Emre Kokmen

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.

Rates of Hippocampal Atrophy Correlate with Change in Clinical Status in Aging and AD

Background: The cognitive continuum in the elderly population can be conceptually divided into those who are functioning normally (control subjects), those with a mild cognitive impairment (MCI), and those with probable AD. Objectives: To test the hypothesis that the annualized rates of hippocampal atrophy differ as a function of both baseline and change in clinical group membership (control, MCI, or AD). Methods: The authors identified 129 subjects from the Mayo Clinic AD Research Center/AD Patient Registry who met established criteria for normal control subjects, MCI, or probable AD, both at entry and at the time of a subsequent clinical follow-up evaluation 3 ± 1 years later. Each subject underwent an MRI examination of the head at the time of the initial assessment and at follow-up clinical assessment; the annualized percentage change in hippocampal volume was computed. Subjects who were classified as controls or patients with MCI at baseline could either remain cognitively stable or could decline to a lower functioning group over the period of observation. Results: The annualized rates of hippocampal volume loss for each of the three initial clinical groups decreased progressively in the following order: AD > MC > control. Within the control and MCI groups, those who declined had a significantly greater rate of volume loss than those who remained clinically stable. The mean annualized rates of hippocampal atrophy by follow-up clinical group were: control-stable 1.73%, control-decliner 2.81%, MCI-stable 2.55%, MCI-decliner 3.69%, AD 3.5%. Conclusion: Rates of hippocampal atrophy match both baseline cognitive status and the change in cognitive status over time in elderly persons who lie along the cognitive continuum from normal to MCI to AD.

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.

Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia.

ObjectivesTo assess the diagnostic specificity of MRI-defined hippocampal atrophy for AD among individuals with a variety of pathologically confirmed conditions associated with dementia as well as changes attributable to typical aging, and to measure correlations among premortem MRI measurements of hippocampal atrophy, mental status examination performance, and the pathologic stage of AD. MethodsAn unselected series of 67 individuals participating in the Mayo Alzheimer’s Disease Research Center/Alzheimer’s Disease Patient Registry who had undergone a standardized antemortem MRI study and also postmortem examination were identified. Hippocampal volumes were measured from antemortem MRI. Each postmortem specimen was assigned a pathologic diagnosis and in addition, the severity of AD pathology was staged using the method of Braak and Braak. ResultsIndividuals with an isolated pathologic diagnosis of AD, hippocampal sclerosis, frontotemporal degeneration, and neurofibrillary tangle–only degeneration usually had substantial hippocampal atrophy, while those with changes of typical aging did not. Among all 67 subjects, correlations (all p < 0.001) were observed between hippocampal volume and Braak and Braak stage (r = −0.39), between hippocampal volume and Mini-Mental State Examination (MMSE) score (r = 0.60), and between MMSE score and Braak and Braak stage (r = −0.41). ConclusionsHippocampal atrophy, while not specific for AD, was a fairly sensitive marker of the pathologic AD stage (particularly among subjects with isolated AD pathology [r = −0.63, p = 0.001]) and consequent cognitive status.

Regional metabolic patterns in mild cognitive impairment and Alzheimer’s disease A 1H MRS study

Background: Mild cognitive impairment (MCI) is a recently described transitional clinical state between normal aging and AD. Assuming that amnestic MCI patients had pathologic changes corresponding to an early phase and probable AD patients to a later phase of the disease progression, the authors could approximate the temporal course of proton MR spectroscopic (1H MRS) alterations in AD with a cross-sectional sampling scheme. Methods: The authors compared 1H MRS findings in the superior temporal lobe, posterior cingulate gyri, and medial occipital lobe in 21 patients with MCI, 21 patients with probable AD, and 63 elderly controls. These areas are known to be involved at different neurofibrillary pathologic stages of AD. Results: The N-acetylaspartate (NAA)/creatine (Cr) ratios were significantly lower in AD patients compared to both MCI and normal control subjects in the left superior temporal and the posterior cingulate volumes of interest (VOI) and there were no between-group differences in the medial occipital VOI. Myoinositol (MI)/Cr ratios measured from the posterior cingulate VOI were significantly higher in both MCI and AD patients than controls. The choline (Cho)/Cr ratios measured from the posterior cingulate VOI were higher in AD patients compared to both MCI and control subjects. Conclusion: These findings suggest that the initial 1H MRS change in the pathologic progression of AD is an increase in MI/Cr. A decrease in NAA/Cr and an increase in Cho/Cr develop later in the disease course.

Usefulness of MRI measures of entorhinal cortex versus hippocampus in AD

Objective: MRI-based measurements of hippocampal atrophy are a sensitive indicator of the early pathologic degeneration of the medial temporal lobe in AD. However, AD pathology appears first in the transentorhinal/entorhinal cortex, not the hippocampus. The authors tested the hypothesis that MRI-based measurements of the entorhinal cortex are more sensitive than measurements of hippocampal volume in discriminating among three clinical groups; controls, patients with a mild cognitive impairment (MCI), and patients with mild probable AD. Methods: The authors studied 30 controls, 30 patients with MCI, and 30 patients with AD who were matched among clinical groups on age, gender, and education. All underwent a standardized MRI protocol from which the authors made measurements of hippocampal volume, entorhinal cortex volume, and the cumulative length of the medial border of the entorhinal cortex. Results: Pairwise intergroup differences (p < 0.01) were found for all MRI measurements with the exception of the cumulative length of the entorhinal cortex, which did not differentiate controls from MCI patients. Whereas the hippocampal and entorhinal cortex volume measurements provided slightly better intergroup discrimination than the entorhinal distance measurement, overall differences in discriminating ability among the three MRI measurements were minor. Conclusions: Despite the theoretical rationale for the superiority of entorhinal measurements in early AD, the authors found MRI measurements of the hippocampus and entorhinal cortex were approximately equivalent at intergroup discrimination. Measurements of the hippocampus may be preferable because MRI depiction of the boundaries of the entorhinal cortex can be obscured by anatomic ambiguity, image artifact, or both.

Dementia after ischemic stroke A population-based study in Rochester, Minnesota (1960-1984)

Article abstract-We used the medical records linkage system for the population of Rochester, Minnesota, to identify persons in the community who had their first cerebral infarct without previous dementia. In this cohort (n = 971), the incidence of dementia in the first year was nine times greater than expected, but if we did not observe dementia in the first year, the risk of dementia in the cohort each year thereafter was about twice the risk in the population. After the first year, a 50% increase was observed in Alzheimers disease in the cohort compared with that in the community. Although the incidence of dementia increased with increasing age, the standardized morbidity ratios decreased with increasing age. Age, sex (male), and second stroke were significant independent predictors of dementia in a multivariate Cox proportional hazards model. There was no effect of location or clinical severity of infarct on the rate of occurrence of dementia. NEUROLOGY 19;: 154-159

REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease.

Background: REM sleep behavior disorder (RBD) has been reported with various neurodegenerative disorders, most frequently in disorders with Lewy body pathology. RBD often precedes the onset of PD, and a recent prospective study showed that 38% of patients with RBD eventually developed PD. Methods: We identified 37 patients with degenerative dementia and a history of bursts of vigorous movement of the arms and legs with vocalization during sleep and associated with dream recall. Patients with and without two or more signs of parkinsonism were compared. Clinical, laboratory, and neuropsychometric features were analyzed, and criteria for the clinical diagnosis of dementia with Lewy bodies (DLB) were applied to all patients. Results: Thirty-four of the 37 patients were male with mean age at onset of 61.5 years for RBD and 68.1 years for cognitive decline. RBD commenced before or concurrently with dementia in all patients but two. Parkinsonism (two or more signs) occurred in 54% of the sample (20/37), with a mean age at onset of 69.1 years. Polysomnography (PSG) confirmed RBD in all patients studied. Neuropsychological testing demonstrated impaired perceptual-organizational skills, verbal fluency, and marked constructional dyspraxia in more than one-half the patients. There were no statistically significant differences in the frequency of clinical features or in neuropsychological performance between patients with and without parkinsonism. Thirty-four patients (92%) met criteria for clinically possible or probably DLB. Three patients were autopsied; all had limbic with or without neocortical Lewy bodies. Conclusions: We report a group of predominantly male patients with a characteristic association of RBD and degenerative dementia. The clinical and neuropsychometric features of the groups of patients with and without parkinsonism are similar. We hypothesize that the underlying pathology in these patients is DLB.