Elizabeth Potter

Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease

Background: Despite convenience, accessibility, and strong correlation to severity of Alzheimer disease (AD) pathology, medial temporal lobe atrophy (MTA) has not been used as a criterion in the diagnosis of prodromal and probable AD. Methods: Using a newly validated visual rating system, mean MTA scores of three bilateral medial temporal lobe structures were compared for subjects with no cognitive impairment (NCI) (n = 117), nonamnestic mild cognitive impairment (MCI) (n = 46), amnestic MCI (n = 45), and probable AD (n = 53). Correlations between MTA scores and neuropsychological test scores at baseline, and predictors of change in diagnosis at 1-year follow-up were evaluated. Results: With NCI as the reference group, a mean MTA cut score of 1.33 yielded an optimal sensitivity/specificity of 85%/82% for probable AD subjects and 80%/82% for amnestic MCI subjects. MTA and Clinical Dementia Rating Sum of Boxes scores at baseline were independent and additive predictors of diagnosis at baseline, and of transition from NCI to MCI or from MCI to dementia at 1-year follow-up. Conclusion: Medial temporal lobe atrophy (MTA) scores 1) distinguish probable Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI) subjects from nonamnestic MCI and no cognitive impairment (NCI) subjects, 2) help predict diagnosis at baseline, and 3) predict transition from NCI to MCI and from MCI to probable AD. MTA scores should be used as a criterion in the clinical diagnosis of AD. AD = Alzheimer disease; ADRDA = Alzheimers Disease and Related Disorders Association; aMCI = amnestic mild cognitive impairment; ANOVA = analysis of variance; CDRSB = Clinical Dementia Rating Sum of Boxes; ERC = entorhinal cortex; FADRC-CC = Florida Alzheimers Disease Research Center–Clinical Core; HPC = hippocampus; HR = hazard ratio; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; MTA = medial temporal lobe atrophy; MTL = medial temporal lobe; NACC = National Alzheimers Coordinating Center; naMCI = nonamnestic mild cognitive impairment; NCI = no cognitive impairment; NINCDS = National Institute of Neurological and Communicative Disorders and Stroke; NS = not significant; PRC = perirhinal cortex; VRS = visual rating system.

Pre-MCI and MCI: neuropsychological, clinical, and imaging features and progression rates.

OBJECTIVE To compare clinical, imaging, and neuropsychological characteristics and longitudinal course of subjects with pre-mild cognitive impairment (pre-MCI), who exhibit features of MCI on clinical examination but lack impairment on neuropsychological examination, to subjects with no cognitive impairment (NCI), nonamnestic MCI (naMCI), amnestic MCI (aMCI), and mild dementia. METHODS For 369 subjects, clinical dementia rating sum of boxes (CDR-SB), ApoE genotyping, cardiovascular risk factors, parkinsonism (UPDRS) scores, structural brain MRIs, and neuropsychological testing were obtained at baseline, whereas 275 of these subjects received an annual follow-up for 2-3 years. RESULTS At baseline, pre-MCI subjects showed impairment on tests of executive function and language, higher apathy scores, and lower left hippocampal volumes (HPCV) in comparison to NCI subjects. Pre-MCI subjects showed less impairment on at least one memory measure, CDR-SB and UPDRS scores, in comparison to naMCI, aMCI and mild dementia subjects. Follow-up over 2-3 years showed 28.6% of pre-MCI subjects, but less than 5% of NCI subjects progressed to MCI or dementia. Progression rates to dementia were equivalent between naMCI (22.2%) and aMCI (34.5%) groups, but greater than for the pre-MCI group (2.4%). Progression to dementia was best predicted by the CDR-SB, a list learning and executive function test. CONCLUSION This study demonstrates that clinically defined pre-MCI has cognitive, functional, motor, behavioral and imaging features that are intermediate between NCI and MCI states at baseline. Pre-MCI subjects showed accelerated rates of progression to MCI as compared to NCI subjects, but slower rates of progression to dementia than MCI subjects.

Amyloid positron emission tomography with 18F-flutemetamol and structural magnetic resonance imaging in the classification of mild cognitive impairment and Alzheimer’s disease

To evaluate the contributions of amyloid‐positive (Am+) and medial temporal atrophy–positive (MTA+) scans to the diagnostic classification of prodromal and probable Alzheimers disease (AD).

Association of White Matter Hyperintensity Measurements on Brain MR Imaging with Cognitive Status, Medial Temporal Atrophy, and Cardiovascular Risk Factors

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) are frequently characterized as markers of cerebrovascular disease, whereas medial temporal atrophy (MTA) is a recognized marker of Alzheimer disease (AD). Our purpose was to test the reliability of a visual rating system (VRS) in evaluating WMHs and MTA and in distinguishing healthy from cognitively impaired subjects. MATERIALS AND METHODS: Subjects (n = 192) enrolled in the Florida Alzheimers Disease Research Center were diagnosed with no cognitive impairment, nonamnestic mild cognitive impairment (na-MCI), amnestic MCI (a-MCI), or probable AD. The severity of WMHs was assessed on T2-weighted fluid-attenuated inversion recovery axial MR images, and the severity of MTA was evaluated on 1.5-mm-thick coronal MR images by using a computer-based visual rating system. Cardiovascular risk factor scores were calculated as the sum of 10 independent cardiovascular risk factors. RESULTS: WMH and MTA scores were greater in subjects with probable AD, relative to those with no cognitive impairment and na-MCI. MTA scores differentiated subjects with a-MCI from those with no cognitive impairment and na-MCI. The total WMH score was significantly related to MTA (r = 0.39; P < .001) but not to cardiovascular risk factor scores (r = 0.07; P = not significant). The overall correct classification rate of probable AD versus no cognitive impairment by using MTA scores was 81.8%, improving to 86.5% when combined with WMH scores. CONCLUSIONS: Both MTA and WMH scores distinguished subjects with no cognitive impairment and probable AD. Combining MTA and WMH scores improved the correct classification rate, whereas WMH scores were significantly related to MTA scores, but not to cardiovascular risk factor scores. This finding suggests that among subjects with a-MCI and probable AD, WMHs on MR images are primarily associated with neurodegenerative disease.

Visual rating system for assessing magnetic resonance images: a tool in the diagnosis of mild cognitive impairment and Alzheimer disease.

Subjects with mild cognitive impairment (MCI) and mild Alzheimer disease (AD) can be distinguished from elderly subjects with no cognitive impairment (NCI) by the degree of atrophy in the entorhinal cortex (ERC) and the hippocampus (HPC), quantified by volumetric magnetic resonance image (MRI) studies. Because volumetric MRI requires rigorous standards for image acquisition and analysis and is not suitable for routine clinical use, we have used calibrated visual rating to measure atrophy in the ERC, HPC, and perirhinal cortex (PRC) and evaluated its utility in the diagnosis of very early AD. Methods: Thus far, visual rating methods, which have been found to be reliable and sensitive only for measurement of atrophy of the HPC or for the entire medial temporal region, have been found to be relatively insensitive for discriminating mild AD from elderly NCI subjects. We have developed a computer-based visual rating system (VRS) using reference images for calibration of atrophy ratings in several discrete brain regions, including the ERC, HPC, and PRC. The VRS reference images facilitate training of raters and promote standardization of all atrophy ratings. Interrater and intrarater reliability measurements were assessed; subsequently, the ability of VRS to discriminate the diagnoses among 73 elderly subjects was studied (NCI = 27, MCI = 23, and AD = 23). Results: Kappa values for interrater reliability of the ERC, HPC, and PRC were between 0.75 and 0.94, and for intrarater reliability, they were between 0.84 and 0.93, indicating that VRS enables highly reliable ratings to be obtained. Atrophy ratings in the ERC, HPC, and PRC distinguished AD from NCI subjects but did not distinguish AD from MCI subjects who tended to have intermediate levels of atrophy. Right and left ERC ratings and the right HPC rating distinguished MCI from NCI subjects. Conclusions: The visual rating system is the first semiquantitative method that enables reliable measurements of ERC atrophy, and ERC measurement was found to be the best discriminator between MCI and NCI subjects. Visual rating system is a user-friendly tool that can allow a radiologist or a clinician to use structural MRI scans to be used as a biomarker in the diagnosis of prodromal AD.

An investigation of PreMCI: Subtypes and longitudinal outcomes

To investigate the clinical features and rates of progression of conditions that are not considered to be normal, but do not fulfill criteria for mild cognitive impairment (MCI).

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 (HP₀; ERC₀), or minimal atrophy of the HP or ERC (HPma; ERCma), among 414 participants. Subjects fell into the following groups: (1) ERC₀/HP₀, (2) ERCma/HP₀, (3) ERC₀/HPma, and (4) ERCma/HPma. HP volume was independently measured using volumetric methods. Results: In comparison to ERC₀/HP₀ subjects, those with ERC₀/HPma had impairment on 1 memory test, ERCma/HP₀ subjects had impairment on 2 memory tests and the Mini Mental State Examination (MMSE), while ERCma/HPma 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 ERCma. 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 ERCma subjects.

Volumetric and visual rating of magnetic resonance imaging scans in the diagnosis of amnestic mild cognitive impairment and Alzheimer's disease

In the diagnosis of Alzheimers disease (AD), structural magnetic resonance imaging (MRI) scans have been used primarily to exclude non‐Alzheimers causes of dementia. However, the pattern and the extent of medial temporal atrophy on structural MRI scans, which correlate strongly with the pathological severity of AD, can be used to support the diagnosis of a degenerative dementia, especially AD, even in its early predementia stage.

A comparative analysis of structural brain MRI in the diagnosis of Alzheimer's disease.

Dementia is a debilitating and life-altering disease which leads to both memory impairment and decline of normal executive functioning. While causes of dementia are numerous and varied, the leading cause among patients 60 years and older is Alzheimer’s disease. The gold standard for Alzheimer’s diagnosis remains histological identification of amyloid plaques and neurofibrillary tangles within the medial temporal lobe, more specifically the entorhinal cortex and hippocampus. Although no definitive cure for Alzheimers disease currently exists, there are treatments targeted at preserving cognition and memory while delaying continued loss of function. Alzheimers disease exists along a spectrum of cognitive decline and is often preceded by Mild Cognitive Impairment (MCI). Patients with MCI demonstrate memory loss and cognitive impairment while still continuing normal activities of daily living, and are considered to be at increased risk for developing Alzheimers Dementia. Identifying patients with prodromal states of Alzheimers dementia such as MCI may allow initiation of appropriate treatment planning and delay of cognitive decline. Therefore, the need for a non-invasive early biomarker for the detection of Alzheimers disease has never been greater. Multiple neuroimaging methods utilizing visual rating scales, volumetric measurements, and automated methods have been developed to identify, quantify, and track anatomic sequelae of Alzheimer’s Disease.

Diagnosis and staging of mild cognitive impairment, using a modification of the clinical dementia rating scale: the mCDR

To examine the reliability and validity of the mCDR, a modified version of the clinical dementia rating (CDR) scale.