Potential Pitfalls of Using Fractional Anisotropy, Axial Diffusivity, and Radial Diffusivity as Biomarkers of Cerebral White Matter Microstructure

Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) are commonly used as MRI biomarkers of white matter microstructure in diffusion MRI studies of neurodevelopment, brain aging, and neurologic injury/disease. Some of the more frequent practices include performing voxel-wise or region-based analyses of these measures to cross-sectionally compare individuals or groups, longitudinally assess individuals or groups, and/or correlate with demographic, behavioral or clinical variables. However, it is now widely recognized that the majority of cerebral white matter voxels contain multiple fiber populations with different trajectories, which renders these metrics highly sensitive to the relative volume fractions of the various fiber populations, the microstructural integrity of each constituent fiber population, and the interaction between these factors. Many diffusion imaging experts are aware of these limitations and now generally avoid using FA, AD or RD (at least in isolation) to draw strong reverse inferences about white matter microstructure, but based on the continued application and interpretation of these metrics in the broader biomedical/neuroscience literature, it appears that this has perhaps not yet become common knowledge among diffusion imaging end-users. Therefore, this paper will briefly discuss the complex biophysical underpinnings of these measures in the context of crossing fibers, provide some intuitive “thought experiments” to highlight how conventional interpretations can lead to incorrect conclusions, and suggest that future studies refrain from using (over-interpreting) FA, AD, and RD values as standalone biomarkers of cerebral white matter microstructure.

Short-Term Treatment with Alirocumab, Flow-Dependent Dilatation of the Brachial Artery and Use of Magnetic Resonance Diffusion Tensor Imaging to Evaluate Vascular Structure: An Exploratory Pilot Study

Background: Short-term effects of alirocumab on vascular function have hardly been investigated. Moreover, there is a scarce of reliable non-invasive methods to evaluate atherosclerotic changes of the vasculature. The ALIROCKS trial was performed to address these issues using standard ultrasound-based procedures and a completely novel magnetic resonance-based imaging technique. Methods: A total of 24 patients with an indication for treatment with PCSK9 antibodies were recruited. There were 2 visits to the study site, the first before initiation of treatment with alirocumab and the second after 10 weeks of treatment. The key outcome measures included the change of carotid vessel wall fractional anisotropy, a novel magnetic resonance-based measure of vascular integrity, and the changes of carotid intima-media thickness and flow-dependent dilatation of the brachial artery measured with ultrasound. Results: A total of 19 patients completed the trial, 2 patients stopped treatment, 3 patients did not undergo the second visit due to the COVID pandemic. All of them had atherosclerotic vascular disease. Their mean (standard deviation) LDL-cholesterol concentration was 154 (85) mg/dL at baseline and was reduced by 76 (44) mg/dL in response to alirocumab treatment (p < 0.001, n = 19). P-selectin and vascular endothelial growth factors remained unchanged. Flow-dependent dilatation of the brachial artery (+41%, p = 0.241, n = 18), carotid intima-media thickness (p = 0.914, n = 18), and fractional anisotropy of the carotid artery (p = 0.358, n = 13) also did not significantly change. Conclusion: Despite a nominal amelioration for flow-dependent dilatation, significant effects of short-term treatment with alirocumab on vascular function were not detectable. More work would be needed to evaluate, whether fractional anisotropy may be useful in clinical atherosclerosis research.

Breast milk exposure is associated with cortical maturation in preterm infants

Breast milk exposure is associated with improved neurocognitive outcomes following preterm birth but the neural substrates linking nutrition with outcome are uncertain. By combining nutritional data with brain MRI, we tested the hypothesis that high versus low breast milk exposure in preterm infants during neonatal care results in a cortical morphology that more closely resembles that of infants born at term. We studied 135 preterm (mean gestational age 30+2 weeks, range 22+1 to 32+6) and 77 term-born infants (mean gestational age 39+4 weeks, range 36+3 to 42+1). Nutritional data was collected from birth until hospital discharge to identify the proportion of days preterm infants received exclusive breast milk. Structural and diffusion MRI were performed at term-equivalent age. Cortical indices (volume, thickness, surface area, gyrification index, sulcal depth, curvature) and water diffusion parameters (fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, neurite density index, orientation dispersion index) were compared between preterm infants who received exclusive breast milk for <75% of inpatient days (n=68), preterm infants who received exclusive breast milk for ≥75% of inpatient days (n=67) and term-born controls (n=77). High breast milk exposure was associated with reduced cortical gray matter volume (d=0.47, p=0.014), thickness (d=0.42, p=0.039) and radial diffusivity (d=0.38, p=0.039), and increased fractional anisotropy (d=0.38, p=0.037) after adjustment for age at MRI. High versus low breast milk exposure in the weeks following preterm birth is associated with a cortical imaging phenotype that more closely resembles the brain morphology of healthy infants born at term.

Microscopic Fractional Anisotropy Detects Cognitive Training-Induced Microstructural Brain Changes

Cognitive training-induced neuroplastic brain changes have been reported. This prospective study evaluated whether microscopic fractional anisotropy (μFA) derived from double diffusion encoding (DDE) MRI could detect brain changes following a 4 week cognitive training. Twenty-nine healthy volunteers were recruited and randomly assigned into the training (n = 21) and control (n = 8) groups. Both groups underwent brain MRI including DDE MRI and 3D-T1-weighted imaging twice at an interval of 4–6 weeks, during which the former underwent the training. The training consisted of hour-long dual N-back and attention network tasks conducted five days per week. Training and time-related changes of DDE MRI indices (μFA, fractional anisotropy (FA), and mean diffusivity (MD)) and the gray and white matter volume were evaluated using mixed-design analysis of variance. In addition, any significant imaging indices were tested for correlation with cognitive training-induced task performance changes, using partial correlation analyses. μFA in the left middle frontal gyrus decreased upon the training (53 voxels, uncorrected p < 0.001), which correlated moderately with response time changes in the orienting component of attention (r = −0.521, uncorrected p = 0.032). No significant training and time-related changes were observed for other imaging indices. Thus, μFA can become a sensitive index to detect cognitive training-induced neuroplastic changes.

Myelin Water Fraction in Relation To Fractional Anisotropy and Reading in 10-Year-Old Children

Diffusion-weighted imaging studies have repeatedly shown that white matter correlates with reading throughout development. However, the neurobiological interpretation of this relationship is constrained by the limited microstructural specificity of diffusion imaging. A critical component of white matter microstructure is myelin, which can be investigated noninvasively using MRI. Here, diffusion-weighted as well as myelin water imaging were applied to examine the links of myelin water fraction (MWF) with fractional anisotropy (FA; a common diffusion index) and reading ability in 10-year-old children (n = 69). The results replicate previous reports on a positive relationship between FA and MWF, which is significant in dorsal but not ventral tracts. Moreover, our findings revealed a negative correlation between word reading and MWF in left reading-related white matter tracts. Altogether, this study contributes important insights into the role of myelin-related processes in the relationship between reading and white matter structure.

Increased muscle fiber fractional anisotropy value using diffusion tensor imaging after compression without fiber injury

Background Recent studies have indicated that injuries such as muscle tears modify the microstructural integrity of muscle, leading to substantial alterations in measured diffusion parameters. Therefore, the fractional anisotropy (FA) value decreases. However, we hypothesized that soft tissue, such as muscle tissue, undergoes reversible changes under conditions of compression without fiber injury. Purpose To evaluate the FA change due to compression in muscle tissue without fiber injury. Material and Methods Diffusion tensor imaging (DTI) was performed on both feet of 10 healthy volunteers (mean age = 35.0 ± 10.39 years; age range = 23–52 years) using a 3.0-T magnetic resonance imaging (MRI) scanner with an eight-channel phased array knee coil. An MRI-compatible sphygmomanometer was applied to the individuals’ lower legs and individuals were placed in a compressed state. Then, rest intervals of 5 min were set in re-rest state after compression. The FA value, apparent diffusion coefficient (ADC), and eigenvalues (λ1, λ2, λ3) of the gastrocnemius and soleus muscle were measured at each state. Results The mean FA values increased in all muscles in a compressed state, while the mean λ3 decreased. In all muscles, significant differences were found between the rest and compressed states in terms of mean FA and λ3 ( P < 0.0001). Conclusion We confirmed the reversibility of the DTI metrics, which suggests that there was no muscle injury during this study. In cases of compression without fiber injury, the FA value increases, because fibers are strongly aligned in the longitudinal direction.

Exposure to prenatal maternal distress and infant white matter neurodevelopment

The prenatal period represents a critical time for brain growth and development. These rapid neurological advances render the fetus susceptible to various influences with life-long implications for mental health. Maternal distress signals are a dominant early life influence, contributing to birth outcomes and risk for offspring psychopathology. This prospective longitudinal study evaluated the association between prenatal maternal distress and infant white matter microstructure. Participants included a racially and socioeconomically diverse sample of 85 mother–infant dyads. Prenatal distress was assessed at 17 and 29 weeks’ gestational age (GA). Infant structural data were collected via diffusion tensor imaging (DTI) at 42–45 weeks’ postconceptional age. Findings demonstrated that higher prenatal maternal distress at 29 weeks’ GA was associated with increased fractional anisotropy, b = .283, t(64) = 2.319, p = .024, and with increased axial diffusivity, b = .254, t(64) = 2.067, p = .043, within the right anterior cingulate white matter tract. No other significant associations were found with prenatal distress exposure and tract fractional anisotropy or axial diffusivity at 29 weeks’ GA, or earlier in gestation.

Age Differences in Diffusivity in the Locus Coeruleus and its Ascending Noradrenergic Tract

The noradrenergic locus coeruleus (LC) is a small brainstem nucleus that promotes arousal and attention. Recent studies have examined the microstructural properties of the LC using diffusion-weighted magnetic resonance imaging and found unexpected age-related differences in fractional anisotropy - a measure of white matter integrity. Here, we used three datasets (Berlin Aging Study-II, N = 301, the Leipzig Study for Mind-Body-Emotion Interactions, N = 220, and Stockholm Sleepy Brain, N = 49), to replicate published findings and expand them by investigating diffusivity in the LC's ascending noradrenergic bundle. In younger adults, LC fractional anisotropy was significantly lower, compared to older adults. However, in the LC's ascending noradrenergic bundle, we observed significantly higher fractional anisotropy in younger adults, relative to older adults. These findings indicate that diffusivity in the LC versus the ascending noradrenergic bundle are both susceptible to microstructural changes in aging that have opposing effects on fractional anisotropy.