Shades of white: diffusion properties of T1- and FLAIR-defined white matter signal abnormalities differ in stages from cognitively normal to dementia.

The underlying pathology of white matter signal abnormalities (WMSAs) is heterogeneous and may vary dependent on the magnetic resonance imaging contrast used to define them. We investigated differences in white matter diffusivity as an indicator for white matter integrity underlying WMSA based on T1-weighted and fluid-attenuated inversion recovery (FLAIR) imaging contrast. In addition, we investigated which white matter region of interest (ROI) could predict clinical diagnosis best using diffusion metrics. One hundred three older individuals with varying cognitive impairment levels were included and underwent neuroimaging. Diffusion metrics were extracted from WMSA areas based on T1 and FLAIR contrast and from their overlapping areas, the border surrounding the WMSA and the normal-appearing white matter (NAWM). Regional diffusivity differences were calculated with linear mixed effects models. Multinomial logistic regression determined which ROI diffusion values classified individuals best into clinically defined diagnostic groups. T1-based WMSA showed lower white matter integrity compared to FLAIR WMSA-defined regions. Diffusion values of NAWM predicted diagnostic group best compared to other ROI's. To conclude, T1- or FLAIR-defined WMSA provides distinct information on the underlying white matter integrity associated with cognitive decline. Importantly, not the "diseased" but the NAWM is a potentially sensitive indicator for cognitive brain health status.

White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-ß.

Cerebral small vessel disease (cSVD) and amyloid-ß (Aß) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Aß have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Aß pathology was assessed as cerebrospinal fluid-derived Aß1 - 42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Aß on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Aß and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Aß and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Aß42 levels, but not in individuals with normal CSF Aß42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Aß levels are at an increased risk of accelerated disease progression when concomitant cSVD is present.

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

Alzheimer's 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.

White matter hyperintensities are positively associated with cortical thickness in Alzheimer's disease.

White matter hyperintensities are associated with an increased risk of Alzheimer's 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.

Measurements of medial temporal lobe atrophy for prediction of Alzheimer's disease in subjects with mild cognitive impairment.

Our aim was to compare the predictive accuracy of 4 different medial temporal lobe measurements for Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Manual hippocampal measurement, automated atlas-based hippocampal measurement, a visual rating scale (MTA-score), and lateral ventricle measurement were compared. Predictive accuracy for AD 2 years after baseline was assessed by receiver operating characteristics analyses with area under the curve as outcome. Annual cognitive decline was assessed by slope analyses up to 5 years after baseline. Correlations with biomarkers in cerebrospinal fluid (CSF) were investigated. Subjects with MCI were selected from the Development of Screening Guidelines and Clinical Criteria for Predementia AD (DESCRIPA) multicenter study (n = 156) and the single-center VU medical center (n = 172). At follow-up, area under the curve was highest for automated atlas-based hippocampal measurement (0.71) and manual hippocampal measurement (0.71), and lower for MTA-score (0.65) and lateral ventricle (0.60). Slope analysis yielded similar results. Hippocampal measurements correlated with CSF total tau and phosphorylated tau, not with beta-amyloid 1-42. MTA-score and lateral ventricle volume correlated with CSF beta-amyloid 1-42. We can conclude that volumetric hippocampal measurements are the best predictors of AD conversion in subjects with MCI.

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 Alzheimer's 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.