[Structural and functional neuronal connectivity in Alzheimer's disease: a combined DTI and fMRI study]. / Strukturelle und funktionelle neuronale Konnektivität bei der Alzheimer-Krankheit : Eine kombinierte DTI- und fMRT-Studie.

BACKGROUND: Cognitive performance depends on intact cortical connectivity. Important for memory processing in the human brain is the connection between posterior cingulate cortex and hippocampus, directly as well as indirectly via the parahippocampal gyrus. These brain areas are involved early in Alzheimer's disease (AD). At the same time, they belong to the default mode network (DMN), a functional network showing high functional connectivity under resting state conditions. In AD, this connectivity in specifically compromised, offering the possibility to investigate the structural basis of functional brain connectivity. METHODS: We studied 18 patients with mild to moderate AD, 16 patients with mild cognitive impairment (MCI) and 20 healthy control subjects using diffusion tensor imaging (DTI) and resting state fMRI at 3.0 Tesla. We determined the effect of structural integrity in the posterior cingulate as assessed by DTI on the functional connectivity between posterior cingulate, hippocampus and parahippocampus during resting state in these three groups. RESULTS: Structural integrity was reduced in posterior cingulate fibre tracts in patients with AD in the left hemisphere; however, this effect was partly accounted for by age differences. All three groups showed high functional connectivity between posterior cingulate cortex and hippocampus, via both the direct and the indirect pathways. Determination of effective connectivity yielded a negative fractional anisotropy (FA)-moderated correlation on the direct pathway in AD and MCI for both hemispheres, and in healthy controls for the right hemisphere. The indirect pathway showed a negative FA-moderated correlation in AD for the right hemisphere and in MCI for both hemispheres. Healthy controls showed a positive correlation on the indirect pathway for the left hemisphere. CONCLUSION: Our data suggest that under healthy conditions, effective connectivity in the DMN between posterior cingulate cortex and hippocampus is mainly maintained by the indirect pathway via the parahippocampal gyrus. Patients with AD and patients with MCI show changes in this connectivity with a partial allocation to the direct pathway, most likely reflecting early parahippocampal lesions. The combination of DTI and fMRI broadens our understanding of human brain connectivity and its pathological changes with AD.

Longitudinal changes of fractional anisotropy in Alzheimer's disease patients treated with galantamine: a 12-month randomized, placebo-controlled, double-blinded study.

Diffusion tensor imaging (DTI) demonstrates decline of fractional anisotropy (FA) as a marker of fiber tract integrity in Alzheimer's disease (AD). We aimed to assess the longitudinal course of white matter microstructural changes in AD and healthy elderly control (HC) subjects and to evaluate the effects of treatment with the cholinesterase inhibitor galantamine on white matter microstructure in AD patients. We enrolled 28 AD patients and 11 healthy elderly control subjects (HC). AD patients were randomly assigned to 6-month double-blind galantamine treatment or placebo, with a 6-month open-label extension phase. DTI was performed at baseline, as well as at 6 and 12-month follow-up in AD patients. The HC subjects underwent DTI at baseline and 12-month follow-up without treatment. We measured FA in regions of interest covering the posterior cingulate and corpus callosum. At 6-month follow-up, the AD group showed significant FA decline in the left posterior cingulate. FA decline was significantly preserved in the posterior body of the corpus callosum in AD group with treatment compared to placebo. At 12-month follow-up, the AD patients showed no differences in FA decline between initial treatment and placebo groups after the 6-month open-label extension phase. A significant FA decline occurred in the left posterior cingulate across the AD and HC groups without between-group differences. DTI demonstrated FA decline in intracortically projecting fiber tracts in aging and AD over 1 year. Galantamine had limited impact on regional FA decline, which was not preserved after additional 6-month open-label treatment.

A novel MRI-biomarker candidate for Alzheimer's disease composed of regional brain volume and perfusion variables.

BACKGROUND: Earlier evidence indicates that regional cerebral volume (rVOL) and blood flow (rCBF) variables carry independent information on incipient and early Alzheimer's disease (AD) and combining these modalities may increase discriminant performance. We compared single variables and combinations regarding their power for optimizing diagnostic accuracy. METHODS: Twelve cognitively normal elderly controls (CN), 30 subjects with mild cognitive impairment (MCI) and 15 with mild AD were examined by structural and perfusion-weighted magnetic resonance imaging (MRI) in single sessions at 1.5 Tesla. rVOLs were measured by manual volumetry, and rCBFs were calculated with a ROI-based co-localization technique. RESULTS: Applying single MRI variables for the differentiation of AD versus CN, the area under curve (AUC) of receiver operating characteristic curves (ROCCs) was highest for rVOL variables (maximum of 0.972 for right amygdala). A composite marker selected and weighted by logistic regression containing left amygdalar rCBF, left hippocampal and right amygdalar rVOLs gave a diagnostic accuracy for AD versus CN of 100%. Internal cross-validation revealed a reliability of 88.9%. CONCLUSIONS: Whilst external revalidation is mandatory employing a naturalistic sample containing disease controls, our phase I/II findings demonstrate that deducing composite markers from multimodal MRI acquisitions can optimize diagnostic accuracy for AD.

[Current status of cognition-based interventions in Alzheimer's disease]. / Kognitionsbezogene Interventionen bei Alzheimer-Krankheit: Aktueller Stand und Perspektiven.

At present more than 1 million patients in Germany suffer from Alzheimer's disease (AD). This number is expected to double by 2050. The effectiveness of presently approved specific antidementive drugs for symptomatic treatment of AD is still not satisfactory. The question arises whether cognition-based nonpharmacologic measures may constitute an effective intervention in AD and its prodromal stages. The paper at hand defines theoretical general principles of cognitive training and gives an overview of recent findings that provide evidence of its effectiveness. We finally present recommendations for future studies and establishment of cognitive training.

[Alzheimer's disease and vascular dementia. Determination of atrophy of the corpus callosum and cerebral cortex]. / Alzheimer-Krankheit und vaskuläre Demenz. Bestimmung der Atrophie des Corpus callosum und des zerebralen Kortex.

BACKGROUND: Measurement of regional atrophy of the corpus callosum and cortical grey matter may differentiate between primary loss of intracortical projecting neurons and primary fibre degeneration in Alzheimer's disease (AD) and vascular dementia (VD). METHODS: The regional corpus callosum area and cortical grey matter volumes were measured in 30 patients with the clinical diagnosis of probable AD, 20 patients with the clinical diagnosis of probable VD and 24 healthy elderly control subjects using MRI in two centers in Munich and Amsterdam. RESULTS: Patients with AD showed significantly reduced volumes of cortical grey matter in all cerebral lobes and atrophy of anterior and posterior corpus callosum areas. In VD patients only occipital lobe grey matter volume and anterior corpus callosum area were significantly reduced. In AD patients reduction of cortical grey matter volumes was significantly correlated with regional reductions of corpus callosum areas, but not in VD patients or controls. CONCLUSION: These findings support the notion that measurement of the corpus callosum and cortical grey matter atrophy may identify the underlying causes of cortical disconnection in AD and VD and may be helpful to differentiate between both conditions.

CSF total and phosphorylated tau protein, regional glucose metabolism and dementia severity in Alzheimer's disease.

BACKGROUND AND PURPOSE: We investigated associations between severity of cognitive impairment, cerebrospinal fluid (CSF) concentrations of total-tau (t-tau) protein and tau phosphorylated at threonin 181 (p-tau(181)) and regional glucose metabolism measured with 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) in patients with probable Alzheimer's disease (AD). METHODS: In 38 patients (mean age 66.5 +/- 8.0 years) with AD, Mini-Mental State Examination (MMSE) scores were evaluated and CSF levels of t-tau and p-tau(181) measured. All patients underwent an 18F-FDG-PET scan. Image analysis including correlation analysis and principal component analysis (PCA) were performed using SPM5 and VINCI. RESULTS: Dementia severity (MMSE 21.2 +/- 4.9) correlated well with metabolic impairment especially in left hemisphere association areas that are typically affected in patients with AD (e.g. inferior parietal lobule, r = 0.512; medial temporal gyrus, r = 0.478; inferior temporal gyrus, r = 0.488; precuneus, r = 0.468; PCA: r = 0.639, F = 7.751; all P < 0.001). There were no associations between t-tau and p-tau(181) with dementia severity and only weak correlations between t-tau and cerebral glucose metabolism (superior parietal gyrus, r = -0.325, P < 0.05; precentral gyrus r = -0.418, P < 0.01; amygdala r = -0.362, P < 0.05). No correlations were found between p-tau(181) and regional hypometabolism in FDG-PET. CONCLUSION: MMSE and CSF t-tau represent different aspects of disease severity. Whilst MMSE is closely related to impaired cerebral glucose metabolism, CSF t-tau is less closely related and appears to be less well suited for assessment of disease progression.

Structural brain alterations at different stages of schizophrenia: a voxel-based morphometric study.

Structural alterations in schizophrenia have mainly been regarded as the result of neurodevelopmental processes. However, it remains unresolved whether the pattern of morphological brain changes differs between different stages of disease. We examined structural brain changes in 93 first-episode (FES) and 72 recurrently ill (REZ) patients with schizophrenia (SZ) and 175 matched healthy control subjects (HC) using cross-sectional and conjunctional voxel-based morphometry (VBM) of whole-brain MRI data in a three-step approach. We found significant grey matter density (GMD) reductions in FES compared to HC bilaterally in the temporal and prefrontal areas, including the anterior cingulate gyrus, as well as in both thalami. Hippocampus and amygdala were affected on the left side (P<0.05, corrected). In REZ patients this pattern was spatially extended. The basal ganglia were exclusively reduced in the recurrently ill group compared to controls. Common to both disease groups were reductions in the bilateral perisylvian regions, the opercular region, the insula, prefrontal cortex, left inferior temporal gyrus, limbic system including hippocampus and amygdala, and the thalami. In FES patients there were no regions affected that were not also affected in REZ patients. In contrast, REZ patients showed extended alterations within the frontal and temporal regions, the hippocampus, amygdala and exclusively in the basal ganglia relative to the FES patients. Our findings suggest a system-specific involvement of neuronal networks in schizophrenia. Furthermore, our data suggest that in the advanced stages of schizophrenia additional cortical and subcortical brain areas become involved in the disease process. Longitudinal data will be required to further test this hypothesis.

Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI.

BACKGROUND: The measurement of hyperphosphorylated tau (p-tau) in CSF has been proposed as a biomarker candidate for the prediction of Alzheimer disease (AD) in patients with mild cognitive impairment (MCI). However, a standard quantitative criterion of p-tau has not been evaluated. OBJECTIVE: To assess in a multicenter study the predictive accuracy of an a priori defined criterion of tau phosphorylated at threonine 231 (p-tau(231)) for the prediction of conversion from MCI to AD during a short-term observation interval. METHODS: The study included 43 MCI converters, 45 stable MCI (average follow-up interval = 1.5 years), and 57 healthy controls (at baseline only). Subjects were recruited at four international expert sites in a retrospective study design. Cox regression models stratified according to center were used to predict conversion status. Bootstrapped 95% CIs of classification accuracy were computed. RESULTS: Levels of p-tau(231) were a significant predictor of conversion (B = 0.026, p = 0.001), independent of age, gender, Mini-Mental State Examination, and ApoE genotype. For an a priori-defined cutoff point (27.32 pg/mL), sensitivity ranged between 66.7 and 100% and specificity between 66.7 and 77.8% among centers. The bootstrapped mean percentage of correctly classified cases was 79.95% (95% CI = 79.9 to 80.00%). Post hoc defined cutoff values yielded a mean bootstrapped classification accuracy of 80.45% (95% CI = 80.24 to 80.76%). CONCLUSIONS: An a priori defined cutoff value of p-tau(231) yields relatively stable results across centers, suggesting a good feasibility of a standard criterion of p-tau(231) for the prediction of Alzheimer disease.

Improving linear modeling of cognitive decline in patients with mild cognitive impairment: comparison of two methods.

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.

Age-dependent differences in human brain activity using a face- and location-matching task: an FMRI study.

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.

[Neurobiological early diagnosis of Alzheimer's disease]. / Neurobiologische frühdiagnostik der Alzheimer-krankheit.

In order to improve diagnosis of Alzheimer's disease (AD), candidate biological markers in CSF as well as structural and functional imaging were investigated. Biomarkers are clearly needed to support detection of incipient AD in subjects with mild cognitive impairment (MCI). To date the most promising core candidate markers are total and hyperphosphorylated tau protein and amyloid beta peptides in the CSF, as well as hippocampus and whole brain volumetry using MRI. None of the candidates has been finally validated and established for clinical routine so far. International controlled multicenter cooperative studies are ongoing to further develop these core diagnostic marker candidates (phase III). The core markers are reviewed in detail. Promising novel approaches are discussed.

[Dementia with Lewy bodies. Clinical improvement under treatment with an acetylcholinesterase inhibitor]. / Demenz mit Lewy-Körperchen. Besserung unter Therapie mit einem Acetylcholinesteraseinhibitor.

Dementia with Lewy Bodies (DLB) is the second most common form of dementia in the elderly. Core features of the DLB are fluctuating cognitive symptoms, visual hallucinations and spontaneous parkinsonism. The clinical diagnostic criteria are very useful in the differentiation between DLB and Alzheimer's disease. The deficits in cholinergic neurotransmission are pronounced and associated with cognitive and psychotic symptoms. An 83 years old patient with DLB showed well formed recurrent visual hallucinations and fluctuating cognition and attention. There was no response to treatment with atypical neuroleptics. The patient responded within few days to treatment with Donepezil. Both cognitive and behavioural symptoms were improved significantly.

Functional connectivity of the fusiform gyrus during a face-matching task in subjects with mild cognitive impairment.

Cognitive function requires a high level of functional interaction between regions of a network supporting cognition. Assuming that brain activation changes denote an advanced state of disease progression, changes in functional connectivity may precede changes in brain activation. The objective of this study was to investigate changes in functional connectivity of the right middle fusiform gyrus (FG) in subjects with mild cognitive impairment (MCI) during performance of a face-matching task. The right middle FG is a key area for processing face stimuli. Brain activity was measured using functional MRI. There were 16 MCI subjects and 19 age-matched healthy controls. The linear correlation coefficient was utilized as a measure of functional connectivity between the right middle FG and all other voxels in the brain. There were no statistical differences found in task performance or activation between groups. The right middle FG of the healthy control and MCI groups showed strong bilateral positive linear correlation with the visual cortex, inferior and superior parietal lobules, dorsolateral prefrontal cortex (DLPFC) and anterior cingulate. The healthy controls showed higher positive linear correlation of the right middle FG to the visual cortex, parietal lobes and right DLPFC than the MCI group, whereas the latter had higher positive linear correlation in the left cuneus. In the healthy controls, the right middle FG had negative linear correlation with right medial frontal gyrus and superior temporal gyrus and with left inferior parietal lobule (IPL), angular gyrus, superior frontal gyrus and anterior cingulate gyrus, but the MCI group had negative linear correlation with the left IPL, angular gyrus, precuneus, anterior cingulate, and to right middle temporal gyrus and posterior cingulate gyrus. In the negatively linearly correlated regions, the MCI group had reduced functional connectivity to the frontal areas, right superior temporal gyrus and left IPL. Different regions of the cuneus and IPL had increased functional connectivity in either group. The putative presence of Alzheimer's disease neuropathology in MCI affects functional connectivity from the right middle FG to the visual areas and medial frontal areas. In addition, higher linear correlation in the MCI group in the parietal lobe may indicate the initial appearance of compensatory processes. The results demonstrate that functional connectivity can be an effective marker for the detection of changes in brain function in MCI subjects.

Resting state glucose utilization and the CERAD cognitive battery in patients with Alzheimer's disease.

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.

Multicenter assessment of reliability of cranial MRI.

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.

Task difficulty in a simultaneous face matching task modulates activity in face fusiform area.

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.

Association between cognitive performance and cortical glucose metabolism in patients with mild Alzheimer's disease.

BACKGROUND: Neuronal and synaptic function in Alzheimer's disease (AD) is measured in vivo by glucose metabolism using positron emission tomography (PET). OBJECTIVE: We hypothesized that neuronal activation as measured by PET is a more sensitive index of neuronal dysfunction than activity during rest. We investigated if the correlations between dementia severity as measured with the Mini Mental State Examination (MMSE) and glucose metabolism are an artifact of brain atrophy. METHOD: Glucose metabolism was measured using [18F]fluorodeoxyglucose PET during rest and activation due to audiovisual stimulation in 13 mild to moderate AD patients (MMSE score > or = 17). PET data were corrected for brain atrophy. RESULTS: In the rest condition, glucose metabolism was correlated with the MMSE score primarily within the posterior cingulate and parietal lobes. For the activation condition, additional correlations were within the primary and association audiovisual areas. Most local maxima remained significant after correcting for brain atrophy. CONCLUSION: PET activity measured during audiovisual stimulation was more sensitive to functional alterations in glucose metabolism in AD patients compared to the resting PET. The association between glucose metabolism and MMSE score was not dependent on brain atrophy.

EEG coherence reflects regional corpus callosum area in Alzheimer's disease.

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.

Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease.

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.