The utility of age-specific cut-offs for visual rating of medial temporal atrophy in classifying Alzheimer's disease, MCI and cognitively normal elderly subjects.

BACKGROUND: New research criteria for diagnosing Alzheimer's disease (AD) in the mild cognitive impairment stage (MCI-AD) incorporate biomarkers to assign a level of certainty to the diagnosis. Structural MRI is widely available but greatly under-utilized for assessing atrophy of structures affected in early AD, such as the hippocampus (HP), because the quantification of HP volumes (HP-v) requires special expertise, and normative values have not been established. METHODS: Elderly subjects (n =273) from the Florida ADRC were classified as having no cognitive impairment (cognitively normal, CN), amnestic mild cognitive impairment (aMCI) or AD. Volumes for the hippocampus (HP-v) were measured on structural MRI scans. A validated visual rating system for measuring medial temporal atrophy (VRS-MTA), including hippocampal, entorhinal cortex and perirhinal cortex atrophy was employed. The participants were subdivided into younger (less than or equal to 75 years of age) and older (greater than 75 years of age) subgroups. RESULTS: Volumetric and VRS-MTA measures were equivalent in predicting classification of CN vs. aMCI for older (area under the receiver operator curves [aROC]: 0.652 vs. 0.723) and younger subjects (aROC: 0.764 vs. 0.736). However, for younger AD subjects, aROC values were significantly higher for VRS-MTA measures (0.920) than for volumetric measures (0.847). Relative to HP-v, VRS-MTA score was significantly more correlated to impairment on a range of memory tests and was more associated with progression of aMCI to AD than HP-v. CONCLUSION: Structural MRI with VRS-MTA assessment can serve as a biomarker for supporting the diagnosis of MCI-AD. Age-adjusted VRS-MTA scores are at least as effective as HP-v for distinguishing aMCI and AD from CN and for predicting progression from aMCI to AD. VRS-MTA is convenient for use in the clinic as well as for clinical trials and can readily be incorporated into a standardized radiological report.

Cognitive and structural magnetic resonance imaging features of Lewy body dementia and Alzheimer's disease.

OBJECTIVE: To assess medial temporal atrophy (MTA) and atrophy adjacent to the third ventricle (Peri-IIIVent) on brain magnetic resonance images as biomarkers for the diagnosis of Alzheimer's disease (AD) and Lewy body dementia (LBD), and to assess the relationship between biomarkers and clinical and functional measures. METHODS: Subjects diagnosed with no cognitive impairment (n = 30), AD (n = 30), or LBD (n = 31) were evaluated with the Mini-Mental State Examination, Multiple Delayed Recall Test, Category Fluency Test, Clinical Dementia Rating Sum of Boxes score, Functional Assessment Questionnaire, and the Unified Parkinson's Disease Rating Scale. A validated visual rating system was used to rate MTA, and volumetric studies were performed to measure total intracranial and hippocampal volumes. Additionally, linear measurements of third ventricle width, Peri-IIIVent height, and Peri-IIIVent width were performed. RESULTS: Subjects with AD and those with LBD were equivalent with respect to age and levels of cognitive impairment. Atrophy in medial temporal and Peri-IIIVent regions was greater among both patients with AD and those with LBD compared with subjects with no cognitive impairment. The best discriminators of AD from LBD were the severity of MTA, using visual rating, and the severity of memory impairment. Only subjects with LBD showed significant correlations between Unified Parkinson's Disease Rating Scale scores and Peri-IIIVent atrophy measures. CONCLUSIONS: Mild AD could be distinguished from mild LBD by the severity of MTA and memory impairment. The severity of parkinsonism was associated with the severity of atrophy in the third ventricular region, but was not a good discriminator between AD and LBD.

Minimal atrophy of the entorhinal cortex and hippocampus: progression of cognitive impairment.

BACKGROUND: In Alzheimer's disease, neurodegenerative atrophy progresses from the entorhinal cortex (ERC) to the hippocampus (HP), limbic system and neocortex. The significance of very mild atrophy of the ERC and HP on MRI scans among elderly subjects is unknown. METHODS: A validated visual rating system on coronal MRI scans was used to identify no atrophy of the HP or ERC (HP(0); ERC(0)), or minimal atrophy of the HP or ERC (HP(ma); ERC(ma)), among 414 participants. Subjects fell into the following groups: (1) ERC(0)/HP(0), (2) ERC(ma)/HP(0), (3) ERC(0)/HP(ma), and (4) ERC(ma)/HP(ma). HP volume was independently measured using volumetric methods. RESULTS: In comparison to ERC(0)/HP(0) subjects, those with ERC(0)/HP(ma) had impairment on 1 memory test, ERC(ma)/HP(0) subjects had impairment on 2 memory tests and the Mini Mental State Examination (MMSE), while ERC(ma)/HP(ma) subjects had impairment on 3 memory tests, the MMSE and Clinical Dementia Rating. Progression rates of cognitive and functional impairment were significantly greater among subjects with ERC(ma). CONCLUSION: Minimal atrophy of the ERC results in greater impairment than minimal atrophy of the HP, and the combination is additive when measured by cognitive and functional tests. Rates of progression to greater impairment were higher among ERC(ma) subjects.

The utility of a brief memory screen in the diagnosis of mild memory impairment in the elderly: preliminary study.

OBJECTIVE: This study evaluated the utility of the Florida Brief Memory Screen (FBMS), a new memory screening measure developed for Spanish-speaking and English-speaking subjects, which takes only 3-4 minutes to administer. METHODS: The FBMS was administered to 25 patients with probable Alzheimer disease, 23 patients with amnestic mild cognitive impairment, and 80 cognitively normal elderly. RESULTS: The FBMS evidenced good test-retest reliability and high correlation with standard measures of memory. In receiver operating characteristic analyses, the FBMS correctly classified 100% of patients with probable Alzheimer disease and 87.5% of normal elderly subjects. Sensitivity and specificity for patients with amnestic mild cognitive impairment was 82.6% and 87.5%, respectively. Performance on the FBMS was generally independent of the effects of age, education, or primary language. CONCLUSION: The FBMS is a reliable and a valid measure when screening for memory impairment in the elderly and when determining whether a more extensive evaluation is warranted.

Stability of different subtypes of mild cognitive impairment among the elderly over a 2- to 3-year follow-up period.

BACKGROUND/AIMS: To investigate the longitudinal stability and progression of different subtypes of mild cognitive impairment (MCI) in older adults. METHODS: We classified 217 individuals with no cognitive impairment (NCI), amnestic MCI (aMCI) based on a single test (aMCI-1) or multiple tests (aMCI-2+), nonamnestic MCI (naMCI) based on a single test (naMCI-1) or multiple tests (naMCI-2+), or amnestic + nonamnestic MCI (a+naMCI), using their baseline neuropsychological test scores, and performed annual follow-up evaluations for up to 3 years. RESULTS: None of the subjects with aMCI-2+ reverted to normal during follow-up, with 50% of these subjects remaining stable and 50% worsening over time. Similarly, less than 20% of subjects with aMCI-2+ and a+naMCI reverted to NCI during the follow-up period, whereas 50% of aMCI-1 and 37% with naMCI-1 reverted to NCI during this same period. CONCLUSION: Reversion to NCI occurs much more frequently when the diagnosis of MCI is based on the results of a single neuropsychological test than when it is based on the results of more memory tests. In epidemiological studies and clinical trials the diagnosis of MCI will likely be more stable if impairment on more than one test is required for amnestic and/or nonamnestic domains.

Severity of medial temporal atrophy and amnestic mild cognitive impairment: selecting type and number of memory tests.

OBJECTIVE: Medial temporal lobe atrophy (MTA) can be used as a biomarker of pathology that affects mechanisms of episodic memory. The authors compared the strength of this biomarker with performance on four memory measures and examined the influence of demographic factors including age, level of education, and primary language (English or Spanish). METHODS: The Hopkins Verbal Learning Test-revised, Fuld Object Memory Evaluation (FOME), delayed memory for a story passage, and delayed visual reproduction of the Wechsler Memory Scale-revised tests were administered to 281 subjects who were diagnosed as having no cognitive impairment, mild cognitive impairment (MCI), impaired non-MCI, or dementia. MTA scores were obtained from visual ratings of the hippocampus, entorhinal cortex, and perirhinal cortex on coronal magnetic resonance imaging scans using a magnetization-prepared rapid gradient echo protocol. RESULTS: Age was associated with scores on all memory measures and MTA. Level of educational attainment had no influence on FOME performance but had greater associations with scores on other memory measures. In regression models, FOME scores had the strongest relationship with MTA scores, accounting for 31% of the explained variability. Among subjects with MCI, an index representing the total number of memory tests that were impaired was also predictive of the severity of MTA scores. CONCLUSION: Among four common tests of memory, the FOME was highly associated with MTA, and it exhibited minimal influences of education. Impairment on more than one memory test was more predictive of MTA than impairment on a single memory test.

Vulnerability to proactive semantic interference and progression to dementia among older adults with mild cognitive impairment.

There is evidence that vulnerability to proactive semantic interference may be an early manifestation of early Alzheimer's disease and other neurodegenerative disorders. At present, there is a paucity of data regarding the extent to which such deficits relate to the progression of cognitive deficits and to clinically significant endpoints such as dementia. In this study, we followed 76 older adults, initially diagnosed with mild cognitive impairment, for a period of up to 3 years. Twenty-seven of these individuals (35.5%) progressed from mild cognitive impairment to dementia. An examination of baseline neuropsychological performance indicated lower baseline scores for object memory among those progressing to dementia. However, baseline Mini-Mental State Examination scores, delayed memory for passages, delayed visual memory, letter fluency, category fluency, Trails B and Block Design did not differ among study groups. In contrast, the Semantic Interference Test, a measure susceptible to vulnerability to proactive semantic interference showed the greatest baseline differentiation between those who progressed and those who did not progress to dementia. Further, scores on this measure predicted future progression to dementia with high accuracy. Vulnerability to proactive interference may be an early manifestation of an early dementing process and may have utility in predicting future progression to dementia.

Influence of sociodemographic variables on neuropsychological test performance in Spanish-speaking older adults.

There is limited information regarding the impact of sociodemographic variables on the neuropsychological test performance of the Spanish-speaking older adult residing in the United States (US). This study examines the influence of age, education, gender, age of arrival in the US, percentage of lifetime in the US, acculturation, and reported depressive symptoms on neuropsychological test performance in a group of cognitively normal Spanish-speaking elders, the majority of whom were Cuban born. Educational attainment had a broad effect on test scores, with the other variables having only limited effects. These results underscore the impact of educational attainment on neuropsychological test performance among the cognitively normal Spanish-speaking older adult.

The use of amnestic and nonamnestic composite measures at different thresholds in the neuropsychological diagnosis of MCI.

Both amnestic and nonamnestic deficits have been observed in patients with mild cognitive impairment (MCI). Most studies have focused on impairment on single cognitive tests rather than amalgamation of the results of several measures to arrive at a composite impairment index. In this investigation, we examined 20 MCI patients diagnosed as prodromal Alzheimer's disease, AD (mean Mini-Mental State Examination, MMSE = 26.1; SD = 1.7) and determined the extent to which they could be differentiated from 70 normal elderly controls based on composite measures at 1.5-SD and 2.0-SD cutoffs for impairment. At the 1.5-SD cutoff, the median number of memory indices impaired in the MCI-AD group was 5 of 7, whereas at the 2.0-SD cutoff, the median number was 4 of 7. A median of 3 of 7 and 2 of 7 nonmemory indices were impaired at 1.5- and 2.0-SD cutoffs for impairment. Receiver operator characteristics (ROC) analyses indicated that the total number of memory tests impaired at 2.0 SD (sensitivity = 95.0%/specificity = 84.3%) and the composite measure of both impaired memory and nonmemory measures (sensitivity of 85.0%/specificity of 100%) had high levels of discrimination and may have utility as indices of early impairment as well as severity of MCI.

Stability of neurocognitive impairment in different subtypes of mild cognitive impairment.

There has been increasing interest in delineating different cognitive subtypes of mild cognitive impairment (MCI). It remains unclear, however, the extent to which neuropsychological impairment associated with amnestic, nonamnestic, and amnestic+ subtypes of MCI remains stable over time. In this study, 70 persons meeting the criteria for MCI and 38 cognitively normal elderly subjects received a baseline neuropsychological evaluation and were reevaluated 1 year later. Our results indicated that 84.6% of the persons initially classified as amnestic, 75% of those classified as nonamnestic, and 80% of the persons classified as MCI+ evidenced stable or more pronounced neuropsychological impairment across the follow-up period. Less than 7% of the amnestic and amnestic+ cases had nonimpaired neuropsychological profiles at their reevaluation at 12 months, and 16.7% of the nonamnestic cases had nonimpaired neuropsychological test profiles at follow-up. Approximately 87% of the cognitively normal subjects at baseline continued to have unimpaired neuropsychological performance at follow-up. These results indicate that the presence of neuropsychological impairment is relatively stable over a 12-month follow-up period among different cognitive subtypes of MCI, although 15-25% of the cases did not exhibit the specific cognitive deficits that characterized their performance at baseline.

Using different memory cutoffs to assess mild cognitive impairment.

OBJECTIVE: Although mild cognitive impairment (MCI) is characterized by performance on memory and other measures below expected normative values, neither a scientific rationale nor a consensus exists regarding which measures have the most use or the optimal cutoffs to use to establish impairment. METHODS: Different memory measures were administered to 80 normal community-dwelling subjects divided into two age groups. This provided conormed data on eight different memory indices by which to compare 23 nondemented clinically diagnosed patients with MCI who met all other criteria for Alzheimer disease (AD). RESULTS: On immediate memory for passages, delayed visual reproduction, object memory, and a measure sensitive to semantic interference, 70%-78% of patients with MCI were identified as impaired at 1.5 standard deviations or greater below expected levels. Conditional logistical regression for age-matched samples indicated that consideration of raw scores for these neuropsychologic tests in combination did not significantly change the odds of MCI diagnosis. When impairment relative to the total normal elderly sample was calculated based on one or more impairments at a 1.5 or greater cutoff, specificity fell below acceptable levels when more than three memory measures were considered. CONCLUSION: An array of widely used neuropsychologic measures demonstrated utility in distinguishing patients with MCI-AD from cognitively normal community-dwelling elders. The appropriateness of more or less stringent cutoffs was highly influenced by the number of measures considered. These findings have important implications regarding the choice of cut points for impairment used for the diagnosis of MCI in both research and clinical settings.

Cognitive profiles in Alzheimer's disease and in mild cognitive impairment of different etiologies.

There has been increasing interest in determining whether amnestic, nonamnestic and multiple-domain subtypes of mild cognitive impairment (MCI) reflect different disease etiologies. In this study, we examined the extent to which cognitive profiles of nondemented patients with MCI diagnosed with prodromal Alzheimer's disease (AD) differed from those MCI patients diagnosed with vascular disease. We also compared these diagnostic groups to mildly demented patients diagnosed with AD and normal elderly controls. Results indicate that a majority of both MCI-AD and MCI-vascular patients experienced amnestic features and that multiple-domain was the most common presentation. MCI-AD and MCI-vascular groups did not differ on neuropsychological measures tapping memory, language, visuospatial skills/praxis or executive function. Further both MCI groups could be distinguished from dementia patients with regards to performance on measures of memory but not on non-memory measures. Considerable variability was observed in the degree of memory impairment among MCI patients with scores as much as 6 standard deviations below expected mean values. MCI-AD and MCI-vascular patients frequently exhibit both common and overlapping amnestic and nonamnestic features. The implication of these findings for future clinical research is discussed.