Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status.

BACKGROUND: APOE4 is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), whereas APOE2 confers protection. However, effects of APOE on neurodegeneration in cognitively intact individuals, and how these associations evolve with cognitive decline, are unclear. Furthermore, few studies have evaluated whether effects of APOE on neurodegenerative changes are modified by other AD key risk factors including age and sex. METHODS: Participants included older adults (57% women; 77 ± 7 years) from the Rancho Bernardo Study of Health Aging and the University of California San Diego Alzheimer's Disease Research Center, including 192 cognitively normal (CN) individuals and 33 with mild cognitive impairment. Participants underwent diffusion MRI, and multicompartment restriction spectrum imaging (RSI) metrics were computed in white matter, gray matter, and subcortical regions of interest. Participants were classified as APOE4 carriers, APOE2 carriers, and APOE3 homozygotes. Analysis of covariance among CN (adjusting for age, sex, and scanner) assessed differences in brain microstructure by APOE, as well as interactions between APOE and sex. Analyses across all participants examined interactions between APOE4 and cognitive status. Linear regressions assessed APOE by age interactions. RESULTS: Among CN, APOE4 carriers showed lower entorhinal cortex neurite density than non-carriers, whereas APOE2 carriers showed lower cingulum neurite density than non-carriers. Differences in entorhinal microstructure by APOE4 and in entorhinal and cingulum microstructure by APOE2 were present for women only. Age correlated with lower entorhinal restricted isotropic diffusion among APOE4 non-carriers, whereas age correlated with lower putamen restricted isotropic diffusion among APOE4 carriers. Differences in microstructure between cognitively normal and impaired participants were stronger for APOE4-carriers in medial temporal regions, thalamus, and global gray matter, but stronger for non-carriers in caudate. CONCLUSIONS: The entorhinal cortex may be an early target of neurodegenerative changes associated with APOE4 in presymptomatic individuals, whereas APOE2 may support beneficial white matter and entorhinal microstructure, with potential sex differences that warrant further investigation. APOE modifies microstructural patterns associated with aging and cognitive impairment, which may advance the development of biomarkers to distinguish microstructural changes characteristic of normal brain aging, APOE-dependent pathways, and non-AD etiologies.

C-NODDI: a constrained NODDI model for axonal density and orientation determinations in cerebral white matter.

Purpose: Neurite orientation dispersion and density imaging (NODDI) provides measures of neurite density and dispersion through computation of the neurite density index (NDI) and the orientation dispersion index (ODI). However, NODDI overestimates the cerebrospinal fluid water fraction in white matter (WM) and provides physiologically unrealistic high NDI values. Furthermore, derived NDI values are echo-time (TE)-dependent. In this work, we propose a modification of NODDI, named constrained NODDI (C-NODDI), for NDI and ODI mapping in WM. Methods: Using NODDI and C-NODDI, we investigated age-related alterations in WM in a cohort of 58 cognitively unimpaired adults. Further, NDI values derived using NODDI or C-NODDI were correlated with the neurofilament light chain (NfL) concentration levels, a plasma biomarker of axonal degeneration. Finally, we investigated the TE dependence of NODDI or C-NODDI derived NDI and ODI. Results: ODI derived values using both approaches were virtually identical, exhibiting constant trends with age. Further, our results indicated a quadratic relationship between NDI and age suggesting that axonal maturation continues until middle age followed by a decrease. This quadratic association was notably significant in several WM regions using C-NODDI, while limited to a few regions using NODDI. Further, C-NODDI-NDI values exhibited a stronger correlation with NfL concentration levels as compared to NODDI-NDI, with lower NDI values corresponding to higher levels of NfL. Finally, we confirmed the previous finding that NDI estimation using NODDI was dependent on TE, while NDI derived values using C-NODDI exhibited lower sensitivity to TE in WM. Conclusion: C-NODDI provides a complementary method to NODDI for determination of NDI in white matter.

REUSED: A deep neural network method for rapid whole-brain high-resolution myelin water fraction mapping from extremely under-sampled MRI.

Changes in myelination are a cardinal feature of brain development and the pathophysiology of several central nervous system diseases, including multiple sclerosis and dementias. Advanced magnetic resonance imaging (MRI) methods have been developed to probe myelin content through the measurement of myelin water fraction (MWF). However, the prolonged data acquisition and post-processing times of current MWF mapping methods pose substantial hurdles to their clinical implementation. Recently, fast steady-state MRI sequences have been implemented to produce high-spatial resolution whole-brain MWF mapping within ∼20 min. Despite the subsequent significant advances in the inversion algorithm to derive MWF maps from steady-state MRI, the high-dimensional nature of such inversion does not permit further reduction of the acquisition time by data under-sampling. In this work, we present an unprecedented reduction in the computation (∼30 s) and the acquisition time (∼7 min) required for whole-brain high-resolution MWF mapping through a new Neural Network (NN)-based approach, named NN-Relaxometry of Extremely Under-SamplEd Data (NN-REUSED). Our analyses demonstrate virtually similar accuracy and precision in derived MWF values using NN-REUSED compared to results derived from the fully sampled reference method. The reduction in the acquisition and computation times represents a breakthrough toward clinically practical MWF mapping.

Lower Myelin Content Is Associated With Lower Gait Speed in Cognitively Unimpaired Adults.

Mounting evidence indicates that abnormal gait speed predicts the progression of neurodegenerative diseases, including Alzheimer's disease. Understanding the relationship between white matter integrity, especially myelination, and motor function is crucial to the diagnosis and treatment of neurodegenerative diseases. We recruited 118 cognitively unimpaired adults across an extended age range of 22-94 years to examine associations between rapid or usual gait speeds and cerebral myelin content. Using our advanced multicomponent magnetic resonance relaxometry method, we measured myelin water fraction (MWF), a direct measure of myelin content, as well as longitudinal and transverse relaxation rates (R1 and R2), sensitive but nonspecific magnetic resonance imaging measures of myelin content. After adjusting for covariates and excluding 22 data sets due to cognitive impairments or artifacts, our results indicate that participants with higher rapid gait speed exhibited higher MWF, R1, and R2 values, that is, higher myelin content. These associations were statistically significant within several white matter brain regions, particularly the frontal and parietal lobes, splenium, anterior corona radiata, and superior fronto-occipital and longitudinal fasciculus. In contrast, we did not find any significant associations between usual gait speed and MWF, R1, or R2, which suggests that rapid gait speed may be a more sensitive marker of demyelination than usual gait speed. These findings advance our understanding on the implication of myelination in gait impairment among cognitively unimpaired adults, providing further evidence of the interconnection between white matter integrity and motor function.

Lower myelin content is associated with more rapid cognitive decline among cognitively unimpaired individuals.

INTRODUCTION: The influence of myelination on longitudinal changes in cognitive performance remains unclear. METHODS: For each participant (N = 123), longitudinal cognitive scores were calculated. Myelin content was probed using myelin water fraction (MWF) or longitudinal relaxation rate (R1 ); both are MRI measures sensitive to myelin, with MWF being specific. RESULTS: Lower MWF was associated with steeper declines in executive function (p < .02 in all regions) and lower R1 was associated with steeper declines in verbal fluency (p < .03 in all regions). Additionally, lower R1 was associated with steeper declines in executive function (p < .02 in all regions) and memory (p < .04 in occipital and cerebral white matter) but did not survive Bonferroni correction. DISCUSSION: We demonstrate significant relationships between myelin content and the rates of change in cognitive performance among cognitively normal individuals. These findings highlight the importance of myelin in cognitive functioning and suggest MWF and R1 as imaging biomarkers to predict cognitive changes.

Evidence of An Association Between Cerebral Blood Flow and Microstructural Integrity in Normative Aging Using a Holistic MRI Approach.

BACKGROUND: Cerebral tissue integrity decline and cerebral blood flow (CBF) alteration are major aspects of motor and cognitive dysfunctions and neurodegeneration. However, little is known about the association between blood flow and brain microstructural integrity, especially in normal aging. PURPOSE: To assess the association between CBF and cerebral microstructural integrity. STUDY TYPE: Cross sectional. POPULATION: A total of 94 cognitively unimpaired adults (mean age 50.7 years, age range between 22 and 88 years, 56 Men). FIELD STRENGTH/SEQUENCE: A 3 T; pseudo-continuous arterial spin labeling (pCASL), diffusion tensor imaging (DTI), Bayesian Monte Carlo analysis of multicomponent driven equilibrium steady-state observation of T1 and T2 (BMC-mcDESPOT). ASSESSMENT: Lobar associations between CBF derived from pCASL, and longitudinal relaxation rate (R1 ), transverse relaxation rate (R2 ) and myelin water fraction (MWF) derived from BMC-mcDESPOT, or radial diffusivity (RD), axial diffusivity (AxD), mean diffusivity (MD) and fractional anisotropy (FA) derived from DTI were assessed. STATISTICAL TESTS: Multiple linear regression models were used using the mean region of interest (ROI) values for MWF, R1 , R2 , FA, MD, RD, or AxD as the dependent variable and CBF, age, age2 , and sex as the independent variables. A two-sided P value of <0.05 defined statistical significance. RESULTS: R1 , R2 , MWF, FA, MD, RD, and AxD parameters were associated with CBF in most of the cerebral regions evaluated. Specifically, higher CBF values were significantly associated with higher FA, MWF, R1 and R2 , or lower MD, RD and AxD values. DATA CONCLUSION: These findings suggest that cerebral tissue microstructure may be impacted by global brain perfusion, adding further evidence to the intimate relationship between cerebral blood supply and cerebral tissue integrity. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 4.

Association of Cerebral Blood Flow With Longitudinal Changes in Cerebral Microstructural Integrity in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Importance: Decreased cerebral tissue integrity and cerebral blood flow (CBF) are features of neurodegenerative diseases. Brain tissue maintenance is an energy-demanding process, making it particularly sensitive to hypoperfusion. However, little is known about the association between blood flow and brain microstructural integrity, including in normative aging. Objective: To assess associations between CBF and changes in cerebral tissue integrity in white matter and gray matter brain regions. Design, Setting, and Participants: In this longitudinal cohort study, magnetic resonance imaging was performed on 732 healthy adults from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective longitudinal study (baseline age of 18-30 years) that examined participants up to 8 times during 30 years (1985-1986 to 2015-2016). Cerebral blood flow was measured at baseline (year 25 of the CARDIA study), and changes in diffusion tensor indices of fractional anisotropy (FA) and mean diffusivity (MD), measures of microstructural tissue integrity, were measured at both baseline and after approximately 5 years of follow-up (year 30). Analyses were conducted from November 5, 2020, to January 29, 2022. Main Outcomes and Measures: Automated algorithms and linear mixed-effects statistical models were used to evaluate the associations between CBF at baseline and changes in FA or MD. Results: After exclusion of participants with missing or low-quality data, 654 at baseline (342 women; mean [SD] age, 50.3 [3.5] years) and 433 at follow-up (230 women; mean [SD] age, 55.1 [3.5] years) were scanned for CBF or FA and MD imaging. In the baseline cohort, 247 participants were Black (37.8%) and 394 were White (60.2%); in the follow-up cohort, 156 were Black (36.0%) and 277 were White (64.0%). Cross-sectionally, FA and MD were associated with CBF in most regions evaluated, with lower CBF values associated with lower FA or higher MD values, including the frontal white matter lobes (for CBF and MD: mean [SE] ß = -1.4 [0.5] × 10-6; for CBF and FA: mean [SE] ß = 2.9 [1.0] × 10-4) and the parietal white matter lobes (for CBF and MD: mean [SE] ß = -2.4 [0.6] × 10-6; for CBF and FA: mean [SE] ß = 4.4 [1.1] × 10-4). Lower CBF values at baseline were also significantly associated with steeper regional decreases in FA or increases in MD in most brain regions investigated, including the frontal (for CBF and MD: mean [SE] ß = -1.1 [0.6] × 10-6; for CBF and FA: mean [SE] ß = 2.9 [1.0] × 10-4) and parietal lobes (for CBF and MD: mean [SE] ß = -1.5 [0.7] × 10-6; for CBF and FA: mean [SE] ß = 4.4 [1.1] × 10-4). Conclusions and Relevance: Results of this longitudinal cohort study of the association between CBF and diffusion tensor imaging metrics suggest that blood flow may be significantly associated with brain tissue microstructure. This work may lay the foundation for investigations to clarify the nature of early brain damage in neurodegeneration. Such studies may lead to new neuroimaging biomarkers of brain microstructure and function for disease progression.

Differential associations between apolipoprotein E alleles and cerebral myelin content in normative aging.

Mounting evidence indicates that myelin breakdown may represent an early phenomenon in neurodegeneration, including Alzheimer's disease (AD). Understanding the factors influencing myelin synthesis and breakdown will be essential for the development and evaluation of therapeutic interventions. In this work, we assessed associations between genetic variance in apolipoprotein E (APOE) and cerebral myelin content. Quantitative magnetic resonance imaging (qMRI) was performed on a cohort of 92 cognitively unimpaired adults ranging in age from 24 to 94 years. We measured whole-brain myelin water fraction (MWF), a direct measure of myelin content, as well as longitudinal and transverse relaxation rates (R1 and R2), sensitive measures of myelin content, in carriers of the APOE ε4 or APOE ε2 alleles and individuals with the ε33 genotype. Automated brain mapping algorithms and statistical models were used to evaluate the relationships between MWF or relaxation rates and APOE isoforms, accounting for confounding variables including age, sex, and race, in several cerebral structures. Our results indicate that carriers of APOE ε2 exhibited significantly higher myelin content, that is, higher MWF, R1 or R2 values, in most brain regions investigated as compared to noncarriers, while ε4 carriers exhibited trends toward lower myelin content compared to noncarriers. Finally, all qMRI metrics exhibited quadratic, inverted U-shape, associations with age; attributed to the development of myelination from young to middle age followed by progressive loss of myelin afterwards. Sex and race effects on myelination were, overall, nonsignificant. These findings suggest that individual genetic background may influence cerebral myelin maintenance. Although preliminary, this work lays the foundation for further investigations to clarify the relationship between APOE genotype and myelination, which may suggest potential targets in treatment or prevention of AD.

Cerebral aggregate g-ratio mapping using magnetic resonance relaxometry and diffusion tensor imaging to investigate sex and age-related differences in white matter microstructure.

Axonal demyelination is a cardinal feature of aging and age-related diseases. The g-ratio, mathematically defined as the inner-to-outer diameter of a myelinated axon, is used as a structural index of optimal axonal myelination and has been shown to represent a sensitive imaging biomarker of microstructural integrity. Several magnetic resonance imaging (MRI) methods for whole-brain mapping of aggregate g-ratio have been introduced. Computation of the aggerate g-ratio requires estimates of the myelin volume fraction (MVF) and the axonal volume fraction (AVF). While accurate determinations of MVF and AVF can be obtained through multicomponent relaxometry or diffusion analyses, respectively, these methods require lengthy acquisition times making their implementation challenging in a clinical context. Therefore, any attempt to overcome this drawback is needed. Expanding on our previous work, we introduced a new MRI method for whole-brain mapping of aggregate g-ratio. This new approach is based on the use of a single-shell diffusion for AVF determination, reducing the acquisition time by approximately ~10 min from our recently introduced approach, while offering the possibility to investigate g-ratio differences in previous studies with existing data for MVF mapping and single-shell diffusion data for AVF mapping. Our comparison analysis indicates that our newly derived aggregate g-ratio values were similar to those derived from our previous method, which requires a longer acquisition time. Further, in agreement with our previous observations, we found quadratic U-shaped relationships between aggregate g-ratio and age in this much larger study cohort. However, our results show that sexual dimorphism in g-ratio was not significant in any brain region investigated.

Insights into human cerebral white matter maturation and degeneration across the adult lifespan.

White matter (WM) microstructural properties change across the adult lifespan and with neuronal diseases. Understanding microstructural changes due to aging is paramount to distinguish them from neuropathological changes. Conducted on a large cohort of 147 cognitively unimpaired subjects, spanning a wide age range of 21 to 94 years, our study evaluated sex- and age-related differences in WM microstructure. Specifically, we used diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) indices, sensitive measures of myelin and axonal density in WM, and myelin water fraction (MWF), a measure of the fraction of the signal of water trapped within the myelin sheets, to probe these differences. Furthermore, we examined regional correlations between MWF and DTI indices to evaluate whether the DTI metrics provide information complementary to MWF. While sexual dimorphism was, overall, nonsignificant, we observed region-dependent differences in MWF, that is, myelin content, and axonal density with age and found that both exhibit nonlinear, but distinct, associations with age. Furthermore, DTI indices were moderately correlated with MWF, indicating their good sensitivity to myelin content as well as to other constituents of WM tissue such as axonal density. The microstructural differences captured by our MRI metrics, along with their weak to moderate associations with MWF, strongly indicate the potential value of combining these outcome measures in a multiparametric approach. Furthermore, our results support the last-in-first-out and the gain-predicts-loss hypotheses of WM maturation and degeneration. Indeed, our results indicate that the posterior WM regions are spared from neurodegeneration as compared to anterior regions, while WM myelination follows a temporally symmetric time course across the adult life span.

Characterization of Age-Related Differences in the Human Choroid Plexus Volume, Microstructural Integrity, and Blood Perfusion Using Multiparameter Magnetic Resonance Imaging.

The choroid plexus (CP) is an important cerebral structure involved in cerebrospinal fluid production and transport of solutes into the brain. Recent studies have uncovered the involvement of the CP in neurological disorders such as Alzheimer's disease and multiple sclerosis. However, our understanding of human age-related microstructural and functional changes in the CP with aging and neuropathology is limited. In this cross-sectional study, we investigated age and sex differences in the CP structure and function using advanced quantitative magnetic resonance imaging methodology in a large cohort (n = 155) of cognitively unimpaired individuals over a wide age range between 21 and 94 years. Our analysis included volumetric measurements, relaxometry measures (T 1 and T 2), diffusion tensor imaging (DTI) measures of fractional anisotropy (FA) and mean diffusivity (MD), as well as measures of cerebral blood flow (CBF). Our results revealed that CP volume was increasing with advancing age. We conjecture that this novel observation is likely attributed to alterations in the CP microstructure or function as well as to ventriculomegaly. Indeed, we also found that CBF was lower with advanced age, while, consistent with previous studies, T 1, T 2 and MD were higher, and FA was lower with advanced age. We attribute these functional and microstructural differences to a deteriorated CP structural integrity with aging. Furthermore, our relaxometry and DTI measures were found to be associated with differences in blood perfusion revealing lower microstructural integrity with lower CBF. Finally, in agreement with literature, sex-related differences in MD and CBF were statistically significant. This work lays the foundation for ongoing investigation of the involvement of CP in neurodegeneration.

Investigation of the association between cerebral iron content and myelin content in normative aging using quantitative magnetic resonance neuroimaging.

Myelin loss and iron accumulation are cardinal features of aging and various neurodegenerative diseases. Oligodendrocytes incorporate iron as a metabolic substrate for myelin synthesis and maintenance. An emerging hypothesis in Alzheimer's disease research suggests that myelin breakdown releases substantial stores of iron that may accumulate, leading to further myelin breakdown and neurodegeneration. We assessed associations between iron content and myelin content in critical brain regions using quantitative magnetic resonance imaging (MRI) on a cohort of cognitively unimpaired adults ranging in age from 21 to 94 years. We measured whole-brain myelin water fraction (MWF), a surrogate of myelin content, using multicomponent relaxometry, and whole-brain iron content using susceptibility weighted imaging in all individuals. MWF was negatively associated with iron content in most brain regions evaluated indicating that lower myelin content corresponds to higher iron content. Moreover, iron content was significantly higher with advanced age in most structures, with men exhibiting a trend towards higher iron content as compared to women. Finally, relationship between MWF and age, in all brain regions investigated, suggests that brain myelination continues until middle age, followed by degeneration at older ages. This work establishes a foundation for further investigations of the etiology and sequelae of myelin breakdown and iron accumulation in neurodegeneration and may lead to new imaging markers for disease progression and treatment.