical neuropsychological memory test data obtained before and after temporal lobectomy and amygdalohippocampectomy for intractable epilepsy in 44 left (LTL) and 36 right (RTL) temporal lobectomy patients. In LTL patients, the difference (right minus left hippocampal volume) between hippocampal volumes (DHF) was significantly (p < 0.001) correlated (r = 0.61) with postoperative verbal memory change as measured by a delayed memory percent retention score from the Wechsler Memory Scale-Revised, Logical Memory subtest. DHF was also positively associated with postoperative memory for abstract geometric designs in LTL patients (r = 0.49, p < 0.005). Resection of a relatively nonatrophic left hippocampus was associated with poorer verbal and visual memory outcome. In RTL patients, larger right adjusted (for total intracranial volume) hippocampal volume was associated with decline in visual-spatial learning, but not memory, following surgery. MRI hippocampal volume data appear to provide meaningful information in evaluating the risk for memory impairment following temporal lobectomy.

Detecting Dementia With the Mini-Mental State Examination in Highly Educated Individuals

OBJECTIVE To evaluate the utility of Mini-Mental State Examination (MMSE) scores in detecting cognitive dysfunction in a sample of highly educated individuals. DESIGN Archival data were reviewed on 4248 participants enrolled in the Mayo Clinic Alzheimer Disease Research Center and Alzheimer Disease Patient Registry. PATIENTS A total of 1141 primarily white (93%) individuals with 16 or more years of self-reported education were identified. These included 307 (164 men and 143 women) patients with dementia (any type), 176 (106 men and 70 women) patients with mild cognitive impairment, and 658 (242 men and 416 women) control participants without dementia. SETTING Mayo Clinic Alzheimer Disease Research Center and Alzheimer Disease Patient Registry cohort. MAIN OUTCOME MEASURES Diagnostic accuracy estimates (sensitivity, specificity, and positive and negative predictive power) of MMSE cut scores in detecting cognitive dysfunction. RESULTS In this sample of highly educated, largely white older adults, the standard MMSE cut score of 24 (23 or below) yielded a sensitivity of 0.66, a specificity of 0.99, and an overall correct classification rate of 89% in detecting dementia. A cut score of up to 27 (26 or below) resulted in an optimal balance of sensitivity and specificity (0.89 and 0.91, respectively) with an overall correct classification rate of 90%. In a cognitively impaired group (dementia and mild cognitive impairment), a cut score of 27 (sensitivity, 0.69; specificity, 0.91) or 28 (sensitivity and specificity, 0.78) might be more appropriate. CONCLUSION Older patients with a college education who present with complaints of cognitive decline (reported by themselves or others) and score less than 27 on the MMSE are at a greater risk of being diagnosed with dementia and should be referred for a comprehensive dementia evaluation, including formal neuropsychological testing.