H. C. Chui

Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease

Background: Neuroimaging in mild cognitive impairment (MCI) and Alzheimer disease (AD) generally shows medial temporal lobe atrophy and diminished glucose metabolism and cerebral blood flow in the posterior cingulate gyrus. However, it is unclear whether these abnormalities also impact the cingulum fibers, which connect the medial temporal lobe and the posterior cingulate regions. Objective: To use diffusion tensor imaging (DTI), by measuring fractional anisotropy (FA), to test 1) if MCI and AD are associated with DTI abnormalities in the parahippocampal and posterior cingulate regions of the cingulum fibers; 2) if white matter abnormalities extend to the neocortical fiber connections in the corpus callosum (CC); 3) if DTI improves accuracy to separate AD and MCI from healthy aging vs structural MRI. Methods: DTI and structural MRI were preformed on 17 patients with AD, 17 with MCI, and 18 cognitively normal (CN) subjects. Results: FA of the cingulum fibers was significantly reduced in MCI, and even more in AD. FA was also significantly reduced in the splenium of the CC in AD, but not in MCI. Adding DTI to hippocampal volume significantly improved the accuracy to separate MCI and AD from CN. Conclusion: Assessment of the cingulum fibers using diffusion tensor imaging may aid early diagnosis of Alzheimer disease.

White matter lesions impair frontal lobe function regardless of their location

Objective: To analyze the effect of white matter lesions in different brain regions on regional cortical glucose metabolism, regional cortical atrophy, and cognitive function in a sample with a broad range of cerebrovascular disease and cognitive function. Methods: Subjects (n = 78) were recruited for a study of subcortical ischemic vascular disease (SIVD) and Alzheimer disease (AD) contributions to dementia. A new method was developed to define volumes of interest from high-resolution three-dimensional T1-weighted MR images. Volumetric measures of MRI segmented white matter signal hyperintensities (WMH) in five different brain regions were related to regional PET glucose metabolism (rCMRglc) in cerebral cortex, MRI measures of regional cortical atrophy, and neuropsychological assessment of executive and memory function. Results: WMH was significantly higher in the prefrontal region compared to the other brain regions. In all subjects, higher frontal and parietal WMH were associated with reduced frontal rCMRglc, whereas occipitotemporal WMH was only marginally associated with frontal rCMRglc. These associations were stronger and more widely distributed in nondemented subjects where reduced frontal rCMRglc was correlated with WMH for all regions measured. In contrast, there was no relationship between WMH in any brain region and rCMRglc in either parietal or occipitotemporal regions. WMHs in all brain regions were associated with low executive scores in nondemented subjects. Conclusions: The frontal lobes are most severely affected by SIVD. WMHs are more abundant in the frontal region. Regardless of where in the brain these WMHs are located, they are associated with frontal hypometabolism and executive dysfunction.

Longitudinal volumetric MRI change and rate of cognitive decline

Objective: To examine how baseline and change of volumetric MRI relate to cognitive decline in older individuals. Background: Memory is associated with hippocampal integrity, whereas executive function has been linked to impaired frontal lobe function. Previous studies have shown that hippocampal and cortical atrophy are more strongly related to cognition than are measures of subcortical cerebrovascular disease (CVD). The authors hypothesized that memory (MEM) decline would be related to change in hippocampal volume (HC), whereas decline in executive function (EXEC) would be related to change of cortical gray matter volume (CGM) and measures of subcortical CVD. Methods: Subjects from a multicenter study (n = 103) included cognitively normal, mildly impaired, and demented cases with and without subcortical lacunes. All had longitudinal cognitive evaluation (mean = 4.8 years) and two or more MRI scans at least one year apart (mean = 3.4 years). MRI measures included HC, CGM, total lacune volume (LAC), and white matter hyperintensity volume (WMH). Random effects modeling of longitudinal data assessed effects of MRI baseline and MRI change on baseline and change of psychometrically matched measures of MEM and EXEC. Results: Change in MEM was related to HC baseline and HC change. Change in EXEC was related to baseline CGM and to change in CGM, HC, and LAC. Results were unchanged when demented cases were excluded. WMH was not associated with change in MEM or EXEC independent of HC, CGM, and LAC. Conclusion: Hippocampal volume was the primary determinant of memory decline, whereas executive function (EXEC) decline was related to multiple brain components. Results support a hypothesis that MEM decline is strongly influenced by Alzheimer disease (AD), whereas EXEC decline may be complexly determined by cerebrovascular disease and AD.

Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia

Background: Mild cognitive impairment (MCI) is widely viewed as the transition phase between normal aging and Alzheimer disease (AD). Given that MCI can also result from cerebrovascular disease (CVD), the authors used clinical, MRI, and cognitive measures of AD and CVD to test the hypothesis that CVD increases the likelihood of progression from MCI to dementia within 3 years. Objective: To examine the impact of CVD on progression of MCI to dementia. Methods: Fifty-two consecutive patients with MCI (71% men) including many with symptomatic CVD were longitudinally evaluated for 3.1 ± 1.3 years. MCI was defined as a Clinical Dementia Rating Scale (CDR) score of 0.5. Dementia was defined as progression to a CDR score of ≥1.0. Results: Forty-four percent of the MCI patients had MRI infarcts, 50% of which were symptomatic. Thirty-three percent of patients progressed to dementia, and 37.8% of these had MRI infarcts. Clinically probable or possible AD was diagnosed in approximately 82% of converters. Of the clinical and MRI measures, only hippocampal volume was associated with increased risk to progression (hazard ratio [HR] = 0.31 [95% CI 0.1 to 0.92], p = 0.03). When neuropsychological measures were included in the analysis, memory (HR = 0.90 [95% CI 0.84 to 0.96], p = 0.002) and executive function (HR = 0.96 [95% CI 0.92 to 1.0], p = 0.045) were associated with increased risk of dementia progression, whereas APOE genotype, cerebrovascular risk factors, clinical stroke, presence or absence of lacunes, and extent of white matter hyperintensities did not predict progression. Conclusion: Within a heterogenous group of MCI patients, including many with clinically significant CVD, baseline memory and executive performance significantly predicted likelihood to develop dementia.

Atrophy rates of entorhinal cortex in AD and normal aging

Objectives: To explore the atrophy rate of entorhinal cortex (ERC) in AD and normal aging and assess the value of rate measurement of ERC atrophy for classifying subjects with AD from cognitively normal (CN) control subjects. Methods: Twenty-one AD patients and 23 CN subjects had MRI scans and clinical evaluations twice within 1.8 ± 0.6 years. ERC volumes were manually measured on volumetric T1-weighted MR images. Results: Patients with AD had a greater annual percentage volume change of ERC than CN subjects on both sides (left: 6.8 ± 4.3%/year for AD vs 1.4 ± 2.5%/year for CN [F1,42 = 25.6, p < 0.001]; right: 6.3 ± 3.3%/year for AD vs 1.4 ± 2.3%/year for CN [F1,42 = 25.6, p < 0.001]). Furthermore, increased ERC atrophy rate was correlated (r = −0.56, p = 0.01) with decreased memory performance in AD. CN subjects had on average annual ERC atrophy rates greater than zero (p < 0.01). Baseline volume of ERC predicted atrophy rate of ERC (left: r = −0.53, p < 0.01; right: r = −0.42, p < 0.05) in CN subjects but not in AD subjects. Using ERC baseline volumes alone resulted in 77% overall correct classification (p < 0.01) between AD and CN subjects, with 76% sensitivity and 78% specificity and an area under receiver operator characteristic (ROC) curve of 0.83. Adding annual atrophy rate of ERC to the model accounted for most of the variance (p < 0.01), diminishing contributions from baseline volume and yielding 82% overall classification, with 76% sensitivity and 86% specificity and an area under the ROC curve of 0.93. Conclusion: ERC volume loss over time may be a better indicator for AD than cross-sectional measurements.

Higher atrophy rate of entorhinal cortex than hippocampus in AD

Objectives: To determine if atrophy rates were higher for entorhinal cortex (ERC) than for hippocampus in Alzheimer disease (AD), to determine the relationship between hippocampal atrophy rate and memory impairment, and to compare atrophy rates of ERC and hippocampus in differentiating between patients with AD and cognitively normal (CN) controls. Methods: Twenty patients with AD and 25 CN subjects had MRI scans and clinical evaluations twice approximately 1.9 years apart. ERC volumes were measured manually and hippocampal volumes were measured semiautomatically on volumetric T1-weighted MR images. Results: In AD, the atrophy rate of ERC (7.1 ± 3.2%/year) was higher (p < 0.02) than that of hippocampus (5.9 ± 2.4%/year). Furthermore, memory deficit in mild AD, measured with the Delayed List Verbal Recall test, correlated significantly with atrophy rates of both ERC (r = −0.61) and hippocampus (r = −0.59). Atrophy rates of ERC and hippocampus were comparable in differentiating between AD and CN. Using atrophy rates of ERC or hippocampus to detect a 20% treatment effect with 90% power (p < 0.05) would require about 100 completed patients per arm in a 2-year study. Conclusion: The finding in AD that the atrophy rate in the entorhinal cortex is higher than in the hippocampus is consistent with the view that AD pathology begins in the entorhinal cortex.

Elevated risk of Alzheimer's disease among workers with likely electromagnetic field exposure.

We conducted a case-control study of the possible association of occupations with likely exposure to electromagnetic fields and Alzheimers disease (AD) with patients from the Alzheimer Disease Treatment and Diagnostic Center, Rancho Los Amigos Medical Center, Downey, CA. Patients with definite or probable AD were the case subjects (86 male, 240 female). Patients with cognitive impairment/dementia other than vascular dementia were control subjects (76 male, 76 female). The study was limited to patients who were at least age 65 at the time of their first examination at Rancho Los Amigos. The odds ratio for both sexes combined was adjusted for sex, education, and age at onset. The odds ratio for males was adjusted only for age at onset, and the odds ratio for females was adjusted for both education and age at onset. The adjusted odds ratio for both sexes was 3.93 (p = 0.006), 95% CI = (1.5 to 10.6). For males the adjusted odds ratio was 4.90 (p = 0.01), 95% CI = (1.3 to 7.9), and for females the adjusted odds ratio was 3.40 (p = 0.10), 95% CI = (0.8 to 16.0). These results are consistent with previous findings regarding the hypothesis that electromagnetic field exposure is etiologically associated with the occurrence of AD. NEUROLOGY 1996;47: 1477-1481

Olfactory tests as possible probes for detecting and monitoring Alzheimer's disease

One of the characteristics of Alzheimers disease is the early loss of neurons in pathways involved in processing olfactory information. Olfactory function was assessed in subjects with Alzheimers disease using a conventional Smell Identification Test and a simple three odor match-to-sample problem. The patients exhibited a diminished capacity to identify common odors but were severely impaired in their ability to use novel odors in a match-to-sample task. Subjects with Parkinsons disease had a severe deficit for identifying common odors with the majority scoring as anosmic. Multiple sclerosis was not accompanied by detectable changes in olfactory functioning. The results of the Alzheimers group are similar to recent animal studies that have shown lesions of the piriform-entorhinal cortex produce a variety of memory deficits that are particularly acute in tasks involving novel odors.

A method to improve interrater reliability of visual inspection of brain MRI scans in dementia

MR scanning is used in the clinical evaluation of patients with dementia but lacks a reliable method of visual inspection. Two neurologists conducted multiple pilot trials of alternate methods for visual inspection of MRIs, including methods that produced at least 75% interrater agreement in repeat trials, and selected a final method for rating ventricular:brain ratio (VBR), cortical atrophy, and white matter changes. Two other neurologists, new to the method, tested interrater reliability for each component of the method after a brief training session. The correlation of VBR measurement was 0.884 (p = 0.0001). The weighted kappa scores were 0.68 for overall frontal lobe atrophy, 0.38 for right temporal lobe atrophy, 0.20 for left temporal lobe atrophy, and 0.54 for parietal lobe atrophy. The weighted kappa scores were 0.77 for overall periventricular white matter hyperintensities and 0.72 for centrum semiovale hyperintensities. The proposed method may provide a rapid and reliable way to assess VBR, frontal lobe atrophy, parietal lobe atrophy, and white matter changes on brain MRIs in the evaluation of dementia, but it was less reliable for the assessment of temporal lobe atrophy.

Comparison of methods for measuring longitudinal brain change in cognitive impairment and dementia

PURPOSE The goal of this project was to compare MRI measures of hippocampal, entorhinal cortex (ERC), and whole brain longitudinal change in cognitively normal elderly controls (C), non-demented subjects with cognitive impairment (CI), and demented (D) subjects. METHODS 16 C, 6 CI, and 7 D subjects of comparable age were studied with MRI twice, at least 1 year apart. Longitudinal change in total brain size was measured by several methods, including computerized segmentation, non-linear warping, and change in the fluid/tissue boundaries between cerebrospinal fluid (CSF) and brain. Change in hippocampal volume was measured by semi-automated methods, and ERC volumes were manually measured. RESULTS The annual rate of atrophy was greater in D versus C and D versus CI for cortical gray matter (cGM) (P=0.009 and 0.002), hippocampus (P=0.0001 and 0.002), and for the change in the fluid/tissue boundary (P=0.03 and 0.03). The annual rate of atrophy of ERC was greater in both CI and D versus C (P=0.01 and 0.0002). No significant differences between groups were found using non-linear warping. CONCLUSIONS In CI, the greatest annual rates of atrophy were in ERC, while in D the greatest annual rates of atrophy were in hippocampus and cortex. Progressive ERC atrophy was observed with a greater degree of cognitive impairment, while hippocampal and cortical atrophy were only observed in demented subjects.