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.

Cerebral White Matter Mediation of Age-Related Differences in Picture Naming Across Adulthood

As people age, one of the most common complaints is difficulty with word retrieval. A wealth of behavioral research confirms such age-related language production deficits, yet the structural neural differences that relate to age-related language production deficits remains an open area of exploration. Therefore, the present study used a large sample of healthy adults across adulthood to investigate how age-related white matter differences in three key left-hemisphere language tracts may contribute to age-related differences in language ability. Specifically, we used diffusion tensor imaging (DTI) to measure fractional anisotropy (FA) and radial diffusivity (RD) which are indicators of white matter structure. We then used a series of path models to test whether white matter from the superior longitudinal fasciculus (SLF), the inferior longitudinal fasciculus (ILF), and the frontal aslant tract (FAT) mediated age-related differences in one form of language production, picture naming. We found that FA, as well as RD from the SLF and FAT mediated the relation between age and picture naming performance, whereas a control tract (corticospinal; CST) was not a mediator. Moreover, differences between mediation of picture naming and a control naming condition suggest that left SLF has a greater role in higher-order aspects of naming, such as semantic and lexical selection whereas left FAT is more sensitive to sensorimotor aspects of fluency or speech motor planning. These results suggest that dorsal white matter contributes to age-related differences in generating speech and may be particularly important in supporting word retrieval across adulthood.

Early-onset vascular leukoencephalopathy caused by bi-allelic NOTCH3 variants

Objective Heterozygous NOTCH3 variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with patients typically presenting in adulthood. We describe three patients presenting at an early age with a vascular leukoencephalopathy. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene. Methods Clinical records and available MRI and CT scans of three patients from two unrelated families were retrospectively reviewed. Results The patients presented at 9-14 months of age with developmental delay, seizures, or both. The disease course was characterized by cognitive impairment and variably recurrent strokes, migraine attacks, and seizures. MRI findings pointed at a small vessel disease, with extensive cerebral white matter abnormalities, atrophy, lacunes in the basal ganglia, microbleeds and microcalcifications. The anterior temporal lobes were spared. Bi-allelic cysteine-sparing NOTCH3 variants in exons 1, 32 and 33 were found. Interpretation This study indicates that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL.

Investigation of the Relationship between MBP Gene Polymorphisms and Delayed Encephalopathy after Acute Carbon Monoxide Poisoning

Background Increasing evidence reveals that delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) results from the combined effects of environmental and genetic factors. The main pathological feature of DEACMP was generalized demyelination of cerebral white matter. Myelin basic protein (MBP) levels in cerebrospinal fluid (CSF) and serum samples from DEACMP patients were elevated.Objectives This study investigated the association of MBP single nucleotide polymorphisms(SNPs) (rs470555, rs470724, rs4890785, rs595997, rs76452994, and rs921336) with DEACMP. Methods We genotyped 416 DEACMP patients and 785 age, educational level, and sex-matched ACMP patients for rs470555, rs470724, rs4890785, rs595997, rs76452994, and rs921336 SNPs using the Agena MassArray. Results There were no significant differences in the allele frequency distribution, four genetic models, and genotype distributions between the DEACMP and ACMP groups for rs470555, rs470724, rs4890785, and rs595997. However, significant differences were observed for rs76452994 and rs921336.Conclusions This study revealed that the MBP polymorphisms, rs470555, rs470724, rs4890785, and rs595997, were not associated with DEACMP. Based on the codominant, dominant, and overdominant genetic inheritability patterns, the MBP rs76452994 and rs921366 polymorphisms were associated with DEACMP. Furthermore, the G allele of rs76452994 and T allele of rs921336 could lead to higher DEACMP risk.

Epstein-Barr Virus Encephalitis in a Patient with Rheumatoid Arthritis

A 53-year-old woman with a 6-year history of rheumatoid arthritis (RA) presented with pharyngeal pain, fever, and altered mental status. The patient had been treated with methotrexate (MTX) 12 mg/week, baricitinib 4 mg/day, and tacrolimus 2 mg/day. Magnetic resonance imaging of the brain revealed diffuse high-intensity lesions in the cerebral white matter, basal ganglia, brainstem, and right cerebellar hemisphere. She was diagnosed with Epstein-Barr virus (EBV) encephalitis due to elevated levels of EBV-DNA in the cerebrospinal fluid and serum. Although MTX-associated lymphoproliferative disorders are well-known complications in patients with RA, EBV encephalitis requires careful attention for such patients undergoing treatment with multiple potent immunosuppressants.

Association of Plasma Oligomerized Amyloid-β and Cerebral White Matter Lesions in a Health Screening Population

Background: Cerebral white matter lesions (WML) are related to a higher risk of vascular and Alzheimer’s dementia. Moreover, oligomerized amyloid-β (OAβ) can be measured from blood for dementia screening. Objective: We aimed to investigate the relationship of plasma OAβ levels with clinical and radiological variables in a health screening population. Methods: WML, other volumetric parameters of magnetic resonance images, cognitive assessment, and plasma OAβ level were evaluated. Results: Ninety-two participants were analyzed. The majority of participants’ clinical dementia rating was 0 or 0.5 (96.7%). White matter hyperintensities (WMH) increased with age, but OAβ levels did not (r2 = 0.19, p < 0.001, r2 = 0.03, p = 0.10, respectively). No volumetric data, including cortical thickness/hippocampal volume, showed any significant correlation with OAβ. Log-WMH volume was positively correlated with OAβ (r = 0.24, p = 0.02), and this association was significant in the periventricular area. White matter signal abnormalities from 3D-T1 images were also correlated with the OAβ in the periventricular area (p = 0.039). Multivariate linear regression showed that log-WMH values were independently associated with OAβ (B = 0.879 (95% confidence interval 0.098 –1.660, p = 0.028)). Higher tertiles of WMH showed higher OAβ levels than lower tertiles showed (p = 0.044). Using a cutoff of 0.78 ng/mL, the high OAβ group had a larger WMH volume, especially in the periventricular area, than the low OAβ group (p = 0.036). Conclusion: Both WML and plasma OAβ levels can be early markers for neurodegeneration in the healthcare population. The lesions, especially in the periventricular area, might be related to amyloid pathogenesis, which strengthens the importance of WML in the predementia stage.

Partial Volume Correction Increases the Sensitivity of 18F-Florbetapir-Positron Emission Tomography for the Detection of Early Stage Amyloidosis

Purpose: To test whether correcting for unspecific signal from the cerebral white matter increases the sensitivity of amyloid-PET for early stages of cerebral amyloidosis.Methods: We analyzed 18F-Florbetapir-PET and cerebrospinal fluid (CSF) Aβ42 data from 600 older individuals enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including people with normal cognition, mild cognitive impairment (MCI), and Alzheimer’s disease (AD) dementia. We determined whether three compartmental partial volume correction (PVC-3), explicitly modeling signal spill-in from white matter, significantly improved the association of CSF Aβ42 levels with global 18F-Florbetapir-PET values compared with standard processing without PVC (non-PVC) and a widely used two-compartmental PVC method (PVC-2). In additional voxel-wise analyses, we determined the sensitivity of PVC-3 compared with non-PVC and PVC-2 for detecting early regional amyloid build-up as modeled by decreasing CSF Aβ42 levels. For replication, we included an independent sample of 43 older individuals with subjective memory complaints from the INveStIGation of AlzHeimer’s PredicTors cohort (INSIGHT-preAD study).Results: In the ADNI sample, PVC-3 18F-Florbetapir-PET values normalized to whole cerebellum signal showed significantly stronger associations with CSF Aβ42 levels than non-PVC or PVC-2, particularly in the lower range of amyloid levels. These effects were replicated in the INSIGHT-preAD sample. PVC-3 18F-Florbetapir-PET data detected regional amyloid build-up already at higher (less abnormal) CSF Aβ42 levels than non-PVC or PVC-2 data.Conclusion: A PVC approach that explicitly models unspecific white matter binding improves the sensitivity of amyloid-PET for identifying the earliest stages of cerebral amyloid pathology which has implications for future primary prevention trials.

Left Atrial Remodeling and Cerebrovascular Disease Assessed by Magnetic Resonance Imaging in Continuously Monitored Patients

<b><i>Background:</i></b> Atrial remodeling is associated with future atrial fibrillation (AF) and stroke. AF has been associated with cognitive impairment and cerebral white matter lesions. We wished to investigate the possible direct association between atrial remodeling and cerebrovascular disease in patients with and without AF documented by implantable loop recorder (ILR). <b><i>Methods:</i></b> Cardiac and cerebral magnetic resonance imaging were acquired in a cross-sectional study, including participants ≥70 years of age with stroke risk factors without known AF. Cerebrovascular disease was visually rated using the Fazekas scale and number of lacunar strokes. Left atrial (LA) and ventricular volumes and function were analyzed. Associations between atrial remodeling and cerebrovascular disease were assessed with logistic regression models. The analyses were stratified according to sinus rhythm or any AF during 3 months of continuous ILR monitoring to account for subclinical AF. <b><i>Results:</i></b> Of 200 participants investigated, 87% had a Fazekas score ≥1 and 45% had ≥1 lacunar infarct. Within 3 months of ILR monitoring, AF was detected in 28 (14%) participants. For participants with sinus rhythm (<i>n</i> = 172), lower LA passive emptying fraction was associated with Fazekas score after multivariable adjustment (OR [95% CI]: 0.51 [0.27; 0.86] <i>p</i> = 0.02), and increased LA maximum (OR [95% CI]: 1.38 [1.07; 1.82] <i>p</i> = 0.01) and minimum volumes (OR [95% CI]: 1.48 [1.03; 2.17] <i>p</i> = 0.04) were associated with lacunar infarcts. There were no significant associations in patients with AF. <b><i>Conclusion:</i></b> In AF-free patients, as documented by ILR monitoring, we found an independent association between LA passive emptying fraction and Fazekas score and between atrial volumes and lacunar infarcts.