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Structural neuroimaging studies in subjects with mild cognitive impairment
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The importance of early identification of dementia has prompted numerous investigations of mild cognitive impairment and the preclinical stages of progressive degenerative disorders. To date, there is limited information from large-scale studies regarding outcomes of persons specifically identified with cognitive impairment but no dementia (CIND).
To investigate outcomes for persons with no cognitive impairment (NCI) or CIND, focusing on its etiologic subcategories, from the Canadian Study of Health and Aging (CSHA) and to examine the predictive validity of a set of core features thought to be early manifestations of subsequent dementia.
Five-year, longitudinal follow-up of all persons without dementia examined during the first phase of the CSHA in 1991.
Community and institutional settings.
Population-based sample of 883 persons with NCI and 801 persons with CIND at the first phase of the CSHA. At follow-up, 517 persons with NCI (59%) and 327 persons with CIND (41%) were alive and received clinical diagnoses.
Mortality, institutionalization, and clinical diagnoses using the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria for dementia.
Persons with CIND were more likely than those with NCI to die (49% vs 30%), to be admitted to facility care (29% vs 14%), or to receive diagnoses of dementia (47% vs 15%) at follow-up. Those subsequently diagnosed as having dementia were more likely to have had impaired memory, informant-reported change in memory, and functional impairment at baseline.
Persons with CIND were more likely to have a negative outcome than persons with NCI during a 5-year interval. This was true across etiologic subcategories and suggests that the use of specific diagnostic criteria sets does not improve our identification of those who develop dementia compared with a broader, more inclusive approach. More factors contributed to the prediction of all forms of dementia than to AD, but the most accurate prediction was for those who remained dementia free.
Sixty patients with senile dementia of the Alzheimer type (DAT) and 30 age and sex-matched healthy controls were examined by cranial computed tomography (CT). We undertook this study to evaluate a simple and unbiased quantitative method for the estimation of ventricular and subarachnoid spaces by measuring areas of defined Hounsfield units (HUs) in four symmetric quadrants: left and right anterior, left and right posterior. The DAT patients showed a significant enlargement of all ventricles and all measured subarachnoid spaces (p< 0.001). These effects were not related to the age but to the diagnosis. They correlated with the duration of disease and partly with the degree of global cognitive impairment. Seventy-eight per cent of the patients and controls could be classified correctly by means of the planimetric measurements.
Early and accurate diagnosis of Alzheimer's disease (AD) has a major impact on the progress of research on dementia. To address the problems involved in diagnosing AD in its earliest stages, the National Institute on Aging, the American Association of Retired Persons, the National Institute of Neurological and Communicative Disorders and Stroke, and the National Institute of Mental Health jointly sponsored a workshop for planning research.
The purpose of the meeting was to identify the most important scientific research opportunities and the crucial clinical and technical issues that influence the progress of research on the diagnosis of AD. The 37 participants included some of the most knowledgeable and eminent scientists and physicians actively involved in the study of AD. The participants were divided among six panels representing the disciplines of neurochemistry, neuropathology, neuroradiology, neurology, neuropsychology, and psychiatry. Within each of the panels, participants discussed specific areas of research requiring further
We investigated the influence of the apolipoprotein (ApoE) ε4 allele on the rate of brain atrophy in patients with clinical dementia and in subjects at risk for dementia. Eighty-one subjects, consecutively referred to a memory clinic due to symptoms of dementia, went through a comprehensive examination, including cerebral magnetic resonance imaging. After an initial investigation these subjects were divided into one of six diagnostic groups; Alzheimer’s disease (AD, n = 23), objective cognitive impairment (OCI, n = 27), subjective cognitive impairment (SCI, n = 17), vascular dementia (VaD), frontotemporal dementia (FTD) and unspecified dementia (USD). The last three groups were joined into one diagnostic group designated ‘other dementia’ (OD, altogether n = 14). In order to study the progression of cognitive impairment as well as the rate of atrophy in different brain regions all subjects were reinvestigated after an average period of 16 monhts. Interest was focused on investigating if those subjects with one or two ε4 alleles differed in either dementia progression or rate of brain atrophy compared to those without the ε4 allele. We found that the ApoE ε4 carriers had a statistically significantly larger increase in ventricular volume as compared with the ApoE ε4 noncarriers. In all diagnostic groups the ApoE ε4 carriers showed a greater rate of ventricular volume increase, as compared to the noncarriers. However, this difference was statistically significant only for the OD subjects. No statistical significant changes over time were seen for whole brain volume or volume of the temporal lobes and the medial temporal lobes. The diagnostic groups differed in dementia progression with the AD subjects having the most pronounced reduction in MMSE scores as compared to subjects at risk for AD (OCI and SCI subjects). The presence of ApoE ε4 allele did not influence the change in MMSE in any of the diagnostic groups.
We pooled clinical and research experience to suggest revised criteria for diagnosing age‐associated memory impairment and to propose guidelines for identifying more select subgroups with age‐consistent memory impairment and late‐life forgetfulness.
In recent years, patients who are at high risk for developing Alzheimer's 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 ε4 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 from the aspect of therapeutic interventions.
In 1962, based on a study of nursing home residents, Kral suggested a distinction between benign and malignant senescent forgetfulness, the latter evolving to dementia and early death and the former remaining relatively static. Although this concept was never operationally described or validated, it clearly rang true with those working with the nascent specialty of geriatric psychiatry and rapidly entered standard textbooks on the subject. The burgeoning of interest in the elderly and the massive expansion of clinical and research work in the field of dementia in the eighties led to a widely expressed need for the development of criteria to categorize a group of subjects with memory problems falling short of dementia. The National Institute of Mental Health (NIMH) responded with the formation of a working group that published its suggested criteria for what Crook et al. (1986) called “age-associated memory impairment” (AAMI). Although some of the detailed components of these criteria have proved controversial, the term has been increasingly quoted in relevant literature and has given rise to specific studies. It has led to wide discussion, and related entities have been incorporated both in the draft of DSM-IV (as “aging-associated cognitive decline [AACD]” [American Psychiatric Association, 1993], an “additional condition that may be the focus of clinical attention”) and in the research criteria for ICD-10 (World Health Organization, 1993), where it is potentially classifiable under FO6.7 Mild Cognitive Disorder, although this does not specifically give aging as a cause. In arriving at our provisional criteria we have drawn to a great degree on these and other related publications that we are pleased to acknowledge.
The cornu ammonis 1 region of the hippocampus (CA1) sector of hippocampus is vulnerable to both Alzheimer's disease (AD)-type neurofibrillary degeneration and anoxia–ischemia. The objective of this article is to compare number and size of neurons in CA1 in AD versus ischemic vascular dementia. Unbiased stereological methods were used to estimate the number and volume of neurons in 28 autopsy-derived brain samples. For each case, the entire hippocampus from one cerebral hemisphere was sliced into 5mm slabs (5–7 slabs/case), cut into 50μm sections, and stained with gallocyanine. Using the optical dissector, we systematically sampled the number and size of neurons throughout the extent of CA1 and CA2. The total number of neurons was significantly less in AD compared with ischemic vascular dementia (p < 0.02), but there was no significant difference in neuron size. The greatest loss of neurons was observed in two cases with combined AD and hippocampal sclerosis. Regardless of causative diagnosis, the number of CA1 neurons correlates with magnetic resonance imaging–derived hippocampal volume (r = 0.72; p < 0.001) and memory score (r = 0.62; p < 0.01). We conclude that although CA1 neuron loss is more consistently observed in AD than ischemic vascular dementia, severity of loss shows the expected correlation with structure and function across causative subtype. Reductions in magnetic resonance imaging–derived hippocampal volume reflect loss, rather than shrinkage, of CA1 neurons. Ann Neurol 2005;57:896–903
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.
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.
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.
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.