Maria F. Falangola

Age‐related non‐Gaussian diffusion patterns in the prefrontal brain

To characterize age‐related MR diffusion patterns of the prefrontal brain cortex microstructure using a new method for investigating the non‐Gaussian behavior of water diffusion called diffusional kurtosis imaging (DKI).

Preliminary evidence of altered gray and white matter microstructural development in the frontal lobe of adolescents with attention‐deficit hyperactivity disorder: A diffusional kurtosis imaging study

To investigate non‐Gaussian water diffusion using diffusional kurtosis imaging (DKI) to assess age effects on gray matter (GM) and white matter (WM) microstructural changes in the prefrontal cortex (PFC) of adolescents with attention‐deficit hyperactivity disorder (ADHD) compared to typically developing controls (TDC).

Preliminary observations of increased diffusional kurtosis in human brain following recent cerebral infarction.

By application of the MRI method of diffusional kurtosis imaging, a substantially increased diffusional kurtosis was observed within the cerebral ischemic lesions of three stroke subjects, 13–26 h following the onset of symptoms. This increase is interpreted as probably reflecting a higher degree of diffusional heterogeneity in the lesions when compared with normal‐appearing contralateral tissue. In addition, for two of the subjects with white matter infarcts, the increase had a strong fiber tract orientational dependence. It is proposed that this effect is consistent with a large drop in the intra‐axonal diffusivity, possibly related to either axonal varicosities or alterations associated with the endoplasmic reticulum. Copyright

MRI assessment of neuropathology in a transgenic mouse model of Alzheimer's disease

The cerebral deposition of amyloid β‐peptide, a central event in Alzheimers disease (AD) pathogenesis, begins several years before the onset of clinical symptoms. Noninvasive detection of AD pathology at this initial stage would facilitate intervention and enhance treatment success. In this study, high‐field MRI was used to detect changes in regional brain MR relaxation times in three types of mice: 1) transgenic mice (PS/APP) carrying both mutant genes for amyloid precursor protein (APP) and presenilin (PS), which have high levels and clear accumulation of β‐amyloid in several brain regions, starting from 10 weeks of age; 2) transgenic mice (PS) carrying only a mutant gene for presenilin (PS), which show subtly elevated levels of Aβ‐peptide without β‐amyloid deposition; and 3) nontransgenic (NTg) littermates as controls. The transverse relaxation time T2, an intrinsic MR parameter thought to reflect impaired cell physiology, was significantly reduced in the hippocampus, cingulate, and retrosplenial cortex, but not the corpus callosum, of PS‐APP mice compared to NTg. No differences in T1 values or proton density were detected between any groups of mice. These results indicate that T2 may be a sensitive marker of abnormalities in this transgenic mouse model of AD. Magn Reson Med 51:794–798, 2004.

Novel White Matter Tract Integrity Metrics Sensitive to Alzheimer Disease Progression

BACKGROUND AND PURPOSE: Along with cortical abnormalities, white matter microstructural changes such as axonal loss and myelin breakdown are implicated in the pathogenesis of Alzheimer disease. Recently, a white matter model was introduced that relates non-Gaussian diffusional kurtosis imaging metrics to characteristics of white matter tract integrity, including the axonal water fraction, the intra-axonal diffusivity, and the extra-axonal axial and radial diffusivities. MATERIALS AND METHODS: This study reports these white matter tract integrity metrics in subjects with amnestic mild cognitive impairment (n = 12), Alzheimer disease (n = 14), and age-matched healthy controls (n = 15) in an effort to investigate their sensitivity, diagnostic accuracy, and associations with white matter changes through the course of Alzheimer disease. RESULTS: With tract-based spatial statistics and region-of-interest analyses, increased diffusivity in the extra-axonal space (extra-axonal axial and radial diffusivities) in several white matter tracts sensitively and accurately discriminated healthy controls from those with amnestic mild cognitive impairment (area under the receiver operating characteristic curve = 0.82–0.95), while widespread decreased axonal water fraction discriminated amnestic mild cognitive impairment from Alzheimer disease (area under the receiver operating characteristic curve = 0.84). Additionally, these white matter tract integrity metrics in the body of the corpus callosum were strongly correlated with processing speed in amnestic mild cognitive impairment (r = |0.80–0.82|, P < .001). CONCLUSIONS: These findings have implications for the course and spatial progression of white matter degeneration in Alzheimer disease, suggest the mechanisms by which these changes occur, and demonstrate the viability of these white matter tract integrity metrics as potential neuroimaging biomarkers of the earliest stages of Alzheimer disease and disease progression.

Non-Gaussian diffusion MRI assessment of brain microstructure in mild cognitive impairment and Alzheimer's disease☆

We report the first application of a novel diffusion-based MRI method, called diffusional kurtosis imaging (DKI), to investigate changes in brain tissue microstructure in patients with mild cognitive impairment (MCI) and AD and in cognitively intact controls. The subject groups were characterized and compared in terms of DKI-derived metrics for selected brain regions using analysis of covariance with a Tukey multiple comparison correction. Receiver operating characteristic (ROC) and binary logistic regression analyses were used to assess the utility of regional diffusion measures, alone and in combination, to discriminate each pair of subject groups. ROC analyses identified mean and radial kurtoses in the anterior corona radiata as the best individual discriminators of MCI from controls, with the measures having an area under the ROC curve (AUC) of 0.80 and 0.82, respectively. The next best discriminators of MCI from controls were diffusivity and kurtosis (both mean and radial) in the prefrontal white matter (WM), with each measure having an AUC between 0.77 and 0.79. Finally, the axial diffusivity in the hippocampus was the best overall discriminator of MCI from AD, having an AUC of 0.90. These preliminary results suggest that non-Gaussian diffusion MRI may be beneficial in the assessment of microstructural tissue damage at the early stage of MCI and may be useful in developing biomarkers for the clinical staging of AD.

Magnetic field correlation as a measure of iron-generated magnetic field inhomogeneities in the brain.

The magnetic field correlation (MFC) at an applied field level of 3 Tesla was estimated by means of MRI in several brain regions for 21 healthy human adults and 1 subject with aceruloplasminemia. For healthy subjects, highly elevated MFC values compared with surrounding tissues were found within the basal ganglia. These are argued as being primarily the result of microscopic magnetic field inhomogeneities generated by nonheme brain iron. The MFC in the aceruloplasminemia subject was significantly higher than for healthy adults in the globus pallidus, thalamus and frontal white matter, consistent with the known increased brain iron concentration associated with this disease. Magn Reson Med 61:481–485, 2009.

White matter tract integrity metrics reflect the vulnerability of late-myelinating tracts in Alzheimer's disease

Post-mortem and imaging studies have observed that white matter (WM) degenerates in a pattern inverse to myelin development, suggesting preferential regional vulnerabilities influencing cognitive decline in AD. This study applied novel WM tract integrity (WMTI) metrics derived from diffusional kurtosis imaging (DKI) to examine WM tissue properties in AD within this framework. Using data from amnestic mild cognitive impairment (aMCI, n = 12), AD (n = 14), and normal control (NC; n = 15) subjects, mixed models revealed interaction effects: specific WMTI metrics of axonal density and myelin integrity (i.e. axonal water fraction, radial extra-axonal diffusivity) in late-myelinating tracts (i.e. superior and inferior longitudinal fasciculi) changed in the course of disease, but were stable in the initial stages for early-myelinating tracts (i.e. posterior limb of the internal capsule, cerebral peduncles). WMTI metrics in late-myelinating tracts correlated with semantic verbal fluency, a cognitive function known to decline in AD. These findings corroborate the preferential vulnerability of late-myelinating tracts, and illustrate an application of WMTI metrics to characterizing the regional course of WM changes in AD.

Histological correlation of diffusional kurtosis and white matter modeling metrics in cuprizone-induced corpus callosum demyelination.

The cuprizone mouse model is well established for studying the processes of both demyelination and remyelination in the corpus callosum, and it has been utilized together with diffusion tensor imaging (DTI) to investigate myelin and axonal pathology. Although some underlying morphological mechanisms contributing to the changes in diffusion tensor (DT) metrics have been identified, the understanding of specific associations between histology and diffusion measures remains limited. Diffusional kurtosis imaging (DKI) is an extension of DTI that provides metrics of diffusional non‐Gaussianity, for which an associated white matter modeling (WMM) method has been developed. The main goal of the present study was to quantitatively assess the relationships between diffusion measures and histological measures in the mouse model of cuprizone‐induced corpus callosum demyelination. The diffusional kurtosis (DK) and WMM metrics were found to provide additional information that enhances the sensitivity to detect the morphological heterogeneity in the chronic phase of the disease process in the rostral segment of the corpus callosum. Specifically, in the rostral segment, axonal water fraction (d = 2.6; p < 0.0001), radial kurtosis (d = 2.0; p = 0.001) and mean kurtosis (d = 1.5; p = 0.005) showed the most sensitivity between groups with respect to yielding statistically significant p values and high Cohens d values. These results demonstrate the ability of DK and WMM metrics to detect white mater changes and inflammatory processes associated with cuprizone‐induced demyelination. They also validate, in part, the application of these new WMM metrics for studying neurological diseases, as well as helping to elucidate their biophysical meaning. Copyright

Diffusional Kurtosis and Diffusion Tensor Imaging Reveal Different Time-Sensitive Stroke-Induced Microstructural Changes

Background and Purpose— Diffusion MRI is a promising, clinically feasible imaging technique commonly used to describe white matter changes after stroke. We investigated the sensitivity of diffusion MRI to detect microstructural alterations in gray matter after sensorimotor cortex stroke in adult male rats. Methods— The mean diffusivity (MD) and mean kurtosis of perilesional motor cortex were compared with measures in the contralesional forelimb area of sensorimotor cortex at 2 hours, 24 hours, 72 hours, or 25 days after surgery. MD and mean kurtosis were correlated to the surface densities of glia, dendrites, and axons. Results— Perilesional mean kurtosis was increased at 72 hours and 25 days after stroke, whereas MD was no longer different from contralesional sensorimotor cortex at 24 hours after stroke. There was a significant increase in the density of glial processes at 72 hours after stroke in perilesional motor cortex, which correlated with perilesional MD. Conclusions— These data support that mean kurtosis and MD provide different but complimentary information on acute and chronic changes in perilesional cortex. Glia infiltration is associated with pseudonormalization of MD in the perilesional motor cortex at 72 hours after lesion; however, this association is absent 25 days after lesion. These data suggest that there are likely several different, time-specific microstructural changes underlying these 2 complimentary diffusion measures.