Cognitive Impairment in Myotonic Dystrophy Type 1 Is Associated with White Matter Damage

Objective

To investigate grey (GM) and white matter (WM) abnormalities and their effects on cognitive and behavioral deficits in a large, phenotypically and genotypically well-characterized cohort of classic adult (aDM1, age at onset ≥20 years) or juvenile (jDM1, age at onset <20 years) patients with myotonic dystrophy type 1 (DM1).

Methods

A case-control study including 51 DM1 patients (17 jDM1 and 34 aDM1) and 34 controls was conducted at an academic medical center. Clinical, cognitive and structural MRI evaluations were obtained. Quantitative assessments of regional GM volumes, WM hyperintensities (WMHs), and microstructural WM tract damage were performed. The association between structural brain damage and clinical and cognitive findings was assessed.

Results

DM1 patients showed a high prevalence of WMHs, severe regional GM atrophy including the key nodes of the sensorimotor and main cognitive brain networks, and WM microstructural damage of the interhemispheric, corticospinal, limbic and associative pathways. WM tract damage extends well beyond the focal WMHs. While aDM1 patients had severe patterns of GM atrophy and WM tract damage, in jDM1 patients WM abnormalities exceeded GM involvement. In DM1, WMHs and microstructural damage, but not GM atrophy, correlated with cognitive deficits.

Conclusions

WM damage, through a disconnection between GM structures, is likely to be the major contributor to cognitive impairment in DM1. Our MRI findings in aDM1 and jDM1 patients support the hypothesis of a degenerative (premature aging) origin of the GM abnormalities and of developmental changes as the principal substrates of microstructural WM alterations in DM1.     

Cortical and Subcortical Grey and White Matter Atrophy in Myotonic Dystrophies Type 1 and 2 Is Associated with Cognitive Impairment,Depression and Daytime Sleepiness

Objectives

Central nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2). We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM).

Methods

12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes of brain, ventricles, cerebellum, brainstem, cervical cord, lesion load and VBM results of the patient groups were compared to 33 matched healthy subjects.

Results

Clinical symptoms were depression (more pronounced in DM2), excessive daytime sleepiness (more pronounced in DM1), reduced attention and flexibility of thinking, and deficits of short-term memory and visuo-spatial abilities in both patient groups. Both groups showed ventricular enlargement and supratentorial GM and WM atrophy, with prevalence for more GM atrophy and involvement of the motor system in DM1 and more WM reduction and affection of limbic structures in DM2. White matter was reduced in DM1 in the splenium of the corpus callosum and in left-hemispheric WM adjacent to the pre- and post-central gyrus. In DM2, the bilateral cingulate gyrus and subgyral medio-frontal and primary somato-sensory WM was affected.Significant structural-functional correlations of morphological MRI findings (global volumetry and VBM) with clinical findings were found for reduced flexibility of thinking and atrophy of the left secondary visual cortex in DM1 and of distinct subcortical brain structures in DM2. In DM2, depression was associated with brainstem atrophy, Daytime sleepiness correlated with volume decrease in the middle cerebellar peduncles, pons/midbrain and the right medio-frontal cortex.

Conclusion

GM and WM atrophy was significant in DM1 and DM2. Specific functional-structural associations related morphological changes to cognitive impairment, depression and daytime sleepiness, partly indicating involvement of complex neuronal networks.     

Frontal White Matter Volume Is Associated with Brain Enlargement and Higher Structural Connectivity in Anthropoid Primates

Previous research has indicated the importance of the frontal lobe and its ‘executive’ connections to other brain structures as crucial in explaining primate neocortical adaptations. However, a representative sample of volumetric measurements of frontal connective tissue (white matter) has not been available. In this study, we present new volumetric measurements of white and grey matter in the frontal and non-frontal neocortical lobes from 18 anthropoid species. We analyze this data in the context of existing theories of neocortex, frontal lobe and white versus grey matter hyperscaling. Results indicate that the ‘universal scaling law’ of neocortical white to grey matter applies separately for frontal and non-frontal lobes; that hyperscaling of both neocortex and frontal lobe to rest of brain is mainly due to frontal white matter; and that changes in frontal (but not non-frontal) white matter volume are associated with changes in rest of brain and basal ganglia, a group of subcortical nuclei functionally linked to ‘executive control’. Results suggest a central role for frontal white matter in explaining neocortex and frontal lobe hyperscaling, brain size variation and higher neural structural connectivity in anthropoids.     

White Matter Injury Due to Experimental Chronic Cerebral Hypoperfusion Is Associated with C5 Deposition

The C5 complement protein is a potent inflammatory mediator that has been implicated in the pathogenesis of both stroke and neurodegenerative disease. Microvascular failure is proposed as a potential mechanism of injury. Along these lines, this investigation examines the role of C5 in the setting of chronic cerebral hypoperfusion. Following experimental bilateral carotid artery stenosis, C5 protein deposition increases in the corpus callosum over thirty days (p<0.05). The time course is temporally consistent with the appearance of white matter injury. Concurrently, systemic serum C5 levels do not appear to differ between bilateral carotid artery stenosis and sham-operated mice, implicating a local cerebral process. Following bilateral carotid artery stenosis, C5 deficient mice demonstrate decreased white matter ischemia in the corpus callosum when compared to C5 sufficient controls (p<0.05). Further, the C5 deficient mice exhibit fewer reactive astrocytes and microglia (p<0.01). This study reveals that the C5 complement protein may play a critical role in mediating white matter injury through inflammation in the setting of chronic cerebral hypoperfusion.     

The Reduction of Regional Cerebral Blood Flow in Normal-Appearing White Matter Is Associated with the Severity of White Matter Lesions in Elderly: A Xeon-CT Study

White matter lesions (WMLs) in normal elderly are related to chronic ischemia, and progression of WML occurs mostly in moderate to severe disease. However, the mechanism is uncertain. Thus, we enrolled fifty-six normal elderly patients without large artery disease. The severity of WML on MRI was graded as grade 0, I, II and III using the modified Fazekas scale. Cerebral blood flow (CBF) was measured by Xenon-CT. We found that CBF (mL/100 g/min) within periventricular lesions and in the right and left centrum semiovales were 20.33, 21.27 and 21.03, respectively, in group I; 16.33, 15.55 and 15.91, respectively, in group II; and 14.05, 14.46 and 14.23, respectively, in group III. CBF of normal-appearing white matter (NAWM) around periventricular areas and in the right and left centrum semiovales were 20.79, 22.26 and 22.15, respectively, in group 0; 21.12, 22.17 and 22.25, respectively, in group I; 18.02, 19.45 and 19.62, respectively, in group II; and 16.38, 18.18 and 16.74, respectively, in group III. Significant reductions in CBF were observed not only within lesions but also in NAWM surrounding the lesions. In addition, CBF was reduced significantly within lesions compared to NAWM of the same grade. Furthermore, CBF was reduced significantly in NAWM in grades II and III when compared to grades 0 and I. Our finding indicates that ischemia may play a role in the pathogenesis of WML. Additionally, our finding provides an alternative explanation for finding that the progression of WML occurred more commonly in patients with moderate to severe WML.     

PECAM-Independent Thioglycollate Peritonitis Is Associated With a Locus on Murine Chromosome 2

Background

Previous studies have demonstrated that knockout or inhibition of Platelet/Endothelial Cell Adhesion Molecule (PECAM, CD31) in a number of murine strains results in impaired inflammatory responses, but that no such phenotype is seen in the C57BL/6 (B6) murine background.

Methodology/Principal Findings

We have undertaken a quantitative trait locus (QTL) mapping effort between FVB/n (FVB) and B6 mice deficient for PECAM to identify the gene or genes responsible for this unique feature of B6 mice. We have identified a locus on murine chromosome 2 at approximately 35.8 Mb that is strongly associated (LOD score = 9.0) with inflammatory responses in the absence of PECAM.

Conclusions/Significance

These data potentiate further study of the diapedesis machinery, as well as potential identification of new components of this machinery. As such, this study is an important step to better understanding the processes of inflammation.     

Low Pre-Existing Gray Matter Volume in the Medial Temporal Lobe and White Matter Lesions Are Associated with Postoperative Cognitive Dysfunction after Cardiac Surgery

Objectives

Postoperative cognitive dysfunction (POCD) is recognized as a complication in the elderly after cardiac surgery. Imaging of the brain provides evidence of neurodegeneration in elderly patients; however, abnormalities in brain structure and their relation to POCD are uncertain. This pilot study investigated whether loss of gray matter in the bilateral medial temporal lobe (MTL), seen in preoperative MRI, was associated with POCD.

Methods

Data were collected prospectively on 28 elderly patients scheduled for elective cardiac surgery. MRI of the brains of all patients were assessed for prior cerebral infarctions, and carotid and intracranial arterial stenosis. Patients also completed six neuropsychological tests of memory, attention and executive function before and after surgery. POCD was defined as an individual decrease in more than two tests of at least 1 standard deviation from the group baseline mean for that test. The degree of gray matter loss in the MTL of each patient was calculated using voxel-based morphometry with three-dimensional, T1-weighted MRI. This represented the degree of gray matter change as a Z score.

Results

Postoperative cognitive dysfunction was identified in 8 of the 28 patients (29%). Patients with POCD had significantly more white matter lesions on MRI, and greater loss of gray matter in the bilateral MTL (average Z score 2.0±0.9) than patients without POCD. An analysis by stepwise logistic regression identified gray matter loss in the MTL and cerebral infarctions on MRI as independent predictors of POCD.

Conclusions

These preliminary findings suggested that reduced gray matter in the bilateral MTL and white matter lesions existed in brains of elderly cardiac surgery patients who experienced POCD. Additional studies with larger sample sizes are needed to confirm these findings.     

Polymorphism of 9p21.3 Locus Is Associated with 5-Year Survival in High-Risk Patients with Myocardial Infarction

Objective

The rs10757278, rs1333049 and rs4977574 are single nucleotide polymorphisms (SNPs) of chromosome 9p21 locus associated with a prevalence of acute coronary syndromes (ACS). Reports concerning their association with long-term outcome after an ACS are equivocal. The aim of our study was to investigate the association of the 9p21.3 locus with 5-year overall mortality in patients with ST-elevation myocardial infarction (STEMI).

Materials and methods

We performed a retrospective analysis of data collected prospectively in 2 independent registries of consecutive patients with STEMI (derivation and validation group). Genotyping was performed with the TaqMan method. The analyzed end-point was total mortality.

Results

The derivation group comprised 589 patients: 25.3% female (n = 149), mean age 62.4±12.0 years, total 5-year mortality 16.6% (n = 98). When all the study group was analyzed, no significant differences in mortality were found between the genotypes. However, in high-risk patients (GRACE risk score ≥155 points, n = 238), homozygotes associated with higher risk for ACS had significantly better 5-year survival compared to other genotypes. The hazard ratio associated with the high-risk genotype (a homozygote of high risk for ACS or a heterozygote) was: HR = 2.2 (1.15–4.2) for the rs10757278 polymorphism, HR = 2.7 (95% CI 1.3–5.4) for the rs4977574 one and HR = 2.3 (1.2–4.5) for the rs1333049 one (Cox proportional hazards model). Survival analysis in the validation group (n = 365) showed a clear trend towards better prognosis in GG homozygotes of the rs10757278 SNP, which confirms our initial results (p = 0.09, log-rank test).

Conclusions

The 9p21.3 locus is associated with 5-year mortality in high-risk patients with STEMI. The genotypes associated with higher risk for ACS show a protective effect in terms of further survival (instead of a deteriorating prognosis, as reported previously). This finding, due to the very high size of the effect, could potentially be applied to clinical practice, if appropriate methods are elaborated.     

A Locus on Chromosome 1p36 Is Associated with Thyrotropin and Thyroid Function as Identified by Genome-wide Association Study

Thyroid hormones are key regulators of cellular growth, development, and metabolism, and thyroid disorders are a common cause of ill health in the community. Circulating concentrations of thyrotropin (TSH), thyroxine (T4) and triiodothyronine (T3) have a strong heritable component and are thought to be under polygenic control, but the genes responsible are mostly unknown. In order to identify genetic loci associated with these metabolic phenotypes, we performed a genome-wide association study of 2,120,505 SNPs in 2014 female twins from the TwinsUK study and found a significant association between rs10917469 on chromosome 1p36.13 and serum TSH (p = 3.2 × 10⁻⁸). The association of rs10917469 with serum TSH was replicated (p = 2.0 × 10⁻⁴) in an independent community-based sample of 1154 participants in the Busselton Health Study. This SNP is located near CAPZB, which might be a regulator of TSH secretion and thus of pituitary-thyroid axis function. Twenty-nine percent of white individuals carry the variant, and the difference in mean TSH concentrations between wild-type individuals and those homozygous for the minor G allele was 0.5 mU/l, which is likely to be clinically relevant. We also provide evidence of suggestive association (p < 5.0 × 10⁻⁶) of other SNPs with serum TSH, free T4, and free T3 concentrations, and these SNPs might be good targets for further studies. These results advance understanding of the genetic basis of pituitary-thyroid axis function and metabolic regulation.     

A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach

Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10⁻⁷), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05–1.32); meta-analysis p = 2.6×10⁻⁸). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10⁻¹⁵; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.     

White Matter Deficits in Psychopathic Offenders and Correlation with Factor Structure

Psychopathic offenders show a persistent pattern of emotional unresponsivity to the often horrendous crimes they perpetrate. Recent studies have related psychopathy to alterations in white matter. Therefore, diffusion tensor imaging followed by tract-based spatial statistics (TBSS) analysis in 11 psychopathic offenders matched to 11 healthy controls was completed. Fractional anisotropy was calculated within each voxel and comparisons were made between groups using a permutation test. Any clusters of white matter voxels different between groups were submitted to probabilistic tractography. Significant differences in fractional anisotropy were found between psychopathic offenders and healthy controls in three main white matter clusters. These three clusters represented two major networks: an amygdalo-prefrontal network, and a striato-thalamo-frontal network. The interpersonal/affective component of the PCL-R correlated with white matter deficits in the orbitofrontal cortex and frontal pole whereas the antisocial component correlated with deficits in the striato-thalamo-frontal network. In addition to replicating earlier work concerning disruption of an amygdala-prefrontal network, we show for the first time that white matter integrity in a striato-thalamo-frontal network is disrupted in psychopathic offenders. The novelty of our findings lies in the two dissociable white matter networks that map directly onto the two major factors of psychopathy.     

Migraine with Aura Susceptibility Locus on Chromosome 19p13 Is Distinct from the Familial Hemiplegic Migraine Locus

Migraine is a common neurological disease with a major genetic component. Recently, it has been proposed that a single locus on chromosome 19p13 contributes to the genetic susceptibility of both rare familial hemiplegic migraine (FHM) and more common types of migraine, migraine with aura and migraine without aura. We analyzed 16 families for co-segregation of migraine with aura and chromosome 19p13 markers. Using multipoint model-free linkage analysis, we obtained a lod score of 4.28 near D19S592. Using an affecteds-only model of linkage, we observed a lod score of 4.79 near D19S592. We were able to provide statistical evidence that this locus on chromosome 19p13 is most likely not the gene CACNA1A, mutations in which cause FHM. These data indicate that chromosome 19p13 contains a locus which contributes to the genetic susceptibility of migraine with aura that is distinct from the FHM locus.     

Regional Gray Matter Volume Is Associated with Empathizing and Systemizing in Young Adults

Empathizing is defined as the drive to identify the mental states of others for predicting their behavior and responding with an appropriate emotion. Systemizing is defined as the drive to analyze a system in terms of the rules that govern the system in order to predict its behavior. Using voxel-based morphometry and questionnaires in a large sample of normal, right-handed young adults, we investigated the regional gray matter volume (rGMV) correlates of empathizing and systemizing and additionally those of the D score, which is the difference between systemizing and empathizing, to reveal the comprehensive picture of those correlates. Negative rGMV correlates of empathizing and positive rGMV correlates of the D score (formed by the negative correlation between rGMV and empathizing), were found primarily in nodes in the default mode network, mirror neuron system, dorsal anterior cingulate cortex, and the lateral part of the prefrontal cortex together with other areas. Positive rGMV correlates of systemizing and of the D score (formed by the positive correlation between rGMV and systemizing) were found primarily in nodes in the external attention system, middle cingulate cortex, and other regions. Negative rGMV correlates of systemizing were found in an area close to the left posterior insula and putamen. These findings reconcile some previously inconsistent findings, provide other new findings and suggest that these areas contribute to empathizing–systemizing. Furthermore, the negative/positive rGMV correlates of empathizing and positive/negative rGMV correlates of systemizing overlapped substantially. This may be in line with the notion that empathizing and systemizing compete neurally in the brain.     

Active Cognitive Lifestyle Is Associated with Positive Cognitive Health Transitions and Compression of Morbidity from Age Sixty-Five

Background

Three factors commonly used as measures of cognitive lifestyle are education, occupation, and social engagement. This study determined the relative importance of each variable to long term cognitive health in those with and without severe cognitive impairment.

Methods

Data came from 12,470 participants from a multi-centre population-based cohort (Medical Research Council Cognitive Function and Ageing Study). Respondents were aged 65 years and over and were followed-up over 16 years. Cognitive states of no impairment, slight impairment, and moderate/severe impairment were defined, based on scores from the Mini-Mental State Examination. Multi-state modelling was used to investigate links between component cognitive lifestyle variables, cognitive state transitions over time, and death.

Results

Higher educational attainment and a more complex mid-life occupation were associated with a lower risk of moving from a non-impaired to a slightly impaired state (hazard ratios 0.5 and 0.8), but with increased mortality from a severely impaired state (1.3 and 1.1). More socially engaged individuals had a decreased risk of moving from a slightly impaired state to a moderately/severely impaired state (0.7). All three cognitive lifestyle variables were linked to an increased chance of cognitive recovery back to the non-impaired state.

Conclusions

In those without severe cognitive impairment, different aspects of cognitive lifestyle predict positive cognitive transitions over time, and in those with severe cognitive impairment, a reduced life-expectancy. An active cognitive lifestyle is therefore linked to compression of cognitive morbidity in late life.     

Sla2p Is Associated with the Yeast Cortical Actin Cytoskeleton via Redundant Localization Signals

Sla2p, also known as End4p and Mop2p, is the founding member of a widely conserved family of actin-binding proteins, a distinguishing feature of which is a C-terminal region homologous to the C terminus of talin. These proteins may function in actin cytoskeleton-mediated plasma membrane remodeling. A human homologue of Sla2p binds to huntingtin, the protein whose mutation results in Huntington's disease. Here we establish by immunolocalization that Sla2p is a component of the yeast cortical actin cytoskeleton. Deletion analysis showed that Sla2p contains two separable regions, which can mediate association with the cortical actin cytoskeleton, and which can provide Sla2p function. One localization signal is actin based, whereas the other signal is independent of filamentous actin. Biochemical analysis showed that Sla2p exists as a dimer in vivo. Two-hybrid analysis revealed two intramolecular interactions mediated by coiled-coil domains. One of these interactions appears to underlie dimer formation. The other appears to contribute to the regulation of Sla2p distribution between the cytoplasm and plasma membrane. The data presented are used to develop a model for Sla2p regulation and interactions.     

The 9p21 Locus Is Associated with Coronary Artery Disease and Cardiovascular Events in the Presence (but Not in the Absence) of Coronary Calcification

Variants at the 9p21 locus have been associated with coronary artery disease (CAD); coronary artery calcification (CAC) is related to CAD and other cardiovascular events. To determine the association of the 9p21 locus with CAD in the presence and absence of CAC, 4 groups were enrolled in a case-control study, including 527 CAD patients without CAC, 692 CAD patients with CAC, 585 individuals with simple CAC but no CAD, and 725 healthy controls. The rs1333049 representing the locus was associated with CAD in the presence of CAC (odds ratio = 1.38 in allelic analysis, 95%CI, 1.19–1.60, P<0.001), but not in the absence of CAC. Additionally, rs1333049 was not associated with simple CAC or CAC severity/extent in CAD patients with CAC. 849 CAD patients undergoing revascularization (660 with CAC and 189 without CAC) were enrolled in a cohort study to test its association with cardiovascular events in CAD patients with and without CAC in a 3-year follow-up. rs1333049 was significantly associated with the incidence of cardiovascular events in non-target vessels in patients with CAC (hazard ratio = 1.44, 95%CI, 1.08–1.91, P = 0.012), but not in those without CAC. The variants at the 9p21 locus were related to CAD and post-revascularization events only in the presence of CAC, suggesting that they may confer risk of calcification-related coronary atherosclerosis.