Lies Clerx

New MRI Markers for Alzheimer's Disease: A Meta-Analysis of Diffusion Tensor Imaging and a Comparison with Medial Temporal Lobe Measurements

The aim of the present study is to evaluate the diagnostic value of diffusion tensor imaging (DTI) for early Alzheimers disease (AD) in comparison to widely accepted medial temporal lobe (MTL) atrophy measurements. A systematic literature research was performed into DTI and MTL atrophy in AD and mild cognitive impairment (MCI). We included seventy-six studies on MTL atrophy including 8,122 subjects and fifty-five DTI studies including 2,791 subjects. Outcome measure was the effect size (ES) expressed as Hedges g. In volumetric studies, atrophy of the MTL significantly differentiated between AD and controls (ES 1.32-1.98) and MCI and controls (ES 0.61-1.46). In DTI-Fractional anisotropy (FA) studies, the total cingulum differentiated best between AD and controls (ES = 1.73) and the parahippocampal cingulum between MCI and controls (ES = 0.97). In DTI-Mean diffusivity (MD) studies, the hippocampus differentiated best between AD and controls (ES = -1.17) and between MCI and controls (ES = -1.00). We can conclude that in general, the ES of volumetric MTL atrophy measurements was equal or larger than that of DTI measurements. However, for the comparison between controls and MCI-patients, ES of hippocampal MD was larger than ES of hippocampal volume. Furthermore, it seems that MD values have somewhat more discriminative power than FA values with higher ES in the frontal, parietal, occipital and temporal lobe.

Sensitivity of Different MRI-Techniques to Assess Gray Matter Atrophy Patterns in Alzheimer’s Disease is Region-Specific

The present study compares four different structural magnetic resonance imaging techniques used to measure gray matter (GM) atrophy in Alzheimers disease (AD): manual and automated volumetry, cortical thickness (CT) and voxel-based morphometry (VBM). These techniques are used interchangeably in AD research and thus far it is unclear which technique is superior in detecting abnormalities early in the disease process. 18 healthy participants without any memory impairment, 18 patients with MCI, and 17 patients with mild AD were included and between-group differences were investigated in AD signature regions (areas in the prefrontal cortex (PFC), medial temporal lobe (MTL) and posterior parietal cortex (PPC)). Both manual volumetric measurements and VBM were able to detect GM atrophy in the early stages (differentiation controls and MCI), mainly in the MTL. In the early phase, automated volumetric measurements showed GM differences in the PPC but not in the MTL. In our sample, CT measurements were not sensitive for group differences in the early stages. PFC regions showed abnormalities in the later stages (controls vs AD) when manual volumetric measurements or VBM are employed. Manual volumetric measurements together with VBM are preferred techniques for assessing GM differences showing abnormalities in most of the investigated regions, with a predominance of the MTL in the early phase. Automated FreeSurfer volumetric measurements show similar performances in the early phase, displaying group differences in the PPC but not in MTL regions. Measurements of CT are less sensitive in the MCI stage and its sensitivity is restricted to the MTL and PPC regions in later stages of the disease (AD).

White Matter Hyperintensities are Positively Associated with Cortical Thickness in Alzheimer's Disease

White matter hyperintensities are associated with an increased risk of Alzheimers disease (AD). White matter hyperintensities are believed to disconnect brain areas. We examined the topographical association between white matter hyperintensities and cortical thickness in controls, mild cognitive impairment (MCI), and AD patients. We examined associations between white matter hyperintensities and cortical thickness among 18 older cognitively healthy participants, 18 amnestic MCI, and 17 mild AD patients. These associations were cluster-size corrected for multiple comparisons. In controls, a positive association between white matter hyperintensities and cortical thickness was found in lateral temporal gyri. In MCI patients, white matter hyperintensities were positively related to cortical thickness in frontal, temporal, and parietal areas. Positive associations between white matter hyperintensities and cortical thickness in AD patients were confined to parietal areas. The results of the interaction group by white matter hyperintensities on cortical thickness were consistent with the findings of positive associations in the parietal lobe for MCI and AD patients separately. In the frontal areas, controls and AD patients showed inverse associations between white matter hyperintensities and cortical thickness, while MCI patients still showed a positive association. These results suggest that a paradoxical relationship between white matter hyperintensities and cortical thickness could be a consequence of neuroinflammatory processes induced by AD-pathology and white matter hyperintensities. Alternatively, it might reflect a region-specific and disease-stage dependent compensatory hypertrophy in response to a compromised network.

Can FreeSurfer Compete with Manual Volumetric Measurements in Alzheimer's Disease?

Alzheimers disease-related pathology results in tremendous structural and functional changes in the brain. These morphological changes might lead to a less precise performance of automated brain segmentation techniques in AD-patients, which in turn could possibly lead to false allocations of gray matter, white matter or cerebrospinal fluid. FreeSurfer has been shown to operate as an accurate and reliable instrument to measure cortical thickness and volume of neuroanatomical structures. Considering the principal role of FreeSurfer in the imaging field of AD, the present study aims to investigate the robustness of FreeSurfer to capture morphological changes in the brain against varying processing variables in comparison to manual measurements (the gold standard). T1-weighted MRI scan data were used pertaining to a sample of 53 individuals (18 healthy participants, 18 patients with mild cognitive impairment, and 18 patients with mild AD). Data were analyzed with different FreeSurfer versions (v4.3.1, v4.5.0, v5.0.0, v5.1.0), on a custom-built cluster (LINUX) and a Macintosh (UNIX) workstation. Group differences across versions and workstations were most consistent for both the hippocampus and posterior cingulate, regions known to be affected in the earliest stages of the disease. The results showed that later versions of FreeSurfer were more sensitive to identify group differences and corresponded best with the results of gold standard manual volumetric methods. In conclusion, later versions of FreeSurfer were more accurate than earlier versions, especially in medial temporal and posterior parietal regions. This development is very promising for future applications of FreeSurfer in research studies and encourages the future role of FreeSurfer output as a candidate marker in clinical practice.

Comparison of measurements of medial temporal lobe atrophy in the prediction of Alzheimer's Disease in subjects with MCI

molecules. The interaction of both labelled donor and acceptor molecules induced a fluorescence at 665nm proportional to the sAPP alpha level. A recombinant protein was used as standard. We investigated the CSF from 30 patients with AD, and 30 controls. CSFs were considered as AD profile according to tau protein, phosphorylated tau and As 1-42 results, as previously described (1). Excluded patients on the basis of CSF markers levels were considered as controls. Results: The test did not recognize recombinant sAPPs protein and As1-42 peptide. Sample dilutions (1/5, 1/10, 1/20) allowed to verify the response linearity. The test detected 3 ng/ml of sAPP alpha. 5 ml of sample was sufficient for the CSF quantification. Using this test, we could observed a significant increase of sAPP alpha in the CSF of 30 AD patients comparatively to 30 controls (AD:530 6 36 ng/ml; controls: 3936 28 ng/ml; p< 0.01). Interestingly, sAPP alpha was significantly correlated with As levels in control CSFs only (r2 :0.31; p< 0.001). No significant correlations were observed between tau or phosphorylated tau and sAPP alpha levels in CSF. Conclusions:We developed a very sensitive test for the quantification of sAPP alpha levels in human CSF. Using this test, we observed an increase of sAPP alpha level in the CSF of AD patients in absence of correlation with other markers contrary to that observed in controls. It will be interesting to investigate a larger population of AD and Mild Cognitive Impairment patients to study the putative correlations of sAPP alpha levels with the biomarkers and parameters of the disease. 1: DumurgierJ et al, (2010) NeurobiolDis. 40: 456-459

New MRI markers for Alzheimer's disease: a meta-analysis of diffusion tensor imaging and a comparison with medial temporal lobe measurements

cognitively normal (CN), mild cognitive impairment (MCI) and Alzheimer’s disease (AD). The purpose of this study is to investigate the change of PIB retention after one-year follow up in CN old individuals and patients with MCI and AD. Methods: 22 CN, 19 MCI, and 19 mild AD subjects were included. For each group, the proportion of apolipoprotein e4 positive cases was approximately 50% for each of the three groups. All subjects underwent clinical assessments and PIB PET at two time points, approximately one year apart. PIB retention was quantified in regional cortical to cerebellar ratio units.Results: In CN, PIB retention at one-year follow up increased significantly compared with baseline value in the diffuse brain regions including the frontal, lateral temporal, medial temporal, lateral parietal, posterior cingulate-precuneus (PC-PRC), and occipital cortices, and basal ganglia. In contrast, such longitudinal increase of regional PIB retention was observed only in the lateral parietal and PC-PRC for MCI, and only in the PC-PRC for AD. Conclusions: The results of this study indicate that the regional pattern of longitudinal PIB retention change is different across the spectrum of cognitive ability. PIB retention seems to be already saturated in diffuse cortical regions in MCI and early clinical AD.

Vascular and amyloid pathologies in memory clinic patients: Synergetic or independent?

Background: The locus coeruleus (LC) is a brainstem nucleus that has widespread projections to modulate states of attention. It has been shown that tau pathology is frequently seen in the LC in individual under 30 years of age, suggesting Alzheimer’s disease (AD)-associated tau pathology begins in the LC. The magnetic resonance (MR) T1-signal derived from neuromelanin (NM) is considered to be a surrogate maker for the neural density of the LC. The purpose of this study was to investigate associations of a cognitive function, years of school education, and MR signal of the LC. Methods:Subjects were 58 cognitively normal elderly subjects (69.4(60-79)y.o., MMSE mean(range): 28.8(25-30)) who underwent T1-wieghted high resolution MR imaging of the brain stem and 3D T1-weighted whole brain MR imaging. The brain stem image was coregistrated to the whole brain image and spatially normalized with DARTEL. The mean signal intensity of LC was calculated using regions of interest (ROI) that were placed on the hyperintensity derived from NM of the LC at -26.0 to -19.0 in Z coordinate in the MNI stereotactic space. The mean signal ratio (mSR) of the LC was calculated as mSR1⁄4(SLC–SDS)/SDS, where SLC and SDS are the signal intensities of the LC and superior cerebellar peduncle decussation, respectively. Single and multiple regression analyses were done for digit span backward score, age, years of school education (Education), and mSR. Results: The mSR declined a mean of 0.289 unit per year in a single regression analysis (p1⁄40.028). Digit span backward score had a positive association with mSR (p1⁄40.028, R̂21⁄40.083) in a single regression. In a multiple regression analysis to predict the digit span backward score, statistically significant terms were mSR (p1⁄40.026) and mSR x Education (p1⁄40.003). Adding the interaction term improved the goodness of fit from F1⁄45.095 (p1⁄40.028) to F1⁄47.921 (p1⁄40.001). The single term of Education was not significant (p1⁄40.071). Conclusions: The results suggest NM in the LC shows age-related decline. Higher educational attainment supports working memory and attention control tasks like digit span backward mainly through the interaction with the LC.

REDUCED CALLOSAL WHITE MATTER INTEGRITY SURPASSES CEREBROSPINAL FLUID AND ATROPHY MARKERS AS PREDICTOR OF DECLINE IN SUBJECTS WITH MILD COGNITIVE IMPAIRMENT: A COMBINED VOLUMETRY AND DTI STUDY

the increased blood inflow from the arterial-venous shunts; increased looping of distal intracranial arterial branches. The degree of vascular changes severity did not depend on AD stage and was practically the same in all cases. Conclusions: The data obtained suggest that microcirculatory disorders and atrophic phenomena are interrelated, but DAAT phenomena are primary in AD progression and occur long before the disease onset, while atrophic changes are secondary and progress against DAAT during AD.

The stability of resting state networks in aging: Relevance for early memory dysfunction

in the preclinical stages of AD. Identifying brain biomarkers of AD risk in this group could help promote preclinical diagnosis of AD and early intervention and prevention strategies. OBJECTIVE: To characterize the relationship between relative cerebral blood flow (rCBF), CSF biomarkers, and age in asymptomatic middle-aged adults with a parental history of AD. Methods: CSF biomarkers were measured in 96 non-demented, middle-aged adult children of persons with AD (mean6SD; age1⁄453.568.0yrs; n1⁄466 [69%] women; n1⁄435 [36%] apolipoprotein E e4 allele carriers [APOE4+]). Among this group, 42 participants (age1⁄453.866.9yrs; n1⁄430 [71%] women; n1⁄414 [33%] APOE4+) underwent 1.5T-DSC perfusionweighted MRI scans which were used to estimate measures of rCBF. CSF b-amyloid1-42 (Ab1-42), total-tau (T-tau) and phosphorylated tau (P-tau 181) were analyzed using the INNO-BIA AlzBio3 (xMAP) assay. CSF Abx-38, Abx-40 and Abx-42 were measured using Meso Scale Discovery (MSD ) electrochemiluminescence. Results: A semi-partial regression model controlling for systolic blood pressure (SBP) and APOE4 status revealed that age was a) negatively associated with rCBF within a region of left parahippocampal gyrus (PHG) (Figure) and b) positively associated with seven CSF measures: Abx-38, Abx-40, Abx-42, T-tau, P-tau 181, the ratio (T-tau)/(Ab42), and the ratio (P-tau 181)/(Ab42). CBF within left PHG, however, was not associated with any of the CSF measures when controlling for age. Conclusions: In asymptomatic adult children of persons with AD, CBF and CSF biomarkers are significantly associated with increasing age but appear to be independent of each other in the preclinical stages of the disease. Whereas cerebrovascular dysfunction and Ab dysregulation likely interact and accelerate neurodegeneration later in the disease course, these processes may not interact with each other as strongly during this asymptomatic stage. The temporal point at which CBF and Ab processes significantly affect each other requires further longitudinal investigation.

De meerwaarde van diffusie gewogen beeldvorming bij de vroegdiagnostiek van de ziekte van Alzheimer

De ziekte van Alzheimer is de meest voorkomende vorm van dementie, die wereldwijd ongeveer 34 miljoen mensen treft. Onderzoekers voorspellen een tsunami van dementie, waarbij de prevalentie van de ziekte zal verdriedubbelen als gevolg van de vergrijzing van de bevolking. De toename in prevalentie en de ernst van deze ziekte leiden tot een dwingende noodzaak voor vroegdiagnostiek. Een behandeling met als doel genezing van de ziekte is tot dusver niet voor handen. Wanneer de ziekte echter in een vroege fase wordt gediagnosticeerd, kan het opstarten van bijvoorbeeld cholinesterase-inhibitoren verdere evolutie enigszins uitstellen en het gedrag van de patiënt positief beïnvloeden. Onderzoek naar de ziekte van Alzheimer heeft zich daarom veelal gefocust op het vroege stadium, de milde cognitieve stoornis, een overgangsfase tussen normale veroudering en beginnende alzheimerdementie (Jack et al.,2005; Petersen et al.,1999). Vijf tot 40 procent van de patiënten met een milde cognitieve stoornis converteert elk jaar naar de ziekte van Alzheimer (Bruscoli & Lovestone,2004). Niet iedereen die lijdt aan een milde cognitieve stoornis zal uiteindelijk naar de ziekte van Alzheimer converteren. Een deel van deze patiënten blijft gedurende lange tijd stabiel, de meerderheid zal echter binnen de twee tot vier jaar duidelijke symptomen van dementie ontwikkelen.Imaging as diagnostic tool for Alzheimer’s disease has been of major importance in the last decade. Measurement of atrophic processes in gray matter structures of the brain such as the medial temporal lobe can aid the diagnostic process. Recently, new techniques are developed which can assess the integrity of white matter. White matter integrity is known to decrease in subjects with mild cognitive impairment and Alzheimer’s disease. Diffusion tensor imaging is a promising technique which evaluates the integrity of white matter in the brain. This technique can be of particular importance to improve current diagnostic practice (e.g. neuropsychological testing and measurement of medial temporal lobe atrophy). A recent meta-analysis has evaluated the value of diffusion tensor imaging for the diagnosis of early Alzheimer’s disease, in relation to existing imaging markers (atrophy of the medial temporal lobe). The main findings of this study are discussed here.