Lower White Matter Fractional Anisotropy Research Articles

Linking sarcopenia, brain structure and cognitive performance: a large-scale UK Biobank study.

Sarcopenia refers to age-related loss of muscle mass and function and is related to impaired somatic and brain health, including cognitive decline and Alzheimer's disease. However, the relationships between sarcopenia, brain structure and cognition are poorly understood. Here, we investigate the associations between sarcopenic traits, brain structure and cognitive performance. We included 33 709 UK Biobank participants (54.2% female; age range 44-82 years) with structural and diffusion magnetic resonance imaging, thigh muscle fat infiltration (n = 30 561) from whole-body magnetic resonance imaging (muscle quality indicator) and general cognitive performance as indicated by the first principal component of a principal component analysis across multiple cognitive tests (n = 22 530). Of these, 1703 participants qualified for probable sarcopenia based on low handgrip strength, and we assigned the remaining 32 006 participants to the non-sarcopenia group. We used multiple linear regression to test how sarcopenic traits (probable sarcopenia versus non-sarcopenia and percentage of thigh muscle fat infiltration) relate to cognitive performance and brain structure (cortical thickness and area, white matter fractional anisotropy and deep and lower brain volumes). Next, we used structural equation modelling to test whether brain structure mediated the association between sarcopenic and cognitive traits. We adjusted all statistical analyses for confounders. We show that sarcopenic traits (probable sarcopenia versus non-sarcopenia and muscle fat infiltration) are significantly associated with lower cognitive performance and various brain magnetic resonance imaging measures. In probable sarcopenia, for the included brain regions, we observed widespread significant lower white matter fractional anisotropy (77.1% of tracts), predominantly lower regional brain volumes (61.3% of volumes) and thinner cortical thickness (37.9% of parcellations), with |r| effect sizes in (0.02, 0.06) and P-values in (0.0002, 4.2e-29). In contrast, we observed significant associations between higher muscle fat infiltration and widespread thinner cortical thickness (76.5% of parcellations), lower white matter fractional anisotropy (62.5% of tracts) and predominantly lower brain volumes (35.5% of volumes), with |r| effect sizes in (0.02, 0.07) and P-values in (0.0002, 1.9e-31). The regions showing the most significant effect sizes across the cortex, white matter and volumes were of the sensorimotor system. Structural equation modelling analysis revealed that sensorimotor brain regions mediate the link between sarcopenic and cognitive traits [probable sarcopenia: P-values in (0.0001, 1.0e-11); muscle fat infiltration: P-values in (7.7e-05, 1.7e-12)]. Our findings show significant associations between sarcopenic traits, brain structure and cognitive performance in a middle-aged and older adult population. Mediation analyses suggest that regional brain structure mediates the association between sarcopenic and cognitive traits, with potential implications for dementia development and prevention.

Left Atrial Function and Arrhythmias in Relation to Small Vessel Disease on Brain MRI: The Multi-Ethnic Study of Atherosclerosis.

Background Atrial fibrillation (AF) is associated with increased stroke risk and accelerated cognitive decline, but the association of early manifestations of left atrial (LA) impairment with subclinical changes in brain structure is unclear. We investigated whether abnormal LA structure and function, greater supraventricular ectopy, and intermittent AF are associated with small vessel disease on magnetic resonance imaging of the brain. Methods and Results In the Multi-Ethnic Study of Atherosclerosis, 967 participants completed 14-day ambulatory electrocardiographic monitoring, speckle tracking echocardiography and, a median 17 months later, magnetic resonance imaging of the brain. We assessed associations of LA volume index and reservoir strain, supraventricular ectopy, and prevalent AF with brain magnetic resonance imaging measures of small vessel disease and atrophy. The mean age of participants was 72 years; 53% were women. In multivariable models, LA enlargement was associated with lower white matter fractional anisotropy and greater prevalence of microbleeds; reduced LA strain, indicating worse LA function, was associated with more microbleeds. More premature atrial contractions were associated with lower total gray matter volume. Compared with no AF, intermittent AF (prevalent AF with <100% AF during electrocardiographic monitoring) was associated with lower white matter fractional anisotropy (-0.25 SDs [95% CI, -0.44 to -0.07]) and greater prevalence of microbleeds (prevalence ratio: 1.42 [95% CI, 1.12-1.79]). Conclusions In individuals without a history of stroke or transient ischemic attack, alterations of LA structure and function, including enlargement, reduced strain, frequent premature atrial contractions, and intermittent AF, were associated with increased markers of small vessel disease. Detailed assessment of LA structure and function and extended ECG monitoring may enable early identification of individuals at greater risk of small vessel disease.

Association of Kidney Function Measures With Signs of Neurodegeneration and Small Vessel Disease on Brain Magnetic Resonance Imaging: The Atherosclerosis Risk in Communities (ARIC) Study

Chronic kidney disease (CKD) is a risk factor for cognitive decline, but evidence is limited on its etiology and morphological manifestation in the brain. We evaluated the association of estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) with structural brain abnormalities visible on magnetic resonance imaging (MRI). We also assessed whether this association was altered when different filtration markers were used to estimate GFR. Cross-sectional study nested in a cohort study. 1,527 participants in the Atherosclerosis Risk in Communities (ARIC) Study. Log(UACR) and eGFR based on cystatin C, creatinine, cystatin C and creatinine in combination, or β2-microglobulin (B2M). Brain volume reduction, infarcts, microhemorrhages, white matter lesions. Multivariable linear and logistic regression models fit separately for each predictor based on a 1-IQR difference in the predictor value. Each 1-IQR lower eGFR was associated with reduced cortex volume (regression coefficient:-0.07 [95% CI,-0.12 to-0.02]), greater white matter hyperintensity volume (logarithmically transformed; regression coefficient: 0.07 [95% CI, 0.01-0.15]), and lower white matter fractional anisotropy (regression coefficient:-0.08 [95% CI,-0.17 to-0.01]). The results were similar when eGFR was estimated with different equations based on cystatin C, creatinine, a combination of cystatin C and creatinine, or B2M. Higher log(UACR) was similarly associated with these outcomes as well as brain infarcts and microhemorrhages (odds ratios per 1-IQR-fold greater UACR of 1.31 [95% CI, 1.13-1.52] and 1.30 [95% CI, 1.12-1.51], respectively). The degree to which brain volume was lower in regions usually susceptible to Alzheimer disease and LATE (limbic-predominant age-related TDP-43 [Tar DNA binding protein 43] encephalopathy) was similar to that seen in the rest of the cortex. No inference about longitudinal effects due to cross-sectional design. We found eGFR and UACR are associated with structural brain damage across different domains of etiology, and eGFR- and UACR-related brain atrophy is not selective for regions typically affected by Alzheimer disease and LATE. Hence, Alzheimer disease or LATE may not be leading contributors to neurodegeneration associated with CKD.

Obstructive Sleep Apnea and the Brain: a Focus on Gray and White Matter Structure.

Obstructive sleep apnea is extremely prevalent in the elderly and may precipitate dementia. We review recent advances on gray and white matter structure in obstructive sleep apnea, the impact of treatment, and potential pathological and neurodegenerative processes underlying brain structural changes. Two opposite patterns are observed in neuroimaging studies of obstructive sleep apnea. One may indicate cellular damage (gray matter atrophy, higher white matter hyperintensity burden, lower white matter fractional anisotropy, higher water diffusivities), while the other (gray matter hypertrophy, restricted white matter diffusivities) may reflect transitory responses, such as intracellular edema, reactive gliosis or compensatory structural changes. Treating obstructive sleep apnea could partly reverse these structural changes. Structural alterations related to obstructive sleep apnea may follow a multi-determined biphasic pattern depending on numerous factors (e.g. severity, symptomatology, age) that could tip the scale toward neurodegeneration and need to be investigated by longitudinal studies.

Proximity to dementia onset and multi-modal neuroimaging changes: The prevent-dementia study

BackgroundFirst-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer's disease (AD). Here, we investigate “estimated years to onset of dementia” (EYO) as a surrogate marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers. Methods89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). MPRAGE, ASL and DWI data were processed using Freesurfer, FSL-BASIL and DTI-TK. White matter lesion maps were segmented from FLAIR scans. The SPM Sandwich Estimator Toolbox was used to test for the main effects of EYO and interactions between EYO, Time, and APOE-ε4+. Threshold free cluster enhancement and family wise error rate correction (TFCE FWER) was performed on voxelwise statistical maps. ResultsThere were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum (TFCEFWERp < 0.05). The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample. ConclusionsAmongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with incipient brain abnormalities, characterised by white matter disruptions and perfusion abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. Further clinical follow-up of our longitudinal sample would provide critical validation of these findings.

Disruption of the structural and functional connectivity of the frontoparietal network underlies symptomatic anxiety in late-life depression

The present study investigated functional connectivity and white matter integrity of the fronto-parietal network (FPN) to reveal the neural mechanisms that underlie late-life depression (LLD). Fifty patients with LLD and 40 non-depressed controls were included in the study. A multi-parametric approach was used by applying independent component analysis (ICA) to estimate functional connectivity of the FPN and by applying tract­based spatial statistics to examine white-matter integrity in tracts to the FPN. Patients with LLD exhibited functional abnormalities in the right inferior frontal gyrus, middle frontal gyrus, and inferior parietal gyrus and lower white matter fractional anisotropy in the right inferior fronto-occipital fasciculus, anterior thalamic radiation, and uncinate fasciculus. Alterations of functional connectivity and white matter fractional anisotropy in these regions were negatively correlated with the severity of symptomatic anxiety in LLD patients. The right inferior frontal gyrus might be a crucial hub in transferring information between these abnormal regions. Significant correlations were found between anxiety symptoms and brain alterations, suggesting that impairments in the FPN network might be involved in symptomatic anxiety in elderly individuals with depression.

Quantitative MRI outcomes in child and adolescent leukemia survivors: Evidence for global alterations in gray and white matter

IntroductionCure rates for pediatric acute lymphoblastic leukemia (ALL) have reached an all-time high (>90%); however, neurocognitive difficulties continue to affect quality of life in at least a subset of survivors. There are relatively few quantitative neuroimaging studies in child and adolescent ALL survivors treated with chemotherapy only. Use of different outcome measures or limited sample sizes restrict our ability to make inferences about patterns of brain development following chemotherapy treatment. In this study, we used magnetic resonance imaging (MRI) to evaluate brain outcomes in ALL survivors, comparing against a group of typically developing, cancer free peers. Materials and methodsParticipants included 71 ALL survivors, on average 8 years after diagnosis and 8–18 years of age, and 83 typically developing controls. Anatomical MRI was performed to evaluate brain structure; diffusion and magnetization transfer MRI were used to examine brain tissue microstructure. ResultsSuccessful MRI scans were acquired in 67 survivors (94%) and 82 controls (99%). Structurally, ALL survivors exhibited widespread reductions in brain volume, with 6% less white matter and 5% less gray matter than controls (p = 0.003 and 0.0006 respectively). Much of the brain appeared affected – 71 of 90 evaluated structures showed smaller volume – with the most notable exception being the occipital lobe, where no significant differences were observed. Average full-scale IQ in the survivor and control groups were 95 (CI 92–99) and 110 (CI 107–113), respectively. Using data from the NIH Pediatric MRI Data Repository, we evaluated the extent to which elevated IQ in the control group might affect the structural differences observed. We estimated that two thirds of the observed brain differences were attributable to ALL and its treatment. In addition to the structural changes, survivors showed, on average, globally lower white matter fractional anisotropy (-3%) and higher radial diffusivity (+5%) (p < 10−6), but no differences in magnetization transfer ratio. ConclusionsNeuroanatomical alterations in late childhood and adolescent ALL survivors treated with chemotherapy-only protocols are widespread, with white matter being somewhat more affected than gray matter. These MRI results indicate brain development is altered in ALL survivors and highlight the need to examine how these alterations emerge.

Diffusion tensor imaging in middle-aged headache sufferers in the general population: a cross-sectional population-based imaging study in the Nord-Tr\xf8ndelag health study (HUNT-MRI)

BackgroundSeveral studies have investigated white matter with diffusion tensor imaging (DTI) in those suffering from headache, but so far only in clinic based samples and with conflicting results.MethodsIn the present study, 1006 individuals (50–66 years) from the general population (Nord-Trøndelag Health Study) participated in an imaging study of the head at 1.5 T (HUNT-MRI). Hundred and ninety-six individuals were excluded because of errors in the data acquisition or brain pathology. Two hundred and forty-six of the remaining participants reported suffering from headache (69 from migraine and 76 from tension-type headache) the year prior to the scanning. DTI data were analysed with Tract-Based Spatial Statistics and automated tractography. Type of headache, frequency of attacks and evolution of headache were investigated for an association with white matter fractional anisotropy (FA), mean diffusivity (MD), axonal diffusivity (AD), radial diffusivity (RD) and tract volume. Correction for various demographical and clinical variables were performed.ResultsHeadache sufferers had widespread higher white matter MD, AD and RD compared to headache free individuals (n = 277). The effect sizes were mostly small with the largest seen in those with middle-age onset headache, who also had lower white matter FA. There were no associations between white matter microstructure and attack frequency or type of headache.ConclusionMiddle-age onset headache may be related to a widespread process in the white matter leading to altered microstructure.

Cerebellar development and its mediation role in cognitive planning in childhood.

Recent evidence suggests that the cerebellum contributes not only to the planning and execution of movement but also to the high-order cognitive planning. Childhood is a critical period for development of the cerebellum and cognitive planning. This study aimed (a) to examine the development of cerebellar morphology and microstructure and (b) to examine the cerebellar mediation roles in the relationship between age and cognitive planning in 6- to 10-year-old children (n = 126). We used an anatomical parcellation to quantify cerebellar regional gray matter (GM) and white matter (WM) volumes, and WM microstructure, including fractional anisotropy (FA) and mean diffusivity (MD). We assessed planning ability using the Stockings of Cambridge (SOC) task in all children. We revealed (a) a measure-specific anterior-to-posterior gradient of the cerebellar development in childhood, that is, smaller GM volumes and greater WM FA of the anterior segment of the cerebellum but larger GM volumes and lower WM FA in the posterior segment of the cerebellum in older children; (b) an age-related improvement of the SOC performance at the most demanding level of five-move problems; and (c) a mediation role of the lateral cerebellar WM volumes in age-related improvement in the SOC performance in childhood. These results highlight the differential development of the cerebellum during childhood and provide evidence that brain adaptation to the acquisition of planning ability during childhood could partially be achieved through the engagement of the lateral cerebellum.

Subclinical Cardiac Dysfunction and Brain Health in Midlife: CARDIA (Coronary Artery Risk Development in Young Adults) Brain Magnetic Resonance Imaging Substudy.

BackgroundWe investigated whether cardiac parameters in young adulthood are associated with indicators of brain health in midlife.Methods and ResultsThis study includes 648 participants from the CARDIA (Coronary Artery Risk Development in Young Adults) study (52% women, 38% black). We studied associations of cardiac parameters assessed by echocardiography (left ventricular ejection fraction, left atrial volume, and left ventricular mass) in young adulthood (mean age: 30 years) with brain measures obtained by magnetic resonance imaging (total brain, gray and white matter volume, white matter integrity, abnormal white matter) in midlife (mean age: 50 years). In 406 individuals with complete measurements, higher left atrial volume was associated with lower white matter fractional anisotropy, independent of traditional cardiovascular risk factors (β=−0.002; P <0.02). The association was strongest in black participants and in men.ConclusionsHigher left atrial volume in early adulthood is associated with impairment of white matter integrity in midlife. Interventions to improve cardiac function in young adults may benefit brain health and should be targeted in particular at black men.

Brain and heart magnetic resonance imaging/spectroscopy in duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked muscle disorder characterized by progressive and irreversible loss of muscular function. As muscular disease progresses, the repair mechanisms cannot compensate for cellular damage, leading inevitably to necrosis and progressive replacement by fibrous and fatty tissue. Cardiomyopathy and respiratory failure are the main causes of death in DMD. In addition to the well-described muscle and heart disease, cognitive dysfunction affects around 30% of DMD boys. Myocardial fibrosis, assessed by late gadolinium enhancement (LGE), using cardiovascular magnetic resonance imaging (CMR), is an early marker of heart involvement in both DMD patients and female carriers. In parallel, brain MRI identifies smaller total brain volume, smaller grey matter volume, lower white matter fractional anisotropy and higher white matter radial diffusivity in DMD patients. The in vivo brain evaluation of mdx mice, a surrogate animal model of DMD, showed an increased inorganic phosphate (P(i))/phosphocreatine (PCr) and pH. In this paper, we propose a holistic approach using techniques of magnetic resonance imaging, spectroscopy and diffusion tensor imaging as a tool to create a "heart and brain imaging map" in DMD patients that could potentially facilitate the patients' risk stratification and also future research studies in the field.

Traumatic Brain Injury in a Community-Based Cohort of Homeless and Vulnerably Housed Individuals

We characterized traumatic brain injury (TBI) and studied its associations with mental and physical health in a community cohort of homeless and vulnerably housed individuals. Detailed mental and physical health structured interviews, neuropsychological testing, and multimodal magnetic resonance imaging (MRI) were performed on 283 participants. Two TBI participant groups were defined for primary analyses: those with a self-reported history of TBI and those with MRI confirmation of TBI. By self-report, 174 participants (61.5%) reported a previous serious head or face injury (symptomatic or asymptomatic), with 100 (35.3%) experiencing symptoms consistent with TBI (any post-injury loss of consciousness, confusion, or memory loss). Persons self-reporting TBI had poorer current mental and physical health, more ongoing neurological symptoms, and a higher rate of mood disorders, compared to those with no TBI. The presence of a mood disorder, a TBI history, and an interaction between these factors contributed to lower mental health. There was evidence of TBI in 20 participants (6.9%) on clinical MRI sequences. These participants had globally lower cortical gray matter volumes and lower white matter fractional anisotropy (FA) values. Neurocognitive test scores positively correlated with both FA and cortical gray matter volumes in participants with MRI evidence of trauma. Previous TBI is associated with poorer mental and physical health in homeless and vulnerably housed individuals and interacts with mood disorders to exacerbate poor mental health. Focal traumatic lesions evident on MRI are associated with diffusely lower gray matter volumes and white matter integrity, which predict cognitive functioning.

Abdominal obesity and white matter microstructure in midlife.

The aging U.S. population and the recent rise in the prevalence of obesity are two phenomena of great importance to public health. In addition, research suggests that midlife body mass index (BMI) is a risk factor for dementia, a particularly costly disease, in later life. BMI could influence brain health by adversely impacting cerebral white matter. Recently, greater BMI has been associated with lower white matter fractional anisotropy (FA), an index of tissue microstructure, as measured by diffusion-tensor imaging in midlife. The aim of this study was to investigate the role of abdominal obesity, the most metabolically active adipose tissue compartment, and white matter microstructure in midlife. Community dwelling participants (N = 168) between the ages of 40-62 underwent MRI scanning at 3T and a general health assessment. Inferences were made on whole brain white matter tracts using full-tensor, high-dimension normalization, and tract-based spatial statistics. Higher waist circumference was associated with higher FA, indicating more directional diffusion in several white matter tracts controlling for age, sex, triglycerides, systolic blood pressure, fasting glucose, and HDL-cholesterol. Post hoc analysis revealed that greater waist circumference was associated with lower axial diffusivity, indicating lower parallel diffusion; lower radial diffusivity, indicating lower perpendicular diffusion; and lower mean diffusivity, indicating restricted diffusion. This is the first study to report a positive relationship between obesity and FA, indicating a more complicated view of this relationship in the aging brain. Hum Brain Mapp 38:3337-3344, 2017. © 2017 Wiley Periodicals, Inc.

Altered functional connectivity in the default mode network is associated with cognitive impairment and brain anatomical changes in Parkinson's disease

ObjectiveTo assess whether functional neural connectivity is disrupted between the regions of the default mode network (DMN) in Parkinson's disease (PD) and how this connectivity is related to cognition, brain gray matter structure and white matter integrity and diffusivity. MethodsThirty-seven PD patients and 16 healthy controls were evaluated, using resting-state functional magnetic resonance imaging (MRI), T1-weighted MRI, diffusion-weighted imaging and a battery of cognitive tests. Functional connectivity between the regions of the DMN, specifically in the precuneus, anterior and posterior cingulate, medial prefrontal and temporal and inferior parietal cortices was assessed with seed-to-voxel connectivity; gray matter volume and white matter values were determined using voxel-based morphometry and tract-based spatial statistics. ResultsReduced functional connectivity was observed between the posterior cingulate and medial temporal lobe in PD. Lower cognitive performance, gray matter loss in posterior, medial temporal and parietal areas, and fractional anisotropy reduction in the white matter adjacent to DMN regions were also observed in PD patients compared with healthy controls. Lower DMN functional connectivity correlated with lower verbal and visual memory and visual abilities performance in PD. In addition, lower DMN functional connectivity correlated with lower gray matter volume in the posterior cingulate and precuneus, and with lower white matter fractional anisotropy of the inferior longitudinal and posterior cingulate fasciculi in PD. ConclusionsBy combining different neuroimaging techniques and cognitive data, results showed that functional connectivity alteration between the regions of the DMN is associated with lower cognitive performance and gray and white matter abnormalities in PD.

Reduced cerebral gray matter and altered white matter in boys with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple dystrophin isoforms are expressed in brain, but little is known about their function. DMD is associated with specific learning and behavioral disabilities that are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms. We used quantitative magnetic resonance (MR) imaging to study brain microstructure in DMD. T1-weighted and diffusion tensor images were obtained on a 3T MR scanner from 30 patients and 22 age-matched controls (age = 8-18 years). All subjects underwent neuropsychological examination. Group comparisons on tissue volume and diffusion tensor imaging parameters were made between DMD patients and controls, and between 2 DMD subgroups that were classified according to predicted Dp140 isoform expression (DMD_Dp140(+) and DMD_Dp140(-) ). DMD patients had smaller total brain volume, smaller gray matter volume, lower white matter fractional anisotropy, and higher white matter mean and radial diffusivity than healthy controls. DMD patients also performed worse on neuropsychological examination. Subgroup analyses showed that DMD_Dp140(-) subjects contributed most to the gray matter volume differences and performed worse on information processing. Both gray and white matter is affected in boys with DMD at a whole brain level. Differences between the DMD_Dp140(-) subgroup and controls indicate an important role for the Dp140 dystrophin isoform in cerebral development.

The SORL1 gene and convergent neural risk for Alzheimer’s disease across the human lifespan

Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer's disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer's risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer's phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: 1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n=118, age 18-86, and n=68, age 8-40); 2) gene expression using the Braincloud postmortem healthy control sample (n=269, age 0-92); and 3) Alzheimer's neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI), and Alzheimer's individuals (n=710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner, in fronto-temporal white matter tracts in both samples at 5% FWE-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression, most prominently during childhood and adolescence, and significantly predicted increases in amyloid pathology in postmortem brain. Importantly, the effects of SORL1 variation on both white matter microstructure and gene expression were observed during neurodevelopmental phases of the human lifespan. Further, the neuropathological mechanism of risk appears to primarily involve amyloidogenic pathways. Interventions targeted toward the SORL1 amyloid risk pathway may be of greatest value during early phases of the lifespan.

Brain injury and development in newborns with critical congenital heart disease.

To determine the relationship between radiologically identifiable brain injuries and delayed brain development as reflected by brain metabolic and microstructural integrity. Term newborns with congenital heart disease (CHD) (120 preoperatively and 104 postoperatively) were studied with MRI to determine brain injury severity (BIS), microstructure reflected by fractional anisotropy (FA) and average diffusivity (Dav), and metabolism reflected by N-acetylaspartate (NAA)/choline (Cho) and lactate/Cho. Brain development is characterized by increasing NAA/Cho and white matter FA, and by decreasing Dav and lactate/Cho. Newly acquired brain injury was common (41% preoperative, 30% postoperative). Lower white matter FA (p = 0.005) and lower NAA/Cho (p = 0.01) were associated with increasing preoperative BIS. Higher neonatal illness severity scores (p = 0.03), lower preoperative oxygen saturation (p = 0.002), hypotension (p < 0.001), and septostomy (p = 0.002) were also predictive of higher preoperative BIS. Preoperative FA, Dav, and NAA/Cho did not predict new postoperative BIS. Increasing preoperative BIS predicted higher postoperative Dav (p = 0.002) and lactate/Cho (p = 0.008). Within the postoperative scan, new brain injuries were associated with lower white matter FA (p = 0.04). Postoperative BIS (new lesions) was associated with lower postoperative systolic (p = 0.03) and mean (p = 0.05) blood pressures. Brain injuries in newborns with CHD are strongly related to abnormalities of brain microstructural and metabolic brain development, especially preoperatively. Both newly acquired preoperative and postoperative brain injuries are related to potentially modifiable clinical risk factors.

Single-ventricle anatomy predicts delayed microstructural brain development

BackgroundTerm newborns with congenital heart disease (CHD) show delayed brain development as early as the third trimester, especially in single ventricle physiology (SVP). Mechanisms causing delayed brain development in CHD are uncertain, but may include impaired fetal brain blood flow. Our objective was to determine if cardiac anatomy associated with obstruction to antegrade flow in the ascending aorta is predictive of delayed brain development measured by diffusion tensor imaging (DTI) and magnetic resonance spectroscopic imaging (MRSI).MethodsEchocardiograms (ECHO) from 36 term newborns with SVP were reviewed for presence of aortic atresia and the diameter of the ascending aorta. Quantitative MR imaging parameters measuring brain microstructural (fractional anisotropy (FA), average diffusivity (Dav)) or metabolic development (N-acetylaspartate (NAA), Lactate/choline (Lac/cho)) were recorded.ResultsIncreasing NAA/cho and white matter FA, and decreasing Dav and lactate/cho characterize normal brain development. Consistent with the hypothesis that delayed brain development is related to impaired brain perfusion, smaller ascending aortic diameter and aortic atresia were associated with higher Dav and lower white matter FA. ECHO variables were not associated with brain metabolic measures.ConclusionsThese observations support the hypothesis that obstruction to fetal cerebral blood flow impairs brain microstructural development.

Relationship of a Variant in theNTRK1Gene to White Matter Microstructure in Young Adults

The NTRK1 gene (also known as TRKA) encodes a high-affinity receptor for NGF, a neurotrophin involved in nervous system development and myelination. NTRK1 has been implicated in neurological function via links between the T allele at rs6336 (NTRK1-T) and schizophrenia risk. A variant in the neurotrophin gene, BDNF, was previously associated with white matter integrity in young adults, highlighting the importance of neurotrophins to white matter development. We hypothesized that NTRK1-T would relate to lower fractional anisotropy in healthy adults. We scanned 391 healthy adult human twins and their siblings (mean age: 23.6 ± 2.2 years; 31 NTRK1-T carriers, 360 non-carriers) using 105-gradient diffusion tensor imaging at 4 tesla. We evaluated in brain white matter how NTRK1-T and NTRK1 rs4661063 allele A (rs4661063-A, which is in moderate linkage disequilibrium with rs6336) related to voxelwise fractional anisotropy-a common diffusion tensor imaging measure of white matter microstructure. We used mixed-model regression to control for family relatedness, age, and sex. The sample was split in half to test reproducibility of results. The false discovery rate method corrected for voxelwise multiple comparisons. NTRK1-T and rs4661063-A correlated with lower white matter fractional anisotropy, independent of age and sex (multiple-comparisons corrected: false discovery rate critical p = 0.038 for NTRK1-T and 0.013 for rs4661063-A). In each half-sample, the NTRK1-T effect was replicated in the cingulum, corpus callosum, superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, superior corona radiata, and uncinate fasciculus. Our results suggest that NTRK1-T is important for developing white matter microstructure.

Extreme Premature Birth is not Associated with Impaired Development of Brain Microstructure

To assess whether birth at <26 weeks gestation is an important predictor of brain microstructure maturation as determined by using diffusion tensor imaging. We performed serial magnetic resonance imaging and diffusion tensor imaging in 176 infants born at <33 weeks gestation. Diffusion parameters were calculated for white and gray matter regions. Linear regression for repeated measures was used to assess the effect of extremely premature birth on brain maturation. In white matter, fractional anisotropy increased by 0.008 per week (95% CI, 0.007-0.009; P < .0001) and mean diffusivity decreased by 0.021 mm(2)/sec per week, (95% CI, -0.24-0.018; P < .0001). Birth at <26 weeks was associated with lower white matter fractional anisotropy (-0.01; 95% CI, -0.018-0.003; P = .008), but this effect was eliminated when co-morbid conditions were added to the model. Moderate-severe brain injury was associated with decreased mean white matter fractional anisotropy (-0.012; 95% CI, -0.02-0.004; P = .002). Brain microstructure maturation as measured serially in premature infants is independent of extremely premature birth. Brain injury and co-morbid conditions may be the important determinants of microstructure maturation.