To test the hypothesis that the atrophy rate measured from serial MRI studies is associated with time to subsequent clinical conversion to a more impaired state in both cognitively healthy elderly ...subjects and in subjects with amnestic mild cognitive impairment (MCI).
Ninety-one healthy elderly patients and 72 patients with amnestic MCI who met inclusion criteria were identified from the Mayo Alzheimer's Disease Research Center and Alzheimer's Disease Patient Registry. Atrophy rates of four different brain structures--hippocampus, entorhinal cortex, whole brain, and ventricle--were measured from a pair of MRI studies separated by 1 to 2 years. The time of the second scan marked the beginning of the clinical observation period.
During follow-up, 13 healthy patients converted to MCI or Alzheimer disease (AD), whereas 39 MCI subjects converted to AD. Among those healthy at baseline, only larger ventricular annual percent volume change (APC) was associated with a higher risk of conversion (hazard ratio for a 1-SD increase 1.9, p = 0.03). Among MCI subjects, both greater ventricular volume APC (hazard ratio for a 1-SD increase 1.7, p < 0.001) and greater whole brain APC (hazard ratio for a 1-SD increase 1.4, p = 0.007) increased the risk of conversion to AD. Both ventricular APC (hazard ratio for a 1-SD increase 1.59, p = 0.001) and whole brain APC (hazard ratio for a 1-SD increase 1.32, p = 0.009) provided additional predictive information to covariate-adjusted cross-sectional hippocampal volume at baseline about the risk of converting from MCI to AD.
Higher whole brain and ventricle atrophy rates 1 to 2 years before baseline are associated with an increased hazard of conversion to a more impaired state. Combining a measure of hippocampal volume at baseline with a measure of either whole brain or ventricle atrophy rates from serial MRI scans provides complimentary predictive information about the hazard of subsequent conversion from mild cognitive impairment to Alzheimer disease. However, overlap among those who did vs those who did not convert indicate that these measures are unlikely to provide absolute prognostic information for individual patients.
We investigated the prevalence of mild cognitive impairment (MCI) in Olmsted County, MN, using in-person evaluations and published criteria.
We evaluated an age- and sex-stratified random sample of ...Olmsted County residents who were 70-89 years old on October 1, 2004, using the Clinical Dementia Rating Scale, a neurologic evaluation, and neuropsychological testing to assess 4 cognitive domains: memory, executive function, language, and visuospatial skills. Information for each participant was reviewed by an adjudication panel and a diagnosis of normal cognition, MCI, or dementia was made using published criteria.
Among 1,969 subjects without dementia, 329 subjects had MCI, with a prevalence of 16.0% (95% confidence interval CI 14.4-17.5) for any MCI, 11.1% (95% CI 9.8-12.3) for amnestic MCI, and 4.9% (95% CI 4.0-5.8) for nonamnestic MCI. The prevalence of MCI increased with age and was higher in men. The prevalence odds ratio (OR) in men was 1.54 (95% CI 1.21-1.96; adjusted for age, education, and nonparticipation). The prevalence was also higher in subjects who never married and in subjects with an APOE epsilon3epsilon4 or epsilon4epsilon4 genotype. MCI prevalence decreased with increasing number of years of education (p for linear trend <0.0001).
Our study suggests that approximately 16% of elderly subjects free of dementia are affected by MCI, and amnestic MCI is the most common type. The higher prevalence of MCI in men may suggest that women transition from normal cognition directly to dementia at a later age but more abruptly.
To correlate different methods of measuring rates of brain atrophy from serial MRI with corresponding clinical change in normal elderly subjects, patients with mild cognitive impairment (MCI), and ...patients with probable Alzheimer disease (AD).
One hundred sixty subjects were recruited from the Mayo Clinic Alzheimer's Disease Research Center and Alzheimer's Disease Patient Registry Studies. At baseline, 55 subjects were cognitively normal, 41 met criteria for MCI, and 64 met criteria for AD. Each subject underwent an MRI examination of the brain at the time of the baseline clinical assessment and then again at the time of a follow-up clinical assessment, 1 to 5 years later. The annualized changes in volume of four structures were measured from the serial MRI studies: hippocampus, entorhinal cortex, whole brain, and ventricle. Rates of change on several cognitive tests/rating scales were also assessed. Subjects who were classified as normal or MCI at baseline could either remain stable or convert to a lower-functioning group. AD subjects were dichotomized into slow vs fast progressors.
All four atrophy rates were greater among normal subjects who converted to MCI or AD than among those who remained stable, greater among MCI subjects who converted to AD than among those who remained stable, and greater among fast than slow AD progressors. In general, atrophy on MRI was detected more consistently than decline on specific cognitive tests/rating scales. With one exception, no differences were found among the four MRI rate measures in the strength of the correlation with clinical deterioration at different stages of the disease.
These data support the use of rates of change from serial MRI studies in addition to standard clinical/psychometric measures as surrogate markers of disease progression in AD. Estimated sample sizes required to power a therapeutic trial in MCI were an order of magnitude less for MRI than for change measures based on cognitive tests/rating scales.
Although incidence rates for mild cognitive impairment (MCI) have been reported, few studies were specifically designed to measure the incidence of MCI and its subtypes using published criteria. We ...estimated the incidence of amnestic MCI (aMCI) and nonamnestic MCI (naMCI) in men and women separately.
A population-based prospective cohort of Olmsted County, MN, residents ages 70-89 years on October 1, 2004, underwent baseline and 15-month interval evaluations that included the Clinical Dementia Rating scale, a neurologic evaluation, and neuropsychological testing. A panel of examiners blinded to previous diagnoses reviewed data at each serial evaluation to assess cognitive status according to published criteria.
Among 1,450 subjects who were cognitively normal at baseline, 296 developed MCI. The age- and sex-standardized incidence rate of MCI was 63.6 (per 1,000 person-years) overall, and was higher in men (72.4) than women (57.3) and for aMCI (37.7) than naMCI (14.7). The incidence rate of aMCI was higher for men (43.9) than women (33.3), and for subjects with ≤12 years of education (42.6) than higher education (32.5). The risk of naMCI was also higher for men (20.0) than women (10.9) and for subjects with ≤12 years of education (20.3) than higher education (10.2).
The incidence rates for MCI are substantial. Differences in incidence rates by clinical subtype and by sex suggest that risk factors for MCI should be investigated separately for aMCI and naMCI, and in men and women.
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).
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.
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.
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.
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.
In older patients with MCI, hippocampal atrophy determined by premorbid MRI-based volume measurements is predictive of subsequent conversion to AD.
The authors assessed whether measures of hippocampal water diffusivity at baseline can predict future progression to Alzheimer disease (AD) in amnestic mild cognitive impairment (aMCI). Higher ...baseline hippocampal diffusivity was associated with a greater risk of progression to AD in aMCI (p = 0.002). Magnetic resonance diffusion-weighted imaging may help identify patients with aMCI who will progress to AD as well as or better than structural MRI measures of hippocampal atrophy.
To 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.
An 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.
Individuals 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).
Hippocampal 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.
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.
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).
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.
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%.
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.
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.
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.
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.
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.
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.
To determine whether an fMRI memory encoding task distinguishes among cognitively normal elderly individuals, patients with mild cognitive impairment (MCI), and patients with early Alzheimer's ...disease (AD).
Twenty-nine subjects (11 normal, 9 MCI, 9 AD) were studied with an fMRI memory encoding task. A passive sensory task was also performed to assess potential intergroup differences in fMRI responsiveness. Activation in the medial temporal lobe for the memory task and in the anatomic rolandic area for the sensory task was studied. Intergroup comparisons were performed using receiver operating characteristic (ROC) analyses. The ROC method provides rigorous control of artifactual false-positive "activation." Subjects were tested for recall and recognition of the encoding task stimuli following the fMRI study.
Medial temporal lobe activation was greater in normal subjects than MCI and AD patients (p = 0.03 and p = 0.04). There was no difference between AD and MCI patients in fMRI memory performance corrected. There was an association between fMRI memory activation (area under the ROC curve) and post-fMRI performance on recognition and free recall. There was no difference among the three groups on the sensory task.
MCI and AD patients had less medial temporal lobe activation on the memory task than the normal subjects but similar activation as normal subjects on the sensory task. These findings suggest decreased medial temporal activation may be a specific marker of limbic dysfunction due to the neurodegenerative changes of AD. In addition, fMRI is sufficiently sensitive to detect changes in the prodromal, MCI, phase of the disease.
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