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Purpose: To evaluate the differences of cortical activation patterns in young and elderly healthy subjects for object and spatial visual processing using a face- and location-matching task., Materials and Methods: We performed a face- and a location-matching task in 15 young (mean age: 28 +/- 9 years) and 19 elderly (mean age: 71 +/- 6 years) subjects. Each experiment consisted of 7 blocks alternating between activation and control condition. For face matching, the subjects had to indicate whether two displayed faces were identical or different. For location matching, the subjects had to press a button whenever two objects had an identical position. For control condition, we used a perception task with abstract images. Functional imaging was performed on a 1.5-tesla scanner using an EPI sequence., Results: In the face-matching task, the young subjects showed bilateral (right > left) activation in the occipito-temporal pathway (occipital gyrus, inferior and middle temporal gyrus). Predominantly right hemispheric activations were found in the fusiform gyrus, the right dorsolateral prefrontal cortex (inferior and middle frontal gyrus) and the superior parietal gyrus. In the elderly subjects, the activated areas in the right fronto-lateral cortex increased. An additional activated area could be found in the medial frontal gyrus (right > left). In the location-matching task, young subjects presented increased bilateral (right > left) activation in the superior parietal lobe and precuneus compared with face matching. The activations in the occipito-temporal pathway, in the right fronto-lateral cortex and the fusiform gyrus were similar to the activations found in the face-matching task. In the elderly subjects, we detected similar activation patterns compared to the young subjects with additional activations in the medial frontal gyrus., Conclusion: Activation patterns for object-based and spatial visual processing were established in the young and elderly healthy subjects. Differences between the elderly and young subjects could be evaluated, especially by using a face-matching task.

Background: High variability of estimates of cognitive decline in patients with Alzheimer's disease (AD) derived from unbalanced longitudinal designs may result as much from the applied statistical model as from true biological variability., Objective: To compare the accuracy of two statistical models, serial subtraction score (SSA) and mixed-effects regression analysis (MEM), to estimate rates of cognitive decline in patients with amnestic mild cognitive impairment (MCI), a group at risk for AD., Methods: We recorded serial mini mental state examination (MMSE) scores from 78 MCI patients. Additionally, we derived simulated trajectories of cognitive decline with unequally spaced observation intervals. Rates of change were assessed from clinical and simulated data using SSA and MEM models., Results: MEM reduced variability of rates of change significantly compared to SSA. In a polynomial model, overall length of observation time explained a significant amount of variance of SSA, but not of MEM estimates. For simulated data, MEM was significantly more accurate in predicting true rates of change compared to SSA (p < 0.001)., Conclusion: MEM yields more accurate estimates of cognitive decline from unbalanced longitudinal data. Simulation studies may be useful to select the appropriate statistical model for a given set of clinical data.

Hyperphosphorylated tau protein (P-tau) in CSF is a core biomarker candidate of Alzheimer's disease. Hyperphosphorylation of tau is thought to lead to neurofibrillary changes, a neuropathological hallmark of this type of dementia. Currently, the question is unresolved whether CSF levels of P-tau reflect neurofibrillary changes within the brain of a patient with the illness. Twenty-six patients were included with intra-vitam CSF as well as post-mortem neuropathological data. In the CSF, P-tau phosphorylated at threonine 231 (P-tau231P) was analysed. Post-mortem, scores of neurofibrillary tangles (NFT) and neuritic plaques (NP) were assessed in frontal, temporal, parietal and hippocampal cortical areas. In the same cortical regions, load of hyperphosphorylated tau protein (HP-tau load) was determined. Concentrations of P-tau231P were measured in frontal cortex homogenates. We found significant correlations between CSF P-tau231P concentrations and scores of NFTs and HP-tau load in all neocortical regions studied. The score of NPs was correlated with CSF P-tau231P only within the frontal cortex. There was a correlation between P-tau231P in CSF and brain homogenates. These findings indicate that CSF P-tau231P may serve as an in vivo surrogate biomarker of neurofibrillary pathology in Alzheimer's disease.

Clinical utility of magnetic resonance imaging (MRI) for the diagnosis and assessment of neurodegenerative diseases may depend upon the reliability of MRI measurements, especially when applied within a multicenter context. In the present study, we assessed the reliability of MRI through a phantom test at a total of eleven clinics. Performance and entry criteria were defined liberally in order to support generalizability of the results. For manual hippocampal volumetry, automatic segmentation of brain compartments and voxel-based morphometry, multicenter variability was assessed on the basis of MRIs of a single subject scanned at ten of the eleven sites. In addition, cranial MRI scans obtained from 73 patients with Alzheimer's disease (AD) and 76 patients with mild cognitive impairment were collected at subset of six centers to assess differences in grey matter volume. Results show that nine out of eleven centers tested met the reliability criteria of the phantom test, where two centers showed aberrations in spatial resolution, slice thickness and slice position. The coefficient of variation was 3.55% for hippocampus volumetry, 5.02% for grey matter, 4.87% for white matter and 4.66% for cerebrospinal fluid (CSF). The coefficient of variation was 12.81% (S.D.=9.06) for the voxel intensities within grey matter and 8.19% (S.D.=6.9) within white matter. Power analysis for the detection of a difference in the volumes of grey matter between AD and MCI patients across centers (d=0.42) showed that the total sample size needed is N=180. In conclusion, despite minimal inclusion criteria, the reliability of MRI across centers was relatively good.

Healthy aging has been associated with brain volume reductions preferentially affecting the frontal cortex, but also involving other regions. We used a network model of regional covariance, the Scaled Subprofile Model, with magnetic resonance imaging voxel-based morphometry to identify the regional distribution of gray matter associated with aging in 26 healthy adults, 22-77 years old. Scaled Subprofile Model analysis identified a pattern that was highly correlated with age (R2=0.66, P

Rationale: Cholinergic enhancement is among the best established treatments of Alzheimer's disease (AD). The cognitive effects of treatment are thought to be mediated by improvement of neuronal transmission. Positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) by measuring cortical metabolic response to activation assesses integrity of neuronal transmission in vivo., Objective: To determine the effects of treatment with donepezil, a centrally selective acetylcholinesterase inhibitor, on cortical metabolism in AD using 18FDG-PET., Methods: We enrolled 23 patients, 18 of which completed the study, with mild to moderate probable AD (mini-mental status exam scores of 15-28, inclusive) in a double-blind cross over trial of 8 weeks donepezil compared to 8 weeks placebo with repeated double 18FDG-PET examinations during passive audio-visual stimulation. Effects of treatment on cortical metabolic response to stimulation were determined with a linear model on a voxel level using Statistical Parametric Mapping (SPM 99, Wellcome Department of Imaging Neuroscience, London)., Results: Effects of treatment on cognitive measures were not different between donepezil and placebo. During passive audio-visual stimulation, patients showed activation in posterior visual and auditory areas and decreased activation in frontal cortex and basal ganglia. Resting state metabolism was increased with donepezil in left prefrontal cortex and decreased in right hippocampus. Cortical response to activation was increased in right hippocampus with donepezil compared to placebo., Conclusion: Donepezil treatment shows a spatially limited functional effect on right hippocampus and left prefrontal cortical metabolism, independently of clinical response to treatment.

Background: Early pathological involvement of specific medial temporal lobe areas is characteristic for Alzheimer's disease (AD)., Objective: To determine the extent of regional medial temporal lobe atrophy, including hippocampus, amygdala, and entorhinal, perirhinal, and parahippocampal cortices in mild AD patients and healthy controls, and to compare diagnostic accuracy across volumetric markers., Methods: We studied 34 patients with clinically probable AD and 22 healthy elderly control subjects. Regional volumetric measures were obtained from volumetric T1-weighted MRI scans after accounting for global brain atrophy using affine transformation into standard space., Results: Volumes of medial temporal lobe structures were significantly smaller in AD patients than in controls with exception of the left entorhinal cortex. The degree of atrophy was comparable between all structures. Diagnostic accuracy (number of correctly allocated cases divided by number of all cases) was highest for the right parahippocampal cortex with 85%, but only slightly lower for the right hippocampus and right entorhinal cortex with 82% and 84%. Using a linear combination of markers, the unilateral volumes of the right hippocampus, parahippocampal cortex and perirhinal cortex yielded an accuracy of 93%., Conclusion: Extent of atrophy is similar between the different regions of the medial temporal lobe in mild AD.Volume measurements of medial temporal lobe structures in addition to the hippocampus only yield improved diagnostic accuracy if a combination of these structures is used.

Aging in Down syndrome (DS) is accompanied by neuropathological features of Alzheimer's disease (AD). Therefore, DS has been proposed as a model to study predementia stages of AD. MRI-based measurement of grey matter atrophy is an in vivo surrogate marker of regional neuronal density. A range of neuroimaging studies have described the macroscopic neuroanatomy of DS. Recent studies using sensitive quantitative measures of region-specific atrophy based on high-resolution MRI suggest that age-related atrophy in DS resembles the pattern of brain atrophy in early stages of AD. The pattern of atrophy determined in predementia DS supports the notion that AD-type pathology leads to neuronal degeneration not only in allocortical, but also in neocortical brain areas before onset of clinical dementia. This has major implications for our understanding of the onset and progression of AD-type pathology both in DS and in sporadic AD.

The present study examined the cortical functional representation of neuropsychological domains in Alzheimer's disease (AD) using positron emission tomography (PET) and the neuropsychological assessment battery of the Consortium to Establish a Registry of Alzheimer's Disease (CERAD). Thirty patients with clinical probable AD and 10 elderly healthy controls underwent (18)FDG brain PET imaging during a resting state. Correlations between metabolic values and cognitive measures were determined using a region of interest analysis with NEUROSTAT (University of Michigan, USA) and a voxel-based analysis with SPM96 (Wellcome Department, London, UK). Specific correlations were seen between measures of episodic memory, verbal fluency and naming and left hemispheric temporal and prefrontal metabolism. Drawing was correlated with metabolism in left prefrontal and left inferior parietal regions. The presented data support the use of metabolic-cognitive correlations to demonstrate the neuronal substrates of cognitive impairment in AD. Subtests of the CERAD battery give a good representation of left, but not of right hemisphere function in AD.

To study the potential diagnostic value of abnormally phosphorylated tau protein in Creutzfeldt-Jakob disease (CJD) compared to Alzheimer's disease (AD), we determined levels of tau phosphorylated at threonine 231 (p-tau231) and of total tau (t-tau) in cerebrospinal fluid (CSF) of CJD patients, AD patients, and healthy controls (HC). CJD patients showed excessively high t-tau levels but relatively low p-tau(231) concentrations compared to the AD group. t-tau alone yielded the best diagnostic accuracy to differentiate between CJD and AD patients, when compared to p-tau231 and the p-tau231/t-tau ratio (97, 78, and 95% correctly allocated cases, respectively). Our findings indicate a dissociation in the direction of change in CSF levels of t-tau and p-tau231 in CJD when compared to AD.

We investigated the correlation between the apolipoprotein E varepsilon4 allele (apoE epsilon4) carrier status, a major risk factor of Alzheimer's disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau(231P)) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau(231P) levels were significantly higher in apoE epsilon4 carriers compared to non-carriers (p<0.001). Controlling for disease duration, the apoE epsilon4 effect on P-tau(231P) remained significant. Our study indicates that the apoE epsilon4 carrier status should be considered when CSF P-tau(231P) is evaluated as biomarker candidate of AD in MCI subjects.

The level of difficulty of a task can alter the neural network that activates for performance of the task. Previous studies have shown increased activation with task difficulty in the frontal lobes while the effects in the extrastriate visual areas have been unclear. We hypothesized that the face fusiform area (FFA), an area specialized for face processing, would increase activation as task difficulty increased in a face matching task. The difficulty level was increased by degrading the quality of the images. The degradation levels were 10%, 20%, 40% and 60%. Based on the correct response rate, the data were divided into a baseline level (composed of non-degraded and 10% degraded images) and a difficult level (composed of the 20%, 40% and 60% degraded images). Brain activation was measured using functional magnetic resonance imaging. The baseline face matching task activated a wide network of regions that included bilaterally the occipital, temporal and parietal lobes and the right frontal lobe. A novel behavioral finding was that task difficulty did not linearly increase with image degradation. The novel brain imaging finding was that the FFA is modulated by task difficulty and performance in the task was linearly correlated to activation in FFA. In addition, we found that activation in the dorsolateral prefrontal cortex (DLPFC) had increased activation as task difficulty increased. When adding the response time as a covariate, the differences in the DLPFC did not remain statistically significant. Increased task difficulty also led to a decrease in activation of visual areas in the extrastriate cortex. Task difficulty increased activation in the FFA to enhance the face processing and suppressed activation in visual extrastriate areas that processed low level properties of the stimuli. Task difficulty led to enhanced response in the FFA and suppressed response in other visual areas.

Alzheimer's disease is characterized by the degeneration and loss of cholinergic neurones in the nucleus basalis Meynert, located within the substantia innominata at the ventral surface of the basal forebrain. An in vivo measure of morphological changes in the nucleus basalis Meynert would be of high relevance to better understand the structural correlate of cholinergic dysfunction in Alzheimer's disease. In this study, we applied a newly developed automated technique of image regression analysis, implemented through code written in Matlab 5.3 (MathWorks, Natick, MA), to the analysis of proton density weighted structural MRI of the basal forebrain from 13 patients with Alzheimer's disease (mean age = 77.5 years, SD = 4.4 years, 8 women) and 12 healthy elderly subjects (mean age = 62.3 years, SD = 5.6 years, 6 women). This technique allows searching a large portion of the substantia innominata for signal changes. We used corresponding MRI and histological sections of a post mortem brain to map the locations of basal forebrain cholinergic nuclei into the MRI standard space. Additionally, we used voxel-based morphometry, implemented in SPM2 (Wellcome Department of Imaging Neuroscience, London, UK) to determine correlations between signal changes in the substantia innominata and cortical grey matter atrophy in the patients with Alzheimer's disease. When matching the locations of signal reductions in the in vivo MRI to the template of basal nuclei based on the postmortem brain, signal intensity was decreased in areas corresponding to anterior lateral and anterior medial nucleus basalis Meynert and increased in the third ventricle, the transverse fissure and the optic tract in patients with Alzheimer's disease compared with controls. The reduction of the signal intensity in an area corresponding to the anterior lateral nucleus basalis Meynert was significantly correlated with reduced grey matter concentration in the bilateral prefrontal cortex, inferior parietal lobule and cingulate gyrus. Our findings suggest that signal changes occur in patients with Alzheimer's disease in the substantia innominata which may be related to the loss or degeneration of cholinergic neurones and correspond to regional cortical grey matter atrophy. If replicated in an independent sample, our technique may be useful to detect degeneration of basal forebrain cholinergic neurones in vivo.

Involvement of the interleukin-6 receptor complex (IL-6RC) in neuroregulatory and immunological processes of the brain and particularly in Alzheimer's disease (AD) has been hypothesized. The functionally active IL-6RC consists of the cytokine IL-6, which acts through the ligand binding IL-6R and the signal transducing gp130. Using a new immunocytochemical protocol on rapid autopsy cryostat brain sections we studied the expression of the IL-6RC in Braak IV-V staged AD patients compared to normal age-matched controls (HC) across five different cortical regions. Inter-rater reliability of the method was high. The "baseline" expression in normal human brain was determined for IL-6,IL-6R and gp130 in all cortical regions. In normal tissue IL-6 expression was lower in parietal cortex. Higher IL-6R expression was shown in frontal, occipital and parietal cortex, lower expression in temporal cortex and cerebellum. In AD IL-6 expression levels were generally increased in parietal cortex and decreased in occipital cortex compared to controls. IL-6R expression levels were strongly increased in AD frontal and occipital cortex and decreased in temporal cortex and cerebellum. Our findings indicate an altered cortical immunoreactivity pattern of the functional IL-6RC in AD supporting the hypothesis of a disease-related role of IL-6 in AD pathophysiology.

Alzheimer's disease (AD) is characterized by a heterogeneous distribution of pathological changes throughout the brain. Magnetic resonance imaging can be used to investigate the regional distribution of cortical atrophy in AD in vivo. One marker for the disease-specific atrophy is the thickness of the cortical mantle across the brain, obtained with automated 3-D image processing. Here, we present data from 36 subjects (17 controls and, 19 patients diagnosed as probable AD) investigated for cortical thickness across the entire brain. We show significant cortical thickness decline in AD in temporal, orbitofrontal and parietal regions, with the most pronounced changes occurring in the allocortical region of the medial temporal lobes, outlining the parahippocampal gyrus, and representing a loss of >1.25 millimeters of cortical thickness. Moreover, focal cortical areas decline with progression of the disease as measured by time from baseline scan as well as the Mini-Mental State Exam. The results demonstrate the ability of this method to detect changes in cortical thickness in AD, across the entire brain, without need of prior anatomical definitions. The regional distribution of changes reported here is consistent with independent findings on the distribution of neuropathological alterations in AD. Using cortical thickness, moreover, we provide a direct quantitative index of atrophy in the disease.

Background: The microtubule-associated tau protein abnormally phosphorylated at threonine 231 (p-tau231) has been investigated as a potential marker of Alzheimer disease. Levels of cerebrospinal fluid (CSF) p-tau231 vary across patients with Alzheimer disease. We hypothesized that these variations partially reflect differences in the degree of neuronal damage and therefore may be used to predict structural disease progression., Objective: To investigate whether CSF p-tau231 levels correlate with rates of hippocampal atrophy as an in vivo marker of regional neuronal loss., Design and Patients: We measured hippocampal volumes on the basis of serial magnetic resonance image examinations in 22 patients with Alzheimer disease. In addition, we determined CSF p-tau231 levels at baseline., Results: Levels of CSF p-tau231 were significantly correlated with baseline hippocampal volumes (P<.001) and rates of hippocampal atrophy (left hippocampus, P<.001; right hippocampus, P = .02), independent of disease duration and severity., Conclusion: These findings suggest that variations in p-tau231 levels may be used to predict progression of brain atrophy in patients with Alzheimer disease.

Background: It is a challenge to reliably measure the lobar volumes from magnetic resonance imaging (MRI) data., Objective: Description of a landmark-based method for volumetric segmentation of the brain into the four cerebral lobes from MR images., Method: The segmentation method relies on a combination of anatomical landmarks and geometrical definitions. The first step, described previously, is a segmentation of the four lobes on the surface of the brain. The internal borders between the lobes are defined on the axial slices of the brain. The intra- and inter- rater reliability was determined from the MRI scans of a group of 10 healthy control subjects measured by 2 independent raters., Results: The intra-rater relative error (and intra-class correlation coefficient) of the lobar volume measures ranged from 0.81% to 3.85% (from 0.97 to 0.99). The inter-rater relative error (and intra-class correlation coefficient) ranged from 0.55% to 3.09% (from 0.94 to 0.99)., Conclusion: This technique has been shown to have high intra- and inter-rater reliability. The current method provides a method to obtain volumetric estimates of the 4 cerebral lobes.

Background: Autoantibodies against amyloid beta (A beta) peptide found in patients with Alzheimer's disease (AD) also occur naturally in the general population independently of the cognitive status., Methods: We compared serum A beta(1-42) autoantibody levels (A beta(1-42)-AL) of 96 AD patients and 30 healthy elderly control subjects (HC), assessing their diagnostic value for AD with a newly developed immunoprecipitation assay with radiolabeled A beta(1-42) peptide., Results: We found a highly significant decrease of A beta(1-42)-AL in AD patients (p = .001) independently of age, cognitive status, and apolipoprotein E epsilon4 carrier status. Amyloid beta(1-42) autoantibody levels were correlated with gender in AD, with a higher level occurring in women. When A beta(1-42) autoantibody sensitivity (specificity) was set >80%, specificity (sensitivity) was below 50% to correctly allocate patients and healthy control subjects., Conclusions: Our data indicate a potentially pathophysiologic decrease of serum A beta(1-42) antibodies in AD. Amyloid beta(1-42) antibodies in the serum alone, however, seem not to be useful as a diagnostic marker of AD.

Objective: Correlations between corpus callosum size and interhemispheric EEG coherence were investigated as measures of interhemispheric connectivity in patients with Alzheimer's disease., Methods: 11 patients underwent both magnetic resonance imaging and quantitative electroencephalography to assess corpus callosum size and interhemispheric coherence. For comparison, corpus callosum size was measured in 24 healthy elderly control subjects., Results: Corpus callosum cross sectional area was significantly reduced in Alzheimer patients relative to controls. Posterior interhemispheric coherence (alpha and beta frequencies) correlated significantly with the size of posterior corpus callosum area, and anterior coherence (delta, theta, and alpha frequencies) with the size of anterior corpus callosum area in the Alzheimer patients., Conclusion: Region specific correlations between corpus callosum size and EEG coherence suggest that the decline in interhemispheric connectivity in Alzheimer's disease results from a specific loss of cortical association neurones projecting through the corpus callosum.

Objective: Active or passive immunisation can mitigate plaque pathology in murine models of Alzheimer's disease (AD). Recently, it has been shown that antibodies against beta-amyloid (Abeta) are present in human immunoglobulin preparations (IVIgG), which specifically recognise and inhibit the neurotoxic effects of Abeta. This study reports the results from a pilot study using IVIgG in patients with AD., Methods: Five patients with AD were enrolled and received monthly IVIgG over a 6 month period. Efficacy assessment included total Abeta/Abeta(1-42) measured in the CSF/serum as well as effects on cognition (ADAS-cog; CERAD) at baseline and at 6 months following IVIgG., Results: Following IVIgG, total Abeta levels in the CSF decreased by 30.1% (17.3-43.5%) compared to baseline (p<0.05). Total Abeta increased in the serum by 233% (p<0.05). No significant change was found in Abeta(1-42) levels in the CSF/serum. Using ADAS-cog, an improvement of 3.7+/-2.9 points was detected. Scores in the MMSE were essentially unchanged (improved in four patients, stable in one patient) following IVIgG compared to baseline., Conclusion: Although the sample size of this pilot study is too small to draw a clear conclusion, the results of this pilot study provide evidence for a more detailed investigation of IVIgG for the treatment of AD.

Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) beta-amyloid(1-42) (Abeta(1-42)) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Abeta(1-42) and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Abeta(1-42) and CSF tau. The levels of CSF tau were increased, whereas levels of Abeta(1-42) were decreased in MCI subjects. Abeta(1-42) predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Abeta(1-42), but not other predictor variables (tau protein, gender, age, apolipoprotein E epsilon4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (P<0.05). Our findings support the notion that CSF tau and Abeta(1-42) may be useful biomarkers in the early identification of AD in MCI subjects.

Ageing in Down's syndrome is accompanied by amyloid and neurofibrillary pathology the distribution of which replicates pathological features of Alzheimer's disease. With advancing age, an increasing proportion of Down's syndrome subjects >40 years old develop progressive cognitive impairment, resembling the cognitive profile of Alzheimer's disease. Based on these findings, Down's syndrome has been proposed as a model to study the predementia stages of Alzheimer's disease. Using an interactive anatomical segmentation technique and volume-of-interest measurements of MRI, we showed recently that non-demented Down's syndrome adults had significantly reduced hippocampus, entorhinal cortex and corpus callosum sizes with increasing age. In this study, we applied the automated and objective technique of voxel-based morphometry, implemented in SPM99, to the analysis of structural MRI from 27 non-demented Down's syndrome adults (mean age 41.1 years, 15 female). Regional grey matter volume was decreased with advancing age in bilateral parietal cortex (mainly the precuneus and inferior parietal lobule), bilateral frontal cortex with left side predominance (mainly middle frontal gyrus), left occipital cortex (mainly lingual cortex), right precentral and left postcentral gyrus, left transverse temporal gyrus, and right parahippocampal gyrus. The reductions were unrelated to gender, intracranial volume or general cognitive function. Grey matter volume was relatively preserved in subcortical nuclei, periventricular regions, the basal surface of the brain (bilateral orbitofrontal and anterior temporal) and the anterior cingulate gyrus. Our findings suggest grey matter reductions in allocortex and association neocortex in the predementia stage of Down's syndrome. The most likely substrate of these changes is alterations or loss of allocortical and neocortical neurons due to Alzheimer's disease-type pathology.

An ever increasing number of patients with neurodegenerative disorders calls for the evaluation of potential diagnostic markers that allow an early diagnosis and an early initiation of specific therapy. Clinical diagnosis of Alzheimer's disease (AD), the most common neurodegenerative disorder, reaches 80-90% accuracy upon autopsy in specialized clinical centers. Diagnosis of AD in early clinical or preclinical stages is far less accurate, as is the differential diagnosis between AD and other primary dementias, such as frontotemporal dementia (FTD). Microtubule-associated tau protein is abnormally phosphorylated in AD and aggregates as paired helical filaments in neurofibrillary tangles. Recently, immunoassays have been developed detecting tau phosphorylated at specific epitopes in cerebrospinal fluid (CSF). Four years of clinical research consistently demonstrate that CSF phosphorylated tau (p-tau) is highly increased in AD compared to healthy controls and may differentiate AD from its most relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau(231)) shows excellent differentiation between AD and FTD, whereas serine 181 (p-tau(181)) enhances accurate differentiation between AD and dementia with Lewy bodies. Moreover, p-tau(231) levels decline with disease progression, correlating with cognitive performance at baseline. Total tau (t-tau) is regarded as a general marker of neurodegeneration for evaluation in future population-based studies. p-tau(231) and p-tau(181) yield excellent discrimination between AD and non-AD dementias including FTD, exceeding the differential diagnostic and prognostic accuracy of t-tau. Therefore, p-tau is a core biological marker candidate for future evaluation in large national and international multicenter networks., (Copyright 2004 S. Karger AG, Basel)

Background: Abnormal hyperphosphorylation of the microtubule-associated protein tau and its incorporation into neurofibrillary tangles are major hallmarks of the pathogenesis of Alzheimer disease (AD). Different tau phosphoepitopes can be sensitively detected in cerebrospinal fluid (CSF)., Objective: To compare the diagnostic accuracy of CSF concentrations of tau proteins phosphorylated at 3 pathophysiologically important epitopes (p-tau) to discriminate among patients with AD, nondemented control subjects, and patients with other dementias., Design and Setting: Cross-sectional, bicenter, memory clinic-based studies., Participants: One hundred sixty-one patients with a clinical diagnosis of AD, frontotemporal dementia, dementia with Lewy bodies, or vascular dementia and 45 nondemented controls (N = 206)., Main Outcome Measures: Levels of tau protein phosphorylated at threonine 231 (p-tau231), threonine 181 (p-tau181), and serine 199 (p-tau199). The CSF p-tau protein levels were measured using 3 different enzyme-linked immunosorbent assays., Results: The mean CSF levels of the studied p-tau proteins were significantly elevated in patients with AD compared with the other groups. Applied as single markers, p-tau231and p-tau181 reached specificity levels greater than 75% between AD and the combined non-AD group when sensitivity was set at 85% or greater. Statistical differences between the assay performances are presented. Particularly, discrimination between AD and dementia with Lewy bodies was maximized using p-tau181at a sensitivity of 94% and a specificity of 64%, and p-tau231 maximized group separation between AD and frontotemporal dementia with a sensitivity of 88% and a specificity of 92%. Combinations of the 3 markers did not add discriminative power compared with the application as single markers., Conclusions: The p-tau proteins in CSF come closest to fulfilling the criteria of a biological marker of AD. There is a tendency for p-tau proteins to perform differently in the discrimination of primary dementia disorders from AD.

Background: White matter hyperintensities (WMH) on MRI scans indicate lesions of the subcortical fiber system. The regional distribution of WMH may be related to their pathophysiology and clinical effect in vascular dementia (VaD), Alzheimer's disease (AD) and healthy aging., Methods: Regional WMH volumes were measured in MRI scans of 20 VaD patients, 25 AD patients and 22 healthy elderly subjects using FLAIR sequences and surface reconstructions from a three-dimensional MRI sequence., Results: The intraclass correlation coefficient for interrater reliability of WMH volume measurements ranged between 0.99 in the frontal and 0.72 in the occipital lobe. For each cerebral lobe, the WMH index, i.e. WMH volume divided by lobar volume, was highest in VaD and lowest in healthy controls. Within each group, the WMH index was higher in frontal and parietal lobes than in occipital and temporal lobes. Total WMH index and WMH indices in the frontal lobe correlated significantly with the MMSE score in VaD. Category fluency correlated with the frontal lobe WMH index in AD, while drawing performance correlated with parietal and temporal lobe WMH indices in VaD., Conclusions: A similar regional distribution of WMH between the three groups suggests a common (vascular) pathogenic factor leading to WMH in patients and controls. Our findings underscore the potential of regional WMH volumetry to determine correlations between subcortical pathology and cognitive impairment., (Copyright 2004 S. Karger AG, Basel)

Objective: Aging in Down's syndrome is accompanied by amyloid and neurofibrillary pathology, the regional and laminar distribution of which resembles pathological changes seen in Alzheimer's disease. Previous studies using magnetic resonance imaging (MRI) demonstrated age-related atrophy of medial temporal lobe structures in nondemented older subjects with Down's syndrome, reflecting early allocortical pathology. Corpus callosum atrophy has been established as a marker of neocortical neuronal loss in Alzheimer's disease. This study investigated whether atrophy of the corpus callosum and hippocampus occurs in nondemented subjects with Down's syndrome and compared the degree of age-related atrophy between these structures., Method: Hippocampus and corpus callosum measures were obtained from volumetric T(1)-weighted MRI scans of 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women) and 31 healthy comparison subjects (mean age=41.8 years, 14 women)., Results: Down's syndrome subjects had smaller corpus callosum areas and hippocampal volumes relative to age-matched healthy comparison subjects, even after age and total intracranial volume were controlled. There was an age-related decrease of corpus callosum area (most prominent in posterior regions) and hippocampal volume in the Down's syndrome group. The degree of the age effect was comparable between the total corpus callosum and hippocampus, and corpus callosum size was correlated with cognitive performance in the Down's syndrome subjects. There was no correlation between age and corpus callosum or hippocampal size in the comparison group., Conclusions: Comparable decrease of corpus callosum and hippocampal size with age in nondemented subjects with Down's syndrome suggests that neocortical neuronal alterations accompany allocortical changes in the predementia phase of Down's syndrome.

Objective: Differentiation of geriatric major depression from Alzheimer's disease is hampered by overlapping symptoms. Increased CSF concentrations of tau protein phosphorylated at threonine 231 (p-tau(231)) have been suggested as a biomarker for Alzheimer's disease. The authors asked whether p-tau(231) levels improve the differential diagnosis between geriatric major depression and Alzheimer's disease., Method: Included were 34 depression subjects, 64 with probable Alzheimer's disease, 17 with possible Alzheimer's disease, and 21 healthy comparison subjects. P-tau(231) concentrations were measured with an enzyme-linked immunosorbent assay., Results: P-tau(231) levels were significantly higher in Alzheimer's disease than in geriatric major depression patients and healthy comparison subjects. For differentiation of probable Alzheimer's disease from major depression, p-tau(231) correctly allocated 87% of subjects. When possible mild Alzheimer's disease was compared to major depression, p-tau(231) correctly allocated 78% of subjects., Conclusions: CSF p-tau(231) should be evaluated as a potential biological marker for differentiation of geriatric depression from Alzheimer's disease.

We used volumetric MRI and analysis of areas under receiver operating characteristic (ROC) curves to directly compare the extent of hippocampus-amygdala formation (HAF) and corpus callosum atrophy in patients with Alzheimer's disease (AD) in different clinical stages of dementia. Based on neuropathological studies, we hypothesized that HAF atrophy, representing allocortical neuronal degeneration, would precede atrophy of corpus callosum, representing loss of neocortical association neurons, in early AD. HAF and corpus callosum sizes were significantly reduced in 27 AD patients (37% and 16%, respectively) compared to 28 healthy controls. In mildly- and moderately-demented AD patients, the ROC derived index of atrophy was greater for HAF volume than for total corpus callosum area. The index of atrophy of posterior corpus callosum was not significantly different from HAF at mild, moderate or severe stages of dementia. In conclusion, these findings suggest a characteristic regional pattern of allocortical and neocortical neurodegeneraton in AD. Our data indicate that neuronal loss in parietotemporal cortex (represented by atrophy of corpus callosum splenium) may occur simultaneously with allocortical neurodegeneration in mild AD. Moreover, ROC analysis may provide a statistical framework to determine atrophy patterns of different brain structures in neurodegenerative diseases in vivo.

In this longitudinal study of 77 patients with mild cognitive impairment (MCI), the authors analyzed whether levels of tau protein phosphorylated at threonine 231 (p-tau(231)) in CSF correlate with progression of cognitive decline. High CSF p-tau(231) levels at baseline, but not total tau protein levels, correlated with cognitive decline and conversion from MCI to AD. Independently, old age and APOE-epsilon 4 carrier status were predictive as well. Our data indicate that an increased p-tau(231) level is a potential risk factor for cognitive decline in patients with MCI.

Background: Phosphorylation of tau protein at threonine 231 (using full-length tau, 441 amino acids, for the numbering scheme) (p-tau(231)) occurs specifically in postmortem brain tissue of patients with Alzheimer disease (AD) and can be sensitively detected in cerebrospinal fluid (CSF)., Objectives: To determine to what extent CSF levels of p-tau(231) distinguish patients with AD from control subjects and from patients with other dementias, and to investigate whether p-tau(231) levels are a better diagnostic marker than levels of total tau protein (t-tau) in CSF., Design and Setting: Cross-sectional, multicenter, memory clinic-based studies., Participants: One hundred ninety-two patients with a clinical diagnosis of AD, frontotemporal dementia (FTD), vascular dementia, Lewy body dementia, or other neurological disorder and healthy controls., Main Outcome Measures: Levels of CSF tau proteins as measured with enzyme-linked immunosorbent assays., Results: Mean CSF levels of p-tau(231) were significantly elevated in the AD group compared with all other groups. Levels of p-tau(231) did not correlate with dementia severity in AD, and discriminated with a sensitivity of 90.2% and a specificity of 80.0% between AD and all non-AD disorders. Moreover, p-tau(231) levels improved diagnostic accuracy compared with t-tau levels when patients with AD were compared with healthy controls (P =.03) and demented subjects (P<.001), particularly those with FTD (P<.001), but not those with vascular and Lewy body dementias. Sensitivity levels between AD and FTD were raised by p-tau(231) compared with t-tau levels from 57.7% to 90.2% at a specificity level of 92.3% for both markers., Conclusion: Increased levels of CSF p-tau(231) may be a useful, clinically applicable biological marker for the differential diagnosis of AD, particularly for distinguishing AD from FTD.

Neuropathological studies in Alzheimer's disease (AD) indicate specific loss of layer III and V large pyramidal neurons in association cortex. These neurons give rise to long cortico-cortical connections, projecting through the corpus callosum, in an anterior-posterior topology. Based on these findings we hypothesized that regional corpus callosum atrophy may be a potential in vivo marker for neocortical neuronal loss in AD. To evaluate this hypothesis, we developed a method to measure cross-sectional area of the corpus callosum and of five corpus callosum subregions on midsagittal magnetic resonance imaging scans (MRI). In a subsequent series of six experimental studies using MRI, (18)FDG-PET and EEG, we investigated the relation of white matter hyperintensities (WMH) to corpus callosum size and correlated regional pattern of corpus callosum atrophy with regional cortical metabolic decline as well as intracortical coherencies. Mean total corpus callosum area was reduced significantly in AD patients compared to healthy age-matched controls, with the greatest changes in the rostrum and the splenium and relative sparing of the truncus. The regional pattern of corpus callosum atrophy was independent of WMH load and correlated significantly with pattern of regional metabolic decline measured with (18)FDG-PET, the degree of cognitive impairment and regional decline of bilateral intracortical-coherency in EEG in AD patients. We further found that hippocampus atrophy, as a marker of early allocortical degeneration, was more pronounced than total corpus callosum atrophy in mild stages of AD. Regional corpus callosum atrophy in mild disease, however, suggested early neocortical degeneration in AD. In a longitudinal study, AD patients showed significantly greater rates of corpus callosum atrophy than controls. Rates of atrophy correlated with progression of clinical dementia severity in AD. Our results indicate that regional corpus callosum atrophy in AD patients represents the loss of callosal efferent neurons in corresponding regions of the neocortex. As these neurons are a subset of cortico-cortical projecting neurons, region-specific corpus callosum atrophy may serve as a marker of progressive neocortical disconnection in AD. In combination with measurement of hippocampal atrophy, assessment of corpus callosum atrophy over time in individual patients is useful to evaluate effects on brain structure of currently developed drugs, thought to slow or modify AD progression.

Objective: The specificity of magnetic resonance imaging (MRI)-based hippocampal measurements in detecting Alzheimer's disease (AD) pathology is reduced by an age-related reduction of the hippocampus volume. We propose an adjustment for this age effect to increase the diagnostic accuracy of hippocampal volumes in AD., Method: Using an orthogonal rotational transformation of the coordinate system, values of MRI-determined volumes of hippocampus-amygdala formation (HAF) were transformed according to the age effect in 27 AD patients and 28 age- and sex-matched healthy control subjects., Results: The age transformation increased the diagnostic accuracy of HAF volumes in the study sample and in an independent sample from the literature. The age-transformed HAF volume predicted AD in a subject with mild cognitive impairment (MCI) with later biopsy-confirmed AD., Conclusion: Age transformation may provide an easily applicable method to increase the clinical diagnostic accuracy of hippocampal measurements by considering the effect of aging on hippocampus volume.

Background: Neurodegenerative and cerebrovascular diseases show a distinct distribution of regional atrophy and subcortical lesions., Objective: To develop an easily applicable landmark-based method for segmentation of the brain into the four cerebral lobes from MRI images., Method: The segmentation method relies on a combination of anatomical landmarks and geometrical definitions. It is applied on the surface reconstruction of the MRI volume. The internal borders between the lobes are defined on the axial slices of the brain. The reliability of this method was determined from MRI scans of 10 subjects. To illustrate the use of the method, it was applied to MRI scans of an independent group of 10 healthy elderly subjects and 10 patients with vascular dementia to determine the regional distribution of white matter hyperintensities (WMH)., Results: The intra-rater relative error (and intra-class correlation coefficient) of the lobe segmentation ranged from 1.6% to 6.9% (from 0.91 to 0.99). The inter-rater relative error (and intra-class correlation coefficient) ranged from 1.4% to 5.2% (from 0.96 to 0.99). Density of WMH was significantly higher in all four lobes in VD patients compared to controls (p<0.05). Within each group, WMH density was significantly higher in frontal and parietal than in temporal and occipital lobes (p<0.05)., Conclusion: This landmark based method can accommodate age and disease-related changes in brain morphology. It may be particularly useful for the study of neurodegenerative and cerebrovascular disease and for the validation of template-based automated techniques.

Background: Atrophy of the corpus callosum in the absence of primary white matter degeneration reflects loss of intracortical projecting neocortical pyramidal neurons in Alzheimer disease (AD)., Objectives: To determine individual rates of atrophy progression of the corpus callosum in patients with AD and to correlate rates of atrophy progression with clinical disease severity and subcortical disease., Methods: Magnetic resonance imaging-derived measurements of corpus callosum size were studied longitudinally in 21 patients clinically diagnosed as having AD (mean observation time, 17.0 +/- 8.5 months) and 10 age- and sex-matched healthy controls (mean observation time, 24.1 +/- 6.8 months)., Results: Corpus callosum size was significantly reduced in AD patients at baseline. Annual rates of atrophy of total corpus callosum, splenium, and rostrum were significantly larger in AD patients (-7.7%, -12.1%, and -7.3%, respectively) than in controls (-0.9%, -1.5%, and 0.6%, respectively). Rates of atrophy of the corpus callosum splenium were correlated with progression of dementia severity in AD patients (rho = 0.52, P<.02). The load of subcortical lesions at baseline (P<.05) predicted rate of anterior corpus callosum atrophy in healthy controls. Rates of atrophy of corpus callosum areas were independent of white matter hyperintensity load in patients with AD., Conclusions: Measurement of corpus callosum size allows in vivo mapping of neocortical neurodegeneration in AD over a wide range of clinical dementia severities and may be used as a surrogate marker for evaluation of drug efficacy.

Objective: Comparative study of CSF levels of tau and AD7C-neuronal thread protein (NTP) in patients with AD and control subjects., Background: AD is characterized by neurofibrillary tangles composed of the abnormally hyperphosphorylated microtubule-associated protein tau. AD7C-NTP is a proposed AD marker expressed at early stages of neurofibrillary degeneration., Methods: Enzyme-linked immunosorbent assays specific for tau and AD7C-NTP. CSF samples were obtained from 35 demented patients (25 with antemortem clinical diagnosis of probable AD, 5 with neuropathologic diagnosis of definite AD, 5 with Lewy body pathology), 29 nondemented patients with PD, and 16 elderly healthy control subjects. Receiver operating characteristics (ROC) and multivariate discriminant analysis for AD versus controls. Correlational analysis of CSF tau and AD7C-NTP and of each marker with Mini-Mental State Examination (MMSE) scores was performed., Results: Levels of both tau and AD7C-NTP were significantly elevated in the AD patients compared with control subjects. ROC analysis showed that CSF tau distinguished between patients with AD and nondemented control subjects with 63% sensitivity and 89% specificity, AD7C-NTP with 70% sensitivity and 87% specificity. Combined evaluation of both markers with discriminant analysis raised the specificity to 93% at a 63% sensitivity level. Both markers positively correlated with each other within the AD group, but not among control subjects. CSF levels of AD7C-NTP, but not of tau, showed a small but significant inverse correlation (r = -0.43) with MMSE scores of AD patients., Conclusions: CSF levels of tau and AD7C-NTP may be useful biomarkers for AD.

Tau protein is consistently reported to be elevated in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF tau alone, however, is not a clinically useful diagnostic marker due to its relatively low diagnostic specificity. Therefore, efforts are under way to combine tau measurements with other criteria in order to improve diagnostic applicability. We investigated whether age could serve as an useful criterion to increase diagnostic accuracy. CSF levels of tau were measured in young old (<70 years) and old old (> or =70 years) patients with probable AD, elderly patients with major depression (MD), and age-matched healthy controls (HC). In AD patients, CSF tau levels were significantly elevated compared with MD patients and HC (P < 0.001). Based on a previously established cut-off of 260 pg/ml, the discriminative power was higher in the young old than in the old old subjects. Similarly, receiver operating characteristics analysis revealed a statistically significant higher correct classification rate in the young old. Our findings indicate that the discriminative power of CSF tau is higher in the young than in the old old. We suggest that the effect of age should be considered in studies investigating CSF tau as a diagnostic marker for neurodegenerative disorders.

Background: Positron emission tomographic studies of patients with Alzheimer disease (AD) suggest a loss of metabolic functional interactions between different cortical regions. Atrophy of the corpus callosum as the major tract of intracortical connective fibers may reflect decreased cortical functional integration in AD., Objectives: To investigate whether regional atrophy of the corpus callosum is correlated with regional reductions of cortical glucose metabolism, as shown by positron emission tomography, and whether primary white matter degeneration is a possible cofactor of corpus callosum atrophy in AD., Patients and Methods: We measured total and regional cross-sectional areas of the corpus callosum on midsagittal magnetic resonance imaging scans from 12 patients with AD and 15 age-matched control subjects. Regional cerebral metabolic rates for glucose in cortical lobes were measured by positron emission tomography using fludeoxyglucose F 18. White matter hyperintensities were rated in T2-weighted magnetic resonance imaging scans., Results: The total cross-sectional area of corpus callosum was significantly reduced in patients with AD, with the most prominent changes in the rostrum and splenium and relative sparing of the body of the corpus callosum. Frontal and parietal lobe metabolism was correlated with the truncal area of the corpus callosum in AD. The ratios of frontal to parietal and of frontal to occipital metabolism were correlated with the ratio of anterior to posterior corpus callosum area in the group with AD. White matter hyperintensities did not correlate with corpus callosum atrophy in the patients with AD., Conclusion: The regional pattern of corpus callosum atrophy correlated with reduced regional glucose metabolism independently of primary white matter degeneration in the patients with AD.

Alzheimer's disease (AD) still can only be definitively diagnosed with certainty by examination of brain tissue. There is a great need for a noninvasive, sensitive and specific in vivo test for AD. We combined cerebrospinal fluid analyses of tau protein (levels were significantly increased in AD patients [p=0.0001]), a putative marker of neuronal degeneration, with components of the soluble interleukin-6 receptor complex (sIL-6RC: IL-6, soluble IL-6 receptor and soluble gp130), putative markers of neuroregulatory and inflammatory processes in the brain. A stepwise multivariate discriminant analysis revealed that tau protein and soluble gp130 (levels were significantly reduced in AD subjects [p=0.007]), the affinity converting and signal-transducing receptor of neuropoietic cytokines, maximized separation between the investigated groups. The discriminant function predicted 23 of 25 clinically diagnosed AD patients (sensitivity 92%) with mild to moderate dementia correctly as having AD. Furthermore, 17 of 19 physically and cognitively healthy age-matched control subjects (specificity 90%) were accurately distinguished by this test. Later predicting with the jackknife procedure each case in turn through the remaining patient group, the discriminant function remained stable. Our data suggest that multivariate discriminant analysis of combined CSF tau protein and sIL-6RC components may add more certainty to the diagnosis of AD, however, the method will need to be extended to an independent group of patients, comparisons and control subjects to assess the true applicability., (Copyright 1999 Elsevier Science B.V.)

Interleukin-6 (IL-6) is hypothesized to play an important role in the interaction between immune mechanisms and the central nervous system. We investigated whether cerebrospinal fluid (CSF) concentrations of interleukin-6 (IL-6), the soluble IL-6 receptor (sIL-6R) and the soluble form of the signal transducing and affinity converting receptor gp130 (sgp130) are altered in geriatric patients with major depression (MD). In 20 geriatric patients with MD and 20 age-matched healthy control subjects CSF concentrations of the three components of the sIL-6R complex were analyzed by enzyme-linked immunosorbent assays (ELISA). All patients except one were treated with psychotropic drugs. We found statistically significant decreased CSF concentrations of IL-6 (P<0.001) and of the sIL-6R (P<0.001) of patients with MD. Levels of sgp130 showed no statistically significant difference between patients and controls.

Objective: To determine whether the size of the corpus callosum is related to the extent of white matter pathology in patients with AD and age-matched healthy control subjects., Methods: White matter hyperintensity load and corpus callosum size were compared between 20 clinically diagnosed AD patients and 21 age-matched healthy control subjects. We investigated the effect of age and disease severity on corpus callosum size and white matter hyperintensity, in addition to the relation between corpus callosum areas and white matter hyperintensity load., Results: We found significant regional atrophy of the corpus callosum in AD when compared with control subjects, although the groups did not differ in their white matter hyperintensity load. We further showed a region-specific correlation between corpus callosum size and white matter hyperintensity in the control group but not in AD patients. In the AD group, corpus callosum size correlated with age and dementia severity, whereas white matter hyperintensity correlated only with age., Conclusion: Corpus callosum atrophy in AD can occur independent of white matter degeneration, likely reflecting specific AD pathology in projecting neurons.

In the first part of a three-part series on the role of positron emission tomography (PET) in the study of neurodegeneration and aging in the human brain, the authors review the historical development of the in vivo measurement of brain function resulting in recent advances in PET technology. An overview is presented of the physical principles of PET scanning and the inherent limitations of this technology to set the basis for the critical interpretation of PET data presented in the second and third parts and in the ever-increasing number of PET studies on the brain in different physiological and pathological conditions. Finally, the authors describe the ability to measure in vivo regional cerebral glucose metabolism with [(18)F]-FDG PET, regional cerebral blood flow and the distribution and binding capacity of neuroreceptors. They conclude with future perspectives of PET technology and its relevance, especially for neuropsychiatric research., ((c) 1988 Prous Science. All rights reserved.)

Background: Pathological studies in Alzheimer disease indicate the specific loss of layer III and V large pyramidal neurons in association cortex. These neurons give rise to long corticocortical connections within and between the cerebral hemispheres., Objective: To evaluate the corpus callosum as an in vivo marker for cortical neuronal loss., Method: Using a new imaging technique, we measured region-specific corpus callosum atrophy in patients with Alzheimer disease and correlated the changes with neuropsychological functioning. Total cross-sectional area of the corpus callosum and areas of 5 callosal subregions were measured on midsagittal magnetic resonance imaging scans of 14 patients with Alzheimer disease (mean age, 64.4 years; Mini-Mental State Examination score, 11.4) and 22 healthy age- and sex-matched control subjects (mean age, 66.6 years; Mini-Mental State Examination score, 29.8). All subjects had minimal white matter changes., Results: The total callosal area was significantly reduced in the patients with Alzheimer disease, with the greatest changes in the rostrum and splenium and relative sparing of the callosal body. Regional callosal atrophy correlated significantly with cognitive impairment in the patients with Alzheimer disease, but not with age or the white matter hyperintensities score., Conclusions: Callosal atrophy in patients with Alzheimer disease with only minimal white matter changes may indicate loss of callosal efferent neurons in corresponding regions of the cortex. Because these neurons are a subset of corticocortical projecting neurons, region-specific callosal atrophy may serve as a marker of progressive neocortical disconnection in Alzheimer disease.

The function of the cytokine interleukin-6 (IL-6) is augmented by soluble IL-6 receptors (sIL-6R). We investigated cerebrospinal fluid sIL-6R concentrations in patients with Alzheimer's disease (AD) compared to age-matched healthy subjects and individuals with at least one first degree relative with AD. We found a statistically significant decrease in sIL-6R levels in the AD group compared to controls. Complete analysis of the IL-6R complex seems crucial to better understand the impact of IL-6 in AD pathophysiology.

One of the most widely used neuroimaging procedures in Psychiatry and Neurology is magnetic resonance imaging (MRI). MRI has gained the position of a standard investigation in the differential diagnosis of dementia syndromes. In the clinical diagnosis of Alzheimer's disease (AD) MRI helps to improve the diagnostical accuracy. Recently new MRI-based techniques for performing volumetric measurement of cortical and subcortical structures have been developed. First reports indicate that MRI-based volumetric measurements can be accurate in differentiating AD patients from cognitively normal elderly individuals. These new techniques may be useful adjunct in assessing the clinical diagnosis of AD. Results could also yield insight in the fundamental pathology of the degenerative disease. It is the objective of this chapter to summarize and comment on the significance of MRI in the diagnosis and research of AD. Future directions are outlined, including the use of microscopic MRI, the differentiation of white matter signal hyperintensities and the combined evaluation of structural MRI and functional imaging techniques.