Polygenic risk for Alzheimer’s disease in healthy aging: age-related and APOE-driven effects on brain structures and cognition

Neuropsychiatric Significance of Subcortical Hyperintensity

Longitudinal structural and functional brain changes associated with stuttering improvement by therapy or brain lesion

Specific Anatomic Associations Between White Matter Integrity and Cognitive Reserve in Normal and Cognitively Impaired Elders

The association between higher order abilities, processing speed, and age are variably mediated by white matter integrity during typical aging

Schizophrenia is accompanied by a loss of integrity of white matter connections that compose the structural brain network, which is believed to diminish the efficiency of information transfer among brain regions. However, it is unclear to what extent these abnormalities are influenced by the genetic liability for developing the disease. To determine whether white matter integrity is associated with the genetic liability for developing schizophrenia. In 70 individual twins discordant for schizophrenia and 130 matched individual healthy control twins, structural equation modeling was applied to quantify unique contributions of genetic and environmental factors on brain connectivity and disease liability. The data for this study were collected from October 1, 2008, to September 30, 2013. The data analysis was performed between November 1, 2013, and March 30, 2015. Structural connectivity and network efficiency were assessed through diffusion-weighted imaging, measuring fractional anisotropy (FA) and streamlines. The sample included 30 monozygotic twins matched to 72 control participants and 40 dizygotic twins matched to 58 control participants. Lower global FA was significantly correlated with increased schizophrenia liability (phenotypic correlation, -0.25; 95% CI, -0.38 to -0.10; P = .001), with 83.4% explained by common genes. In total, 8.1% of genetic variation in global FA was shared with genetic variance in schizophrenia liability. Local reductions in network connectivity (as defined by FA-weighted local efficiency) of frontal, striatal, and thalamic regions encompassed 85.7% of genetically affected areas. Multivariate genetic modeling revealed that global FA contributed independently of other genetic markers, such as white matter volume and cortical thickness, to schizophrenia liability. Global reductions in white matter integrity in schizophrenia are largely explained by the genetic risk of developing the disease. Network analysis revealed that genetic liability for schizophrenia is primarily associated with reductions in connectivity of frontal and subcortical regions, indicating a loss of integrity along the white matter fibers in these regions. The reported reductions in white matter integrity likely represent a separate and novel genetic vulnerability marker for schizophrenia.

Cognitive and structural brain abnormalities are common following traumatic brain injury (TBI). The authors compared cognition and brain structure in 14 TBI survivors and 28 matched healthy comparison subjects. TBI survivors showed reduced cerebral volume, due mainly to white matter changes, and poorer attention, psychomotor speed, and memory. Severity of white matter abnormality correlated with worse performance on several cognitive measures that distinguished between groups. Using voxel-based morphometry, regions of reduced white matter concentration were found throughout the cerebrum along with more localized gray matter reductions. Findings suggest that diffuse rather than focal aspects of TBI contribute most to cognitive outcome.

Processing speed predicts functional outcome and is a potential endophenotype for schizophrenia. Establishing the neural basis of processing speed impairment may inform the treatment and etiology of schizophrenia. Neuroimaging investigations in healthy subjects have linked processing speed to brain anatomical connectivity. However, the relationship between processing speed impairment and white matter (WM) integrity in schizophrenia is unclear. Individuals with schizophrenia and healthy subjects underwent diffusion tensor imaging (DTI) and completed a brief neuropsychological assessment that included measures of processing speed, verbal learning, working memory and executive functioning. Group differences in WM integrity, inferred from fractional anisotropy (FA), were examined throughout the brain and the hypothesis that processing speed impairment in schizophrenia is mediated by diminished WM integrity was tested. WM integrity of the corpus callosum, cingulum, superior and inferior frontal gyri, and precuneus was reduced in schizophrenia. Average FA in these regions mediated group differences in processing speed but not in other cognitive domains. Diminished WM integrity in schizophrenia was accounted for, in large part, by individual differences in processing speed. Cognitive impairment in schizophrenia was mediated by reduced WM integrity. This relationship was strongest for processing speed because deficits in working memory, verbal learning and executive functioning were not mediated by WM integrity. Larger sample sizes may be required to detect more subtle mediation effects in these domains. Interventions that preserve WM integrity or ameliorate WM disruption may enhance processing speed and functional outcome in schizophrenia.

Healthy cognitive ageing is a societal and public health priority. Cerebrovascular risk factors increase the likelihood of dementia in older people but their impact on cognitive ageing in younger, healthy brains is less clear. The UK Biobank provides cognition and brain imaging measures in the largest population cohort studied to date. Here we show that cognitive abilities of healthy individuals (N = 22,059) in this sample are detrimentally affected by cerebrovascular risk factors. Structural equation modelling revealed that cerebrovascular risk is associated with reduced cerebral grey matter and white matter integrity within a fronto-parietal brain network underlying executive function. Notably, higher systolic blood pressure was associated with worse executive cognitive function in mid-life (44–69 years), but not in late-life (>70 years). During mid-life this association did not occur in the systolic range of 110–140 mmHg. These findings suggest cerebrovascular risk factors impact on brain structure and cognitive function in healthy people.

Recent studies have reported abnormal functional connectivity patterns in the brains of people with autism that may be accompanied by decreases in white matter integrity. Since autism is a developmental disorder, we aim to investigate the nature and location of decreases in white and grey matter integrity in an adolescent sample while accounting for age. We used structural (T1) imaging to study brain volumetrics and diffusion tensor imaging (DTI) to investigate white and grey matter integrity in people with autism. We obtained magnetic resonance images for adolescents aged 12-18 years with high-functioning autism and from matched controls. Fractional anisotropy and mean diffusivity, as well as grey and white matter volumetrics were analyzed. There were 17 participants with autism and 25 matched controls included in this study. Participants with autism had lower fractional anisotropy in the left and right superior and inferior longitudinal fasciculus, but this effect was not significant after adjusting for age and intelligence quotient (IQ). The kurtosis of the white matter fractional anisotropy probability distribution was higher in this participant group, with and without adjustment for age and IQ. Most notably, however, the mean diffusivity levels were markedly increased in the autism group throughout the brain, and the mean diffusivity probability distributions of both grey and white matter were shifted toward a higher value, particularly with age and IQ adjustment. No volumetric differences in grey and white matter were found. We corrected for age and IQ using a linear model. The study was also limited by its sample size, investigated age range and cross-sectional design. The findings suggest that autism is characterized by a generalized reduction of white matter integrity that is associated with an increase of interstitial space. The generalized manifestation of the white matter abnormalities provides an important new perspective on autism as a connectivity disorder.

Lifetime depression, sleep disruption and brain structure in the UK Biobank cohort.

The authors reviewed neuroimaging studies of obstructive sleep apnea (OSA) to summarize findings, evaluate their contribution to a current understanding of the neurophysiology of the disorder, and propose directions for future research. Manuscripts were identified using the National Institutes of Health PubMed literature search system. Search terms included obstructive sleep apnea, sleep apnea, imaging, neuroimaging, magnetic resonance imaging, MRI, functional magnetic resonance imaging, fMRI, magnetic resonance spectroscopy, and MRS. Inclusion criteria required that research articles (1) were written in English, (2) examined an adult population, and (3) focused on imaging of the brain. Support for structural abnormalities is mixed, but converging evidence suggests the hippocampus may be atrophic in patients with OSA. Neurochemical evidence is supportive of white-matter impairment in OSA, particularly in the frontal lobes. Functional studies utilizing respiratory challenges report widespread neural differences in motor, sensory, and autonomic brain regions. Functional neuroimaging cognitive challenges have reported either a lack of brain activation in dorsolateral prefrontal cortex or increased neural response in frontal lobe, cingulate, thalamus, cerebellum, and juncture of parietal and temporal lobes, depending on the cognitive task employed. The current literature examining neuroimaging-derived neural correlates in patients with OSA has made many important preliminary contributions. Future studies would be strengthened by consideration of potential moderating participant characteristics, such as sex, age, education, OSA severity, and comorbid conditions. Additional investigation employing neuroimaging techniques is needed to advance our understanding of the neurophysiology of OSA.

Normal aging is associated with reduced cerebral structural integrity and altered functional brain activity, yet the association of aging with the relationship between structural and functional brain changes remains unclear. Using combined diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) modalities, we hypothesized that aging-related changes in white matter integrity (i.e., fractional anisotropy) was associated with the short- or long-range functional connectivity density (FCD) in hub regions. We tested this hypothesis by using a healthy aging cohort comprised of 140 younger adults aged 20–39 years and 109 older adults aged 60–79 years. Compared with the younger group, older adults exhibited widespread reductions in white matter integrity with selective preservation in brain stem tracts and the cingulum connected to the hippocampus and cingulate cortex, whereas FCD mapping in older adults showed a reduced FCD in the visual, somatosensory, and motor functional networks and an increased FCD in the default mode network. The older adults exhibited significantly increased short- or long-range FCD in functional hubs of the precuneus, posterior, and middle cingulate, and thalamus, hippocampus, fusiform, and inferior temporal cortex. Furthermore, DTI-fMRI relationship were predominantly identified in older adults in whom short- and long-range FCD in the left precuneus was negatively correlated to structural integrity of adjacent and nonadjacent white matter tracts, respectively. We also found that long-range FCD in the left precuneus was positively correlated to cognitive function. These results support the compensatory hypothesis of neurocognitive aging theory and reveal the DTI-fMRI relationship associated with normal aging.

Does the active participation in leisure time activities promote cognitive and neuroanatomical health?

Persons with HIV (PWH) are at increased risk of frailty, a clinically recognizable state of increased vulnerability resulting from aging-associated decline in multiple physiologic systems. Frailty is often defined by the Fried criteria, which includes subjective and objective standards concerning health resiliency. However, these frailty metrics do not incorporate cognitive performance or neuroimaging measures. We compared structural (diffusion tensor imaging [DTI]) and functional (cerebral blood flow [CBF]) neuroimaging markers in PWH with frailty and cognitive performance. Virologically controlled PWH were dichotomized as either frail (≥3) or nonfrail (<3) using the Fried criteria. Cognitive Z-scores, both domain (executive, psychomotor speed, language, and memory) and global, were derived from a battery of tests. We identified three regions of reduced CBF, based on a voxel-wise comparison of frail PWH compared with nonfrail PWH. These clusters (bilateral frontal and posterior cingulate) were subsequently used as seed regions of interest (ROIs) for DTI probabilistic white matter tractography. White matter integrity connecting the ROIs was significantly decreased in frail compared with nonfrail PWH. No differences in cognition were observed between frail and nonfrail PWH. However, reductions in white matter integrity among these ROIs was significantly associated with worse psychomotor speed and executive function across the entire cohort. We conclude that frailty in PWH can lead to structural and functional brain changes, including subtle changes that are not detectable by standard neuropsychological tests. Multimodal neuroimaging in conjunction with frailty assessment could identify pathological brain changes observed in PWH.

A structural equation modeling investigation of age-related variance in executive function and DTI measured white matter damage