Alzheimer Disease: Korf ES

Scheltens P, Korf ES. · Department of Neurology, Academisch Ziekenhuis VU, Amsterdam, The Netherlands. · Curr Opin Neurol. · Pubmed #10970055 No free full text.

Abstract: This paper reviews the use of neuroimaging in the diagnosis of dementia, especially Alzheimer's disease. Computed tomography is still used to determine reversible causes of dementia; however, without clinical symptoms these causes are hard to find and computed tomography scanning is only cost-effective in a defined group of patients. Using magnetic resonance imaging, atrophy of the medial temporal lobe can be assessed volumetrically and visually, with a high correlation between the two methods. Medial temporal lobe atrophy is highly predictive of Alzheimer's disease, and correlates with neuropsychological performance and postmortem histologically measured volume. Cerebral volume changes over time seem to differentiate Alzheimer's disease and mild cognitive impairment progressing to Alzheimer's disease from controls with high accuracy. Studies of the corpus callosum in dementia indicate a cortico-cortical disconnection caused by atrophy. Of the new techniques, functional magnetic resonance imaging seems the most promising. This technique can possibly play a role in predicting Alzheimer's disease in patients with mild cognitive impairment. The use of single-photon emission computed tomography and positron emission tomography in (early) differential diagnoses seems limited. Lower regional cerebral blood flow is related to the severity of dementia and survival. Iodine-123 iodobenzamide single-photon emission computed tomography in dementia with Lewy bodies seems promising. Current and future positron emission tomography studies concentrate on memory function and receptor imaging. The focus in neuroimaging, especially magnetic resonance imaging, has shifted to early diagnosis and monitoring of the disease course, with a special interest in predicting dementia in patients with mild cognitive impairment.

van de Pol LA, van der Flier WM, Korf ES, Fox NC, Barkhof F, Scheltens P. · Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, The Netherlands. · Neurology. · Pubmed #17923611 No free full text.

Abstract: OBJECTIVE: A large cohort of subjects with mild cognitive impairment (MCI) was categorized into tertiles based on hippocampal atrophy rates, as a proxy for Alzheimer-type pathology. We compared baseline clinical, neuropsychological, and MRI measures to characterize these MCI subgroups. METHODS: Serial MRI data of 323 subjects with MCI (49% men; mean +/- SD age: 69 +/- 9 years), followed for 2 years in a clinical trial, were available. Baseline hippocampal and whole brain volumes (WBV) were measured, and hippocampal volume change was assessed. Baseline medial temporal lobe atrophy (MTA), white matter hyperintensities (WMH), and lacunes were rated visually. The cohort was categorized into tertiles based on hippocampal atrophy rates (absent, moderate, and severe). RESULTS: Rates of hippocampal atrophy (%/year) were 0.0 +/- 0.8 in the absent, 1.7 +/- 0.4 in the moderate, and 3.6 +/- 1.0 in the severe (mean +/- SD) tertile. Older age and the APOE epsilon 4 allele were associated with higher hippocampal atrophy rates (p < 0.0001 and p = 0.015). General cognition deteriorated over the MCI groups (p < 0.0001), whereas, after adjustment for age and sex, episodic memory and executive function did not. Baseline hippocampal atrophy was associated with increasing atrophy rates (hippocampal volume: p = 0.025; MTA score: p = 0.008); in contrast, WBV, WMH, and lacunes, adjusted for age and sex, were not significantly associated with hippocampal atrophy rates. CONCLUSIONS: In mild cognitive impairment (MCI), older age, poorer general cognition, hippocampal atrophy, and APOE epsilon 4 predict subsequent accelerated rates of hippocampal atrophy, suggestive of the accumulation of Alzheimer-type pathology, which may become clinically manifest in the future. These markers may improve identification of subjects with MCI at risk for Alzheimer disease.

Roks G, Korf ES, van der Flier WM, Scheltens P, Stam CJ. · Alzheimer Center, VU University Medical Center, Department of Neurology, Amsterdam, The Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #17682010 No free full text.

Abstract: Although reports on EEG in dementia with Lewy bodies (DLB) are conflicting, the recent diagnostic guidelines define EEG abnormalities as being supportive for the diagnosis. We examined EEG abnormalities in 18 patients with DLB, 34 patients with Alzheimer's disease (AD) and 36 patients with subjective memory complaints (SMC) using the Grand Total EEG (GTE) score. There was a difference in median GTE score of DLB (11.0), AD (4.8) and SMC (2.5) (p<0.001). Patients with DLB had higher scores than patients with AD. ROC analyses revealed that patients with DLB could be distinguished from those with AD with a sensitivity of 72% and a specificity of 85% at a GTE cut-off of 9.5. The association between GTE and DLB was independent of age, gender, Mini Mental State Examination and medication use. Frontal intermittent rhythmic delta activity (FIRDA) was found in 2.9% of the patients with AD and in 33.3% of the patients with DLB. The GTE is a simple EEG scoring method that can be helpful in the differential diagnosis between DLB and AD with good sensitivity and specificity.

van de Pol LA, Korf ES, van der Flier WM, Brashear HR, Fox NC, Barkhof F, Scheltens P. · Department of Neurology, Alzheimer Centre, VU Medical Centre, Vrije Universiteit Amsterdam, De Boelelaan 1117, PO Box 7057, 1007 MB Amsterdam, the Netherlands. · Arch Neurol. · Pubmed #17620494 links to  free full text

Abstract: OBJECTIVES: To describe magnetic resonance imaging characteristics in a large sample of subjects with mild cognitive impairment (MCI) and to investigate associations between these characteristics and cognition. DESIGN: Cohort study. SETTING: Baseline data of a randomized, double-blind, placebo-controlled clinical trial of galantamine in MCI. PATIENTS: Included in the study were 896 subjects with MCI (age [mean +/- SD], 70 +/- 9 years; 54% women) with available clinical and magnetic resonance imaging data. MAIN OUTCOME MEASURES: Neuropsychology: Alzheimer Disease Assessment Scale, cognitive subscale, MCI version, assessing global cognition; delayed recall on the New York University Paragraph Recall Test, assessing episodic memory; and Digit Symbol Substitution Test, assessing executive function. Neuroimaging: Medial Temporal Lobe Atrophy (MTA) Rating Scale (0-4) and Age-Related White Matter Changes Scale (0-30), assessing white matter hyperintensities (WMHs); and lacune counts. RESULTS: Median MTA score was 2 (range, 0-4), and mean (+/- SD) Age-Related White Matter Changes Scale score 6.0 (+/- 4.7). Lacunes were present in 33% of subjects. In unadjusted models, increasing MTA and WMHs were associated with poorer performance on all cognitive tests, and lacunes with poorer performance on the Alzheimer Disease Assessment Scale, cognitive subscale, MCI version, and the Digit Symbol Substitution Test. In multivariable models, including magnetic resonance imaging measures simultaneously, MTA remained a predictor of cognition, whereas WMH had no independent predictive value. There was an interaction between MTA and lacunes: the strength of the association with the Digit Symbol Substitution Test increased with decreasing MTA. CONCLUSIONS: Medial temporal lobe atrophy seems to be a more important predictor of cognition than small-vessel disease in MCI. Lacunes were associated with performance on the Digit Symbol Substitution Test, especially in subjects with milder MTA. Although WMHs were prevalent and associated with cognition in unadjusted analyses, there was no discernible association between WMHs and the cognitive measures in this study after adjustment for age.

Scher AI, Xu Y, Korf ES, White LR, Scheltens P, Toga AW, Thompson PM, Hartley SW, Witter MP, Valentino DJ, Launer LJ. · Department of Preventive Medicine and Biometrics, Uniformed Services University, Bethesda, MD 20814, USA. · Neuroimage. · Pubmed #17434756 No free full text.

Abstract: BACKGROUND: Hippocampal atrophy--particularly of the CA1 region--may be useful as a biomarker for Alzheimer's disease (AD) or the risk for AD. The extent to which the AD hippocampus can be distinguished in vivo from changes due to normal aging or other processes that affect the hippocampus is of clinical importance and is an area of active research. In this study, we use structural imaging techniques to model hippocampal size and regional shape differences between elderly men with incident AD and a non-demented comparison group of elderly men. METHODS: Participants are Japanese-American men from the Honolulu Asia Aging Study (HAAS). The HAAS cohort has been followed since 1965. The following analysis is based on a sub-group of men who underwent MRI examination in 1994-1996. Participants were diagnosed with incident AD (n=24: age=82.5+/-4.6) or were not demented (n=102: age=83.0+/-5.9). One reader, blinded to dementia diagnosis, manually outlined the left and right hippocampal formation using published criteria. We used 3D structural shape analysis methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal diameter between the AD cases and the non-demented comparison group. RESULTS: Mean total hippocampal volume was 11.5% smaller in the AD cases than the non-demented controls (4903+/-857 mm(3) vs. 5540+/-805 mm(3)), with a similar size difference for the median left (12.0%) and median right (11.6%) hippocampus. Shape analysis showed a regional pattern of shape difference between the AD and non-demented hippocampus, more evident for the hippocampal body than the head, and the appearance of more consistent differences in the left hippocampus than the right. While assignment to a specific sub-region is not possible with this method, the surface changes primarily intersect the area of the hippocampus body containing the CA1 region (and adjacent CA2 and distal CA3), subiculum, and the dentate gyrus-hilar region.

Korf ES, van Straaten EC, de Leeuw FE, van der Flier WM, Barkhof F, Pantoni L, Basile AM, Inzitari D, Erkinjuntti T, Wahlund LO, Rostrup E, Schmidt R, Fazekas F, Scheltens P, Anonymous00104. · Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands. · Diabet Med. · Pubmed #17257279 No free full text.

Abstract: HYPOTHESIS: Based on recent findings on the association between vascular risk factors and hippocampal atrophy, we hypothesized that hypertension and diabetes mellitus (DM) are associated with medial temporal lobe atrophy (MTA) in subjects without disability, independent of the severity of white matter hyperintensities. METHODS: In the Leukoaraiosis And DISability in the elderly (LADIS) study, we investigated the relationships between DM, hypertension, blood pressure and MTA in 582 subjects, stratified by white matter hyperintensity severity, using multinomial logistic regression. MTA was visually scored for the left and right medial temporal lobe (score 0-4), and meaned. RESULTS: Mean age was 73.5 years (sd 5.1), 54% was female. Of the subjects, 15% had DM, and 70% had a history of hypertension. The likelihood of having MTA score 3 was significantly higher in subjects with DM (OR 2.9; 95% CI: 1.1-7.8) compared with an MTA score of 0 (no atrophy). The odds ratio for MTA score 2 was not significantly increased (OR 1.8; CI: 0.9-4). Systolic and diastolic blood pressure and a history of hypertension were not associated with MTA. There was no interaction between DM and hypertension. Stratification on white matter hyperintensities (WMH) did not alter the associations. CONCLUSION: Our study strengthens the observation that MTA is associated with DM, independently of the amount of small vessel disease as reflected by WMH.

Hartley SW, Scher AI, Korf ES, White LR, Launer LJ. · Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Neuroimage. · Pubmed #16376107 No free full text.

Abstract: As population-based epidemiologic studies may acquire images from thousands of subjects, automated image post-processing is needed. However, error in these methods may be biased and related to subject characteristics relevant to the research question. Here, we compare two automated methods of brain extraction against manually segmented images and evaluate whether method accuracy is associated with subject demographic and health characteristics. MRI data (n = 296) are from the Honolulu Asia Aging Study, a population-based study of elderly Japanese-American men. The intracranial space was manually outlined on the axial proton density sequence by a single operator. The brain was extracted automatically using BET (Brain Extraction Tool) and BSE (Brain Surface Extractor) on axial proton density images. Total intracranial volume was calculated for the manually segmented images (ticvM), the BET segmented images (ticvBET) and the BSE segmented images (ticvBSE). Mean ticvBSE was closer to that of ticvM, but ticvBET was more highly correlated with ticvM than ticvBSE. BSE had significant over (positive error) and underestimated (negative error) ticv, but net error was relatively low. BET had large positive and very low negative error. Method accuracy, measured in percent positive and negative error, varied slightly with age, head circumference, presence of the apolipoprotein eepsilon4 polymorphism, subcortical and cortical infracts and enlarged ventricles. This epidemiologic approach to the assessment of potential bias in image post-processing tasks shows both skull-stripping programs performed well in this large image dataset when compared to manually segmented images. Although method accuracy was statistically associated with some subject characteristics, the extent of the misclassification (in terms of percent of brain volume) was small.

Korf ES, Scheltens P, Barkhof F, de Leeuw FE. · Department of Neurology, Alzheimer Center Vrije University Medical Center, Amsterdam, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #16179827 No free full text.

Abstract: BACKGROUND: Vascular factors are recognized as important risk factors for Alzheimer's disease, although it is unknown whether these factors directly lead to the typical degenerative pathology such as medial temporal lobe atrophy. We set out to investigate the relation between blood pressure and medial temporal lobe atrophy in patients with senile and presenile Alzheimer's disease with or without white matter lesions. METHODS: We determined the relation between blood pressure and pulse pressure and medial temporal lobe atrophy on MRI in 159 patients with Alzheimer's disease, stratified on white matter lesions and age at onset of dementia. RESULTS: There was a linear relation between systolic blood pressure and pulse pressure (both in tertiles) and the severity of medial temporal lobe atrophy (p(trend) = 0.05 and p(trend) 0.03, respectively). A significant relation was found between pulse pressure [beta = 0.08 (95% CI: 0.00-0.15; p = 0.05) per 10 mm Hg] and (borderline significant) systolic blood pressure [beta = 0.05 (95% CI: -0.01 to 0.11; p = 0.1) per 10 mm Hg] and medial temporal lobe atrophy. White matter lesions and age-stratified analysis revealed a significant association between systolic blood pressure and pulse pressure and medial temporal lobe atrophy, only in the subsample with white matter lesions and in the subsample with a senile onset of dementia. The relations were independent of severity of dementia and diabetes mellitus. CONCLUSIONS: Systolic blood pressure and pulse pressure are associated with medial temporal lobe atrophy in Alzheimer's disease, especially in the presence of white matter lesions and in patients with a late onset of dementia. Our finding may be another step in providing a rationale on how vascular factors could ultimately result in Alzheimer's disease.

Korf ES, Wahlund LO, Visser PJ, Scheltens P. · Department of Neurology and Alzheimer Center, Vrije Universiteit Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Neurology. · Pubmed #15249617 No free full text.

Abstract: BACKGROUND: Although detailed volumetric MRI assessment of medial temporal lobe atrophy (MTA) can predict dementia in patients with mild cognitive impairment (MCI), it is not easily applied to routine clinical practice. OBJECTIVE: To test the predictive accuracy of visually assessed MTA in MCI patients using a standardized visual rating scale. METHODS: Seventy-five MCI patients (mean age 63 years) underwent a coronal three-dimensional magnetization-prepared rapid gradient echo brain MRI sequence. MTA was rated visually using a 5-point rating scale. RESULTS: The mean follow-up period for the cohort was 34 months. At follow-up, 49% of the enrolled MCI patients fulfilled criteria for dementia. MTA assessed using a standardized visual rating scale was significantly associated with dementia at follow-up, with a hazard ratio of 1.5 for every point increase in atrophy score (p < 0.001) and of 3.1 for the presence of atrophy based on the dichotomized atrophy score (p = 0.003). The predictive accuracy of visually assessed MTA was independent of age, gender, education, Mini-Mental State Examination score, Clinical Dementia Rating Sum of Boxes score, Verbal Delayed Recall, and the presence of hypertension, depression, the APOE epsilon4 allele, and white matter hyperintensities. CONCLUSIONS: Visual assessment of MTA on brain MRI using a standardized rating scale is a powerful and independent predictor of conversion to dementia in relatively young MCI patients. As overlap existed in MTA scores between patients with and without dementia at follow-up, the results should be interpreted in the light of the odds for the individual patient.

Korf ES, White LR, Scheltens P, Launer LJ. · Department of Neurology and Alzheimer Center, Universiteit Medical Center, Amsterdam, The Netherlands. · Hypertension. · Pubmed #15159381 links to  free full text

Abstract: Hippocampal atrophy (HA) is usually attributed to the neurofibrillary tangles and neuritic plaques of Alzheimer disease. However, the hippocampus is vulnerable to global ischemia, which may lead to atrophy. We investigated the association of midlife blood pressure (BP) and late-life HA in a sample of Japanese-American men born between 1900 and 1919. BP was measured on 3 occasions between 1965 and 1971. In 1994 to 1996 a subsample underwent magnetic resonance imaging (MRI) of the brain. Hippocampal volume was estimated by manually drawing regions of interest on relevant scan slices; HA was defined as the lowest quartile of hippocampal volume. Also assessed on the MRI were cortical and subcortical infarcts, lacunes, and white matter hyperintensities. The risk (OR, 95% CI) was estimated for HA associated with systolic (<140 versus > or =140 mm Hg) and diastolic (<90 versus > or =90 mm Hg) BP and with antihypertensive treatment. Analyses were adjusted for sociodemographic factors, other cardiovascular risk factors, apolipoprotein E allele, and correlated brain pathology. Those never treated with antihypertensive medication had a significantly increased risk for HA (OR 1.7; CI=1.12; 2.65). The nontreated subjects with high systolic BP had an increased risk (OR=1.98; CI=0.89; 4.39) for HA. Results were similar for untreated men with high diastolic BP (OR=3.51; CI=1.26; 9.74). In conclusion, treatment with antihypertensive treatment modifies the association of BP and HA, such that high levels of BP adversely affect the hippocampus in persons never treated with antihypertensives.