Gyrification, cortical and subcortical morphometry in neurofibromatosis type 1: an uneven profile of developmental abnormalities.

Background: Neurofibromatosis type 1 (NF1) is a monogenic disorder associated with cognitive impairments. In order to understand how mutations in the NF1 gene impact brain structure it is essential to characterize in detail the brain structural abnormalities in patients with NF1. Previous studies have reported contradictory findings and have focused only on volumetric measurements. Here, we investigated the volumes of subcortical structures and the composite dimensions of the cortex through analysis of cortical volume, cortical thickness, cortical surface area and gyrification. Methods: We studied 14 children with NF1 and 14 typically developing children matched for age, gender, IQ and right/left-handedness. Regional subcortical volumes and cortical gyral measurements were obtained using the FreeSurfer software. Between-group differences were evaluated while controlling for the increase in total intracranial volume observed in NF1. Results: Subcortical analysis revealed disproportionately larger thalami, right caudate and middle corpus callosum in patients with NF1. Cortical analyses on volume, thickness and surface area were however not indicative of significant alterations in patients. Interestingly, patients with NF1 had significantly lower gyrification indices than typically developing children primarily in the frontal and temporal lobes, but also affecting the insula, cingulate cortex, parietal and occipital regions. Conclusions: The neuroanatomic abnormalities observed were localized to specific brain regions, indicating that particular areas might constitute selective targets for NF1 gene mutations. Furthermore, the lower gyrification indices were accompanied by a disproportionate increase in brain size without the corresponding increase in folding in patients with NF1. Taken together these findings suggest that specific neurodevelopmental processes, such as gyrification, are more vulnerable to NF1 dysfunction than others. The identified changes in brain organization are consistent with the patterns of cognitive dysfunction in the NF1 phenotype. © 2013 Violante et al

The Role of Corpus Callosum Development in Functional Connectivity and Cognitive Processing

The corpus callosum is hypothesized to play a fundamental role in integrating information and mediating complex behaviors. Here, we demonstrate that lack of normal callosal development can lead to deficits in functional connectivity that are related to impairments in specific cognitive domains. We examined resting-state functional connectivity in individuals with agenesis of the corpus callosum (AgCC) and matched controls using magnetoencephalographic imaging (MEG-I) of coherence in the alpha (8–12 Hz), beta (12–30 Hz) and gamma (30–55 Hz) bands. Global connectivity (GC) was defined as synchronization between a region and the rest of the brain. In AgCC individuals, alpha band GC was significantly reduced in the dorsolateral pre-frontal (DLPFC), posterior parietal (PPC) and parieto-occipital cortices (PO). No significant differences in GC were seen in either the beta or gamma bands. We also explored the hypothesis that, in AgCC, this regional reduction in functional connectivity is explained primarily by a specific reduction in interhemispheric connectivity. However, our data suggest that reduced connectivity in these regions is driven by faulty coupling in both inter- and intrahemispheric connectivity. We also assessed whether the degree of connectivity correlated with behavioral performance, focusing on cognitive measures known to be impaired in AgCC individuals. Neuropsychological measures of verbal processing speed were significantly correlated with resting-state functional connectivity of the left medial and superior temporal lobe in AgCC participants. Connectivity of DLPFC correlated strongly with performance on the Tower of London in the AgCC cohort. These findings indicate that the abnormal callosal development produces salient but selective (alpha band only) resting-state functional connectivity disruptions that correlate with cognitive impairment. Understanding the relationship between impoverished functional connectivity and cognition is a key step in identifying the neural mechanisms of language and executive dysfunction in common neurodevelopmental and psychiatric disorders where disruptions of callosal development are consistently identified

Different patterns of white matter degeneration using multiple diffusion indices and volumetric data in mild cognitive impairment and Alzheimer patients

Alzheimeŕs disease (AD) represents the most prevalent neurodegenerative disorder that causes cognitive decline in old age. In its early stages, AD is associated with microstructural abnormalities in white matter (WM). In the current study, multiple indices of diffusion tensor imaging (DTI) and brain volumetric measurements were employed to comprehensively investigate the landscape of AD pathology. The sample comprised 58 individuals including cognitively normal subjects (controls), amnestic mild cognitive impairment (MCI) and AD patients. Relative to controls, both MCI and AD subjects showed widespread changes of anisotropic fraction (FA) in the corpus callosum, cingulate and uncinate fasciculus. Mean diffusivity and radial changes were also observed in AD patients in comparison with controls. After controlling for the gray matter atrophy the number of regions of significantly lower FA in AD patients relative to controls was decreased; nonetheless, unique areas of microstructural damage remained, e.g., the corpus callosum and uncinate fasciculus. Despite sample size limitations, the current results suggest that a combination of secondary and primary degeneration occurrs in MCI and AD, although the secondary degeneration appears to have a more critical role during the stages of disease involving dementia

Interleukin-6, age, and corpus callosum integrity.

The contribution of inflammation to deleterious aging outcomes is increasingly recognized; however, little is known about the complex relationship between interleukin-6 (IL-6) and brain structure, or how this association might change with increasing age. We examined the association between IL-6, white matter integrity, and cognition in 151 community dwelling older adults, and tested whether age moderated these associations. Blood levels of IL-6 and vascular risk (e.g., homocysteine), as well as health history information, were collected. Processing speed assessments were administered to assess cognitive functioning, and we employed tract-based spatial statistics to examine whole brain white matter and regions of interest. Given the association between inflammation, vascular risk, and corpus callosum (CC) integrity, fractional anisotropy (FA) of the genu, body, and splenium represented our primary dependent variables. Whole brain analysis revealed an inverse association between IL-6 and CC fractional anisotropy. Subsequent ROI linear regression and ridge regression analyses indicated that the magnitude of this effect increased with age; thus, older individuals with higher IL-6 levels displayed lower white matter integrity. Finally, higher IL-6 levels were related to worse processing speed; this association was moderated by age, and was not fully accounted for by CC volume. This study highlights that at older ages, the association between higher IL-6 levels and lower white matter integrity is more pronounced; furthermore, it underscores the important, albeit burgeoning role of inflammatory processes in cognitive aging trajectories

Quantification of structural changes in the corpus callosumin children with profound hypoxic-ischaemic brain injury

Background Birth-related acute profound hypoxic–ischaemic brain injury has specific patterns of damage including the paracentral lobules. Objective To test the hypothesis that there is anatomically coherent regional volume loss of the corpus callosum as a result of this hemispheric abnormality. Materials and methods Study subjects included 13 children with proven acute profound hypoxic–ischaemic brain injury and 13 children with developmental delay but no brain abnormalities. A computerised system divided the corpus callosum into 100 segments, measuring each width. Principal component analysis grouped the widths into contiguous anatomical regions. We conducted analysis of variance of corpus callosum widths as well as support vector machine stratification into patient groups. Results There was statistically significant narrowing of the mid–posterior body and genu of the corpus callosum in children with hypoxic–ischaemic brain injury. Support vector machine analysis yielded over 95% accuracy in patient group stratification using the corpus callosum centile widths. Conclusion Focal volume loss is seen in the corpus callosum of children with hypoxic–ischaemic brain injury secondary to loss of commissural fibres arising in the paracentral lobules. Support vector machine stratification into the hypoxic–ischaemic brain injury group or the control group on the basis of corpus callosum width is highly accurate and points towards rapid clinical translation of this technique as a potential biomarker of hypoxic–ischaemic brain injur

EXPLAINING LATERALITY

Working with multi-species allometric relations and drawing on mammalian theorist Denenberg’s works, I provide an explanatory theory of the mammalian dual-brain as no prior account has

Interactive Effects of Physical Activity and APOE-ε4 On White Matter Tract Diffusivity in Healthy Elders

Older adult apolipoprotein-E epsilon 4 (APOE-ε4) allele carriers vary considerably in the expression of clinical symptoms of Alzheimer\u27s disease (AD), suggesting that lifestyle or other factors may offer protection from AD-related neurodegeneration. We recently reported that physically active APOE-ε4 allele carriers exhibit a stable cognitive trajectory and protection from hippocampal atrophy over 18 months compared to sedentary ε4 allele carriers. The aim of this study was to examine the interactions between genetic risk for AD and physical activity (PA) on white matter (WM) tract integrity, using diffusion tensor imaging (DTI) MRI, in this cohort of healthy older adults (ages of 65 to 89). Four groups were compared based on the presence or absence of an APOE-ε4 allele (High Risk; Low Risk) and self-reported frequency and intensity of leisure time physical activity (PA) (High PA; Low PA). As predicted, greater levels of PA were associated with greater fractional anisotropy (FA) and lower radial diffusivity in healthy older adults who did not possess the APOE-ε4 allele. However, the effects of PA were reversed in older adults who were at increased genetic risk for AD, resulting in significant interactions between PA and genetic risk in several WM tracts. In the High Risk-Low PA participants, who had exhibited episodic memory decline over the previous 18-months, radial diffusivity was lower and fractional anisotropy was higher, compared to the High Risk-High PA participants. In WM tracts that subserve learning and memory processes, radial diffusivity (DR) was negatively correlated with episodic memory performance in physically inactive APOE-ε4 carriers, whereas DR was positively correlated with episodic memory performance in physically active APOE-ε4 carriers and the two Low Risk groups. The common model of demyelination-induced increase in radial diffusivity cannot directly explain these results. Rather, we hypothesize that PA may protect APOE-ε4 allele carriers from selective neurodegeneration of individual fiber populations at locations of crossing fibers within projection and association WM fiber tracts

HIV-associated structural brain changes as related to cognition

Nearly half of all HIV-positive individuals present with some form of HIV-associated neurocognitive disorder (HAND). The experiments described in this thesis examined the structural changes that occur in the brain as a result of HIV infection. While previous work has established that HIV targets the basal ganglia and fronto-striatal systems and impacts cortical and white matter pathways, it was unknown whether these changes occur in the absence of HAND. The studies described here focused on cognitively asymptomatic HIV+ individuals (CAHIV+) without HAND as determined by widely accepted neuropsychological performance guidelines. Experiment 1 utilized diffusion tensor imaging (DTI) to examine HIV-associated alterations in white matter (WM) fractional anisotropy (FA) in the absence of HAND in 23 HIV+ individuals and 17 control participants (HIV-) matched for age, education, and verbal IQ. The hypothesis was that CAHIV+ participants would show lower FA values than HIV- in the corpus callosum, frontotemporal, and parietal regions of interest (ROIs). CAHIV+ individuals demonstrated higher FA in the frontotemporal region and posterior corpus callosum, but lower FA in parietal WM relative to HIV- individuals. Experiment 2 utilized structural MRI to compare cortical thickness in 22 CAHIV+ individuals and 19 control participants (HIV-) matched for age, education, and verbal IQ. The hypothesis was that CAHIV+ participants would have thinner frontal, temporal, and parietal regions than HIV- participants. Reduced cortical thickness measures were identified in the cingulate and superior temporal gyri, with increased cortical thickness measures in the inferior occipital gyrus, for HIV+ participants compared to HIV-. Experiment 3 examined the relationship between the structural alterations identified in Experiments 1 and 2, neuropsychological performance on tests sensitive to HAND identification, and immunological characteristics in 30 HIV+ participants and 28 HIV- control participants. As hypothesized, regional FA values, cortical thickness, and viral load were related to neuropsychological composite scores for CAHIV+, but not HIV-. Together, results from these three studies suggest that regional FA and cortical alterations identified in CAHIV+ patients may contribute to the cognitive deficits often seen in later stages of HIV disease

Regional Distribution and Clinical Correlates of White Matter Structural Damage in Huntington Disease: A Tract-Based Spatial Statistics Study

BACKGROUND AND PURPOSE: HD entails damage of the WM. Our aim was to explore in vivo the regional volume and microstructure of the brain WM in HD and to correlate such findings with clinical status of the patients. MATERIALS AND METHODS: Fifteen HD gene carriers in different clinical stages of the disease and 15 healthy controls were studied with T1-weighted images for VBM and DTI for TBSS. Maps of FA, MD, and λ∥ and λ⊥ were reconstructed. RESULTS: Compared with controls, in addition to neostriatum and cortical GM volume loss, individuals with HD showed volume loss in the genu of the internal capsule and subcortical frontal WM bilaterally, the right splenium of the corpus callosum, and the left corona radiata. TBSS revealed symmetrically decreased FA in the corpus callosum, fornix, external/extreme capsule, inferior fronto-occipital fasciculus, and inferior longitudinal fasciculus. Areas of increased MD were more extensive and included arciform fibers of the cerebral hemispheres and cerebral peduncles. Increase of the λ∥ and a comparatively more pronounced increase of the λ⊥ underlay the decreased FA of the WM in HD. Areas of WM atrophy, decreased FA, and increased MD correlated with the severity of the motor and cognitive dysfunction, whereas only the areas with increased MD correlated with disease duration. CONCLUSIONS: Microstructural damage accompanies volume decrease of the WM in HD and is correlated with the clinical deficits and disease duration. MR imaging−based measures could be considered as a biomarker of neurodegeneration in HD gene carriers

Brain Structure in Older Adult Siblings

Considerable variability exists in patterns of brain aging within and across individuals. Quantifying familial contributions to brain structure in late life may help us understand this variability. We estimated heritability of gray and white matter volumes and cortical thickness in a sample of older adult full siblings: 2-4 individuals per pedigree; N = 75). Estimation of heritability was based on computation of intraclass correlations. Heritability estimates were higher for total cortical thickness compared to volumes. There was no evidence of overall laterality in heritability estimates, or differences between primary sensory and association regions. There was a tendency for lower estimates of heritability in the frontal lobe relative to other lobes, but greater estimates for amygdala and hippocampus relative to parahippocampus and for caudate relative to putamen and globus pallidus. Strong heritability was observed across callosal regions. This study provides a comprehensive assessment of heritability of brain structure in older adults