Disconnected aging: cerebral white matter integrity and age-related differences in cognition.

Cognition arises as a result of coordinated processing among distributed brain regions and disruptions to communication within these neural networks can result in cognitive dysfunction. Cortical disconnection may thus contribute to the declines in some aspects of cognitive functioning observed in healthy aging. Diffusion tensor imaging (DTI) is ideally suited for the study of cortical disconnection as it provides indices of structural integrity within interconnected neural networks. The current review summarizes results of previous DTI aging research with the aim of identifying consistent patterns of age-related differences in white matter integrity, and of relationships between measures of white matter integrity and behavioral performance as a function of adult age. We outline a number of future directions that will broaden our current understanding of these brain-behavior relationships in aging. Specifically, future research should aim to (1) investigate multiple models of age-brain-behavior relationships; (2) determine the tract-specificity versus global effect of aging on white matter integrity; (3) assess the relative contribution of normal variation in white matter integrity versus white matter lesions to age-related differences in cognition; (4) improve the definition of specific aspects of cognitive functioning related to age-related differences in white matter integrity using information processing tasks; and (5) combine multiple imaging modalities (e.g., resting-state and task-related functional magnetic resonance imaging; fMRI) with DTI to clarify the role of cerebral white matter integrity in cognitive aging

Microstructural Alterations in Hippocampal Subfields Mediate Age-Related Memory Decline in Humans.

Aging, even in the absence of clear pathology of dementia, is associated with cognitive decline. Neuroimaging, especially diffusion-weighted imaging, has been highly valuable in understanding some of these changes in live humans, non-invasively. Traditional tensor techniques have revealed that the integrity of the fornix and other white matter tracts significantly deteriorates with age, and that this deterioration is highly correlated with worsening cognitive performance. However, traditional tensor techniques are still not specific enough to indict explicit microstructural features that may be responsible for age-related cognitive decline and cannot be used to effectively study gray matter properties. Here, we sought to determine whether recent advances in diffusion-weighted imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI) and Constrained Spherical Deconvolution, would provide more sensitive measures of age-related changes in the microstructure of the medial temporal lobe. We evaluated these measures in a group of young (ages 20-38 years old) and older (ages 59-84 years old) adults and assessed their relationships with performance on tests of cognition. We found that the fiber density (FD) of the fornix and the neurite density index (NDI) of the fornix, hippocampal subfields (DG/CA3, CA1, and subiculum), and parahippocampal cortex, varied as a function of age in a cross-sectional cohort. Moreover, in the fornix, DG/CA3, and CA1, these changes correlated with memory performance on the Rey Auditory Verbal Learning Test (RAVLT), even after regressing out the effect of age, suggesting that they were capturing neurobiological properties directly related to performance in this task. These measures provide more details regarding age-related neurobiological properties. For example, a change in fiber density could mean a reduction in axonal packing density or myelination, and the increase in NDI observed might be explained by changes in dendritic complexity or even sprouting. These results provide a far more comprehensive view than previously determined on the possible system-wide processes that may be occurring because of healthy aging and demonstrate that advanced diffusion-weighted imaging is evolving into a powerful tool to study more than just white matter properties

Sleep quality relates to emotional reactivity via intracortical myelination

A good quality and amount of sleep are fundamental to preserve cognition and affect. New evidence also indicates that poor sleep is detrimental for brain myelination. In this study, we test the hypothesis that sleep quality and/or quantity relate to variability in cognitive and emotional function via the mediating effect of inter-individuals differences in proxy neuroimaging measures of white-matter integrity and intra-cortical myelination. By employing a demographically and neuropsychologically well-characterized sample of healthy people drawn from the Human Connectome Project (n=974), we found that quality and amount of sleep were only marginally linked to cognitive performance. In contrast, poor quality and short sleep increased negative affect (i.e., anger, fear, and perceived stress) and reduced life satisfaction and positive emotionality. At the brain level, poorer sleep quality and shorter sleep duration related to lower intra-cortical myelin in the mid-posterior cingulate cortex (p=0.038), middle temporal cortex (p=0.024), and anterior orbitofrontal cortex (OFC, p=0.034) but did not significantly affect different measures of white-matter integrity. Finally, lower intra-cortical myelin in the OFC mediated the association between poor sleep quality and negative emotionality (p<0.05). We conclude that intra-cortical myelination is an important mediator of the negative consequences of poor sleep on affective behaviour

White matter damage and cognitive impairment after traumatic brain injury

White matter disruption is an important determinant of cognitive impairment after brain injury, but conventional neuroimaging underestimates its extent. In contrast, diffusion tensor imaging provides a validated and sensitive way of identifying the impact of axonal injury. The relationship between cognitive impairment after traumatic brain injury and white matter damage is likely to be complex. We applied a flexible technique—tract-based spatial statistics—to explore whether damage to specific white matter tracts is associated with particular patterns of cognitive impairment. The commonly affected domains of memory, executive function and information processing speed were investigated in 28 patients in the post-acute / chronic phase following traumatic brain injury and in 26 age-matched controls. Analysis of fractional anisotropy and diffusivity maps revealed widespread differences in white matter integrity between the groups. Patients showed large areas of reduced fractional anisotropy, as well as increased mean and axial diffusivities, compared with controls, despite the small amounts of cortical and white matter damage visible on standard imaging. A stratified analysis based on the presence or absence of microbleeds (a marker of diffuse axonal injury) revealed diffusion tensor imaging to be more sensitive than gradient-echo imaging to white matter damage. The location of white matter abnormality predicted cognitive function to some extent. The structure of the fornices was correlated with associative learning and memory across both patient and control groups, whilst the structure of frontal lobe connections showed relationships with executive function that differed in the two groups. These results highlight the complexity of the relationships between white matter structure and cognition. Although widespread and, sometimes, chronic abnormalities of white matter are identifiable following traumatic brain injury, the impact of these changes on cognitive function is likely to depend on damage to key pathways that link nodes in the distributed brain networks supporting high-level cognitive functions

Role of amyloid B oligomers in oligodendrocyte and myelin pathology in Alzheimers's disease

145 p.La enfermedad de Alzheimer (EA) es un desorden neurodegenerativo caracterizado por la presencia de placas seniles compuestas por agregados del péptido beta amiloide (Aß), siendo las formas solubles las que mejor correlacionan con la progresión de la enfermedad. Aunque ha sido considerada una patología principalmente asociada a la muerte de las neuronas, se ha descrito un deterioro de sustancia blanca incluso previo al daño neuronal. Por tanto, proponemos que el Aß modula directamente la proliferación y la diferenciación de los oligodendrocitos (OLGs), alterando el estado de la mielina y contribuyendo así al deterioro de la sustancia blanca. En esta tesis, hemos observado que Aß modula la diferenciación de los OLGs, promoviendo la síntesis de la proteína básica de la mielina (MBP) a través de la inducción de la traducción local. Esta modulación está mediada por el receptor integrina ß1, Fyn y CaMKII. Además, el análisis detallado sobre el estado de los OLGs y la mielina en el modelo animal de EA triple transgénico reveló un aumento en la síntesis de MBP así como una desregulación en el patrón de diferenciación de los OLGs. Además, tras realizar estudio de la ultraestructura de la mielina observamos que el animal transgénico mostraba un daño en la integridad de la misma que conllevo fallos en la neurotransmisión. Finalmente, paciente con Alzheimer en fases avanzadas también mostraron un aumento de MBP en la corteza prefrontal y en el hipocampo. Asimismo, elevados niveles tanto de MBP como de CNPase se detectaron en pacientes con problemas cognitivos leves. Estos resultados describen el papel del Aß sobre la función oligodendroglial como parte clave en la progresión de la enfermedad.Achucarro: Basque Center for Neuroscience Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED

Influence of corpus callosum damage on cognition and physical disability in multiple sclerosis: a multimodal study.

Background Corpus callosum (CC) is a common target for multiple sclerosis (MS) pathology. We investigated the influence of CC damage on physical disability and cognitive dysfunction using a multimodal approach. Methods Twenty-one relapsing-remitting MS patients and 13 healthy controls underwent structural MRI and diffusion tensor of the CC (fractional anisotropy; mean diffusivity, MD; radial diffusivity, RD; axial diffusivity). Interhemisferic transfer of motor inhibition was assessed by recording the ipsilateral silent period (iSP) to transcranial magnetic stimulation. We evaluated cognitive function using the Brief Repeatable Battery and physical disability using the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC) z-score. Results The iSP latency correlated with physical disability scores (r ranged from 0.596 to 0.657, P values from 0.004 to 0.001), and with results of visual memory (r = −0.645, P = 0.002), processing speed (r = −0.51, P = 0.018) and executive cognitive domain tests (r = −0.452, P = 0.039). The area of the rostrum correlated with the EDSS (r = −0.442, P = 0.045). MD and RD correlated with cognitive performance, mainly with results of visual and verbal memory tests (r ranged from −0.446 to −0.546, P values from 0.048 to 0.011). The iSP latency correlated with CC area (r = −0.345, P = 0.049), volume (r = −0.401, P = 0.002), MD (r = 0.404, P = 0.002) and RD (r = 0.415, P = 0.016). Conclusions We found evidence for structural and microstructural CC abnormalities associated with impairment of motor callosal inhibitory conduction in MS. CC damage may contribute to cognitive dysfunction and in less extent to physical disability likely through a disconnection mechanism

Age-related delay in visual and auditory evoked responses is mediated by white- and grey-matter differences

Slowing is a common feature of ageing, yet a direct relationship between neural slowing and brain atrophy is yet to be established in healthy humans. We combine magnetoencephalo-graphic (MEG) measures of neural processing speed with magnetic resonance imaging (MRI) measures of white and grey matter in a large population-derived cohort to investigate the relationship between age-related structural differences and visual evoked field (VEF) and auditory evoked field (AEF) delay across two different tasks. Here we use a novel technique to show that VEFs exhibit a constant delay, whereas AEFs exhibit delay that accumulates over time. White-matter (WM) microstructure in the optic radiation partially mediates visual delay, suggesting increased transmission time, whereas grey matter (GM) in auditory cortex partially mediates auditory delay, suggesting less efficient local processing. Our results demonstrate that age has dissociable effects on neural processing speed, and that these effects relate to different types of brain atrophy.Peer reviewe