White Matter Atrophy Research Articles

Chronic behavior disturbance and neurocognitive deficits in neuro-Behcet’s disease: a case study

ABSTRACTBehcet’s disease is a vasculitis and multisystem inflammatory syndrome. Neurological abnormalities occur in a subset of patients. This report presents a case of neuro-Behcet’s disease characterized by an initial onset of behavior changes prior to diagnosis, which evolved into a chronic behavioral syndrome. Neuroimaging investigations revealed progressive periventricular white matter and brainstem atrophy and lesions in the basal ganglia and deep white matter tracts, while neuropsychological investigations revealed reductions in information processing, executive functioning, and memory. The case indicates that behavior changes may be the first symptoms to emerge in Behcet’s, before other defining features of the disease.

The effects of chronic smoking on the pathology of alcohol-related brain damage

Both pathological and neuroimaging studies demonstrate that chronic alcohol abuse causes brain atrophy with widespread white matter loss limited gray matter loss. Recent neuroimaging studies suggest that tobacco smoking also causes brain atrophy in both alcoholics and neurologically normal individuals; however, this has not been confirmed pathologically. In this study, the effects of smoking and the potential additive effects of concomitant alcohol and tobacco consumption were investigated in autopsied human brains. A total of 44 cases and controls were divided into four groups: 16 non-smoking controls, nine smoking controls, eight non-smoking alcoholics, and 11 smoking alcoholics. The volumes of 26 gray and white matter regions were measured using an established point-counting technique. The results showed trends for widespread white matter loss in alcoholics (p<0.007) but no effect on gray matter regions. In contrast, smoking alone had no effect on brain atrophy and the combination of smoking and alcohol showed no additional effect. Neuronal density was analyzed as a more sensitive assay of gray matter integrity. Similar to the volumetric analysis, there was a reduction in neurons (29%) in the prefrontal cortex of alcoholics, albeit this was only a trend when adjusted for potential confounders (p<0.06). There were no smoking or combinatorial effects on neuronal density in any of the three regions examined. These results do not support the hypothesis that smoking exacerbates alcohol-related brain damage. The trends here support previous studies that alcohol-related brain damage is characterized by focal neuronal loss and generalized white matter atrophy. These disparate effects suggest that two different pathogenic mechanisms may be operating in the alcoholic brain. Future studies using ultrastructural or molecular techniques will be required to determine if smoking has more subtle effects on the brain and how chronic alcohol consumption leads to widespread white matter loss.

Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease.

White matter (WM) atrophy is a significant feature of Huntington disease (HD), although its aetiology and early pathological manifestations remain poorly defined. In this study, we aimed to characterize WM-related features in the transgenic YAC128 and BACHD models of HD. Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural WM abnormalities occur from an early age in YAC128 mice. Similarly, electron microscopy analysis of myelinated fibres of the corpus callosum indicated that myelin sheaths are thinner in YAC128 mice as early as 1.5 months of age, well before any neuronal loss can be detected. Transcript levels of myelin-related genes in striatal and cortical tissues were significantly lower in YAC128 mice from 2 weeks of age, and these findings were replicated in differentiated primary oligodendrocytes from YAC128 mice, suggesting a possible mechanistic explanation for the observed structural deficits. Concordant with these observations, we demonstrate reduced expression of myelin-related genes at 3 months of age and WM microstructural abnormalities using DT-MRI at 12 months of age in the BACHD rats. These findings indicate that WM deficits in HD are an early phenotype associated with cell-intrinsic effects of mutant huntingtin on myelin-related transcripts in oligodendrocytes, and raise the possibility that WM abnormalities may be an early contributing factor to the pathogenesis of HD.

Patterns of Regional Gray Matter and White Matter Atrophy Progression Contributing to Clinical Deterioration in MS: A 5-Year Tensor-Based Morphometry Study (P4.136)

Patterns of Regional Gray Matter and White Matter Atrophy Progression Contributing to Clinical Deterioration in MS: A 5-Year Tensor-Based Morphometry Study (P4.136)

Sex‐specific and Obesity‐specific Association of Serum Uric Acid with Cognitive Function in Older Adults

Lower serum uric acid concentrations have been linked to cognitive dysfunction. Uric acid is an antioxidant that accounts for over half of the free radical scavenging activity in humans. Higher serum concentrations of uric acid have been associated with slower progression of several neurodegenerative diseases. On the other hand, elevated serum uric acid levels have been associated with poorer processing speed and executive functioning and greater white matter atrophy. Our aim in this study was to ascertain the relation between uric acid and cognitive function in older adults with mild cognitive decline (defined at 1–1.5 SD below the mean on the Montreal Cognitive Assessment, MoCA). Cognitive function was assessed using the MoCA and Cambridge Neuropsychological Test Automated Battery (CANTAB). Mean concentrations of serum uric acid in 107 individuals (mean age = 72.7 ± 4.3 years) were 5.9 ± 2.3 mg/dl; males had significantly higher uric acid concentrations (6.3 ± 1.1 mg/dl) compared to females (5.4 ± 1.1 mg/dl). Obese individuals’ concentrations were higher (6.2 ± 1.1 mg/dl) as compared to overweight (6.0 ± 1.1 mg/dl) and normal weight individuals (5.1 ± 1.2 mg/dl). Hyperuricemia (in males, serum uric acid &gt; 7mg/dl and in females, serum uric acid &gt; 6mg/dl) was present in 24% of the individuals. Compared with normouricemic individuals, hyperuricemic had significantly (p &lt; 0.05) elevated serum triglyceride levels (122.1 ± 67 vs. 184.5 ± 152 mg/dl) and higher waist circumference (39.3 ±4 vs. 41.1 ± 3 in). Serum uric acid was positively correlated with BMI, waist circumference, serum creatinine, serum glucose, serum cholesterol ( p &lt; 0.00001). Serum uric acid was negatively associated with MoCA scores (r2 = −0.23, p = 0.02). When stratified by sex, serum uric acid was positively associated with errors made on the CANTAB spatial working memory task (t = 2.6, p = 0.014) in men, but not in women. Similarly, when stratified by BMI, serum uric acid was positively associated with spatial working memory errors (t = 2.9, p = 0.013) and rapid visual processing errors (t = 3.0, p = 0.01) from the CANTAB in obese individuals but not in normal or overweight individuals. In summary, among older adults, higher serum uric acid concentrations are linked to poorer cognitive function in all individuals, poorer spatial working memory in men and obese individuals, and poorer processing in obese individuals compared to other groups. These findings indicate a potential role for serum uric acid concentrations in cognitive function in older adults.Support or Funding InformationThis research was funded by grants from the United States Department of Agriculture (2010‐2342‐02 and 2015‐2809‐01) to the first author and a small grant from the Nutrition Research Institute to the first and last authors.

Assessing the Relationship between Neurocognitive Performance and Brain Volume in Chronic Moderate-Severe Traumatic Brain Injury.

Characterize the scale and pattern of long-term atrophy in gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) in chronic moderate-severe traumatic brain injury (TBI) and its relationship to neurocognitive outcomes. The TBI group consisted of 17 males with primary diagnosis of moderate-severe closed head injury. Participants had not received any systematic, post-acute rehabilitation and were recruited on average 8.36 years post-injury. The control group consisted of 15 males matched on age and education. Neurocognitive battery included widely used tests of verbal memory, visual memory, executive functioning, and attention/organization. GM, WM, and CSF volumes were calculated from segmented T1-weighted anatomical MR images. Voxel-based morphometry was employed to identify brain regions with differences in GM and WM between TBI and control groups. Chronic TBI results in significant neurocognitive impairments, and significant loss of GM and WM volume, and significant increase in CSF volume. Brain atrophy is not widespread, but it is rather distributed in a fronto-thalamic network. The extent of volume loss is predictive of performance on the neurocognitive tests. Significant brain atrophy and associated neurocognitive impairments during the chronic stages of TBI support the notion that TBI results in a chronic condition with lifelong implications.

Cortical abnormalities in Parkinson’s disease patients and relationship to depression: A surface-based morphometry study

Depression is a common occurrence in patients with Parkinson's disease (PD). Brain deficits may be the underlying cause of depression in PD. In the present study, we investigated whether morphometric alterations contribute to depression in PD. Seventeen depressed PD patients, 17 non-depressed PD patients and 45 normal controls were enrolled in the study. All subjects went through neurological and psychiatric clinical assessments. T1 weighted magnetic resonance imaging and surface-based morphometric analyses were performed to examine morphometric abnormalities in PD patients and their relationship to depression. We found that compared with normal controls, PD patients exhibited significantly decreased cortical thickness in the left precentral gyrus and the right postcentral gyrus extending to the middle frontal gyrus. Compared with non-depressed PD patients, depressed patients showed significantly increased cortical areas in the orbitofrontal regions and insula, which may imply white matter atrophy in these areas. The results of orbitofrontal and insula white matter atrophy are consistent with our previous finding that white matter integrity and functional connectivity are damaged in these regions in depressed PD patients, confirming their contribution to depression in PD.

Vasa previa: diagnosis and management

Vasa previa is a rare condition that is associated with a high rate of fetal or neonatal death when not diagnosed antenatally. The majority of available studies are either small, do not include antepartum data, limited to single institutions, or are biased by inclusion of patients from registries and online vasa previa support groups. The purpose of this study was to investigate the diagnostic and management strategies for this potentially catastrophic entity and to describe further maternal and placental risk factors that may aid in the establishment of a screening protocol for vasa previa. This was a retrospective multicenter descriptive study that included all pregnancies that were complicated by vasa previa that delivered between January 1, 2000, and December 31, 2012. Nine maternal fetal medicine practices and the hospitals in which they practice participated in data collection of diagnosis, treatment, and maternal-neonatal outcomes. Sixty-eight pregnancies were identified that included the diagnosis of vasa previa or "possible vasa previa" either in the ultrasound record or in the hospital record at the time of delivery. Four cases (5.8%) appeared to resolve on repeat ultrasound examination. Fifteen of the 64 cases that were suspected of having vasa previa could not be verified or were not documented at delivery. Of the remaining 49 cases, where vasa previa was documented, 47 cases (96%) were diagnosed by ultrasound scanning antenatally. Known risk factors for vasa previa were present in 41 of 47 cases (87%). Of the 49 cases, 41 were delivered by planned cesarean delivery at a mean gestational age of 34.7 weeks, and 8 cases required emergent cesarean delivery at a mean gestational age of 34.6 weeks (range, 32.4-36.0 weeks gestation). Seven of these emergent cesarean deliveries had been diagnosed previously; 1 case had not. All of the emergent cesarean deliveries were for vaginal bleeding; 1 case was also for a concerning fetal heart rate, but only 1 of the known cases had a documented ruptured fetal vessel. None of these cases were found to have cervical shortening before the onset of bleeding. One of the undiagnosed cases resulted in a ruptured fetal vessel and a baby with no heart beat at birth who survived but had periventricular leukomalacia at 1 month of age with mild white-matter atrophy. Of the remaining neonates in this group, there were no deaths and no major complications beyond mild respiratory distress syndrome in 9 cases. There were no other major neonatal complications, which included no cases of periventricular leukomalacia, neonatal sepsis, necrotizing enterocolitis, or any grade of intraventricular hemorrhage in the confirmed cases of vasa previa. This study confirms most current recommendations that include risk-based ultrasound screening, early hospitalization at 30-34 weeks gestation, antenatal corticosteroids at 30-32 weeks gestation, and elective delivery at 33-34 weeks gestation. Thus, with these recommendations for current identification and management of vasa previa in this series of geographically diverse mostly private practice maternal fetal medicine practices, we have confirmed recent reports that show a dramatic improvement in neonatal survival and complications compared with earlier reports.

Brain atrophy in multiple sclerosis: therapeutic, cognitive and clinical impact.

Multiple sclerosis (MS) was always considered as a white matter inflammatory disease. Today, there is an important body of evidence that supports the hypothesis that gray matter involvement and the neurodegenerative mechanism are at least partially independent from inflammation. Gray matter atrophy develops faster than white matter atrophy, and predominates in the initial stages of the disease. The neurodegenerative mechanism creates permanent damage and correlates with physical and cognitive disability. In this review we describe the current available evidence regarding brain atrophy and its consequence in MS patients.

Abstract 47: White Matter Atrophy in Cerebral Amyloid Angiopathy

Background/Purpose: Cerebral Amyloid Angiopathy (CAA) leads to leukoaraiosis, lacunar infarcts and cortical tissue loss. We hypothesized that CAA is also associated with white matter atrophy (WMA). Methods: We have compared volumetric multimodal MRIs from 72 prospectively enrolled non-demented patients with probable CAA (per Boston criteria), to 3 other well-studied cohorts: 289 Healthy Controls (HC) from the Harvard Aging Brain (HAB) study, 231 HC and 198 patients with AD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Validated FreeSurfer algorithms were used to calculate White Matter Volume (WMV), white matter hyperintensity volume (WMHv), and cortical thickness. Microbleeds (MBs) were counted on SWI-MRI. Measures were obtained from the contralateral hemisphere if intracerebral hemorrhage present. All volumes were corrected for total intracranial volume (ICV), so reported as percent of ICV. Results: The CAA patients were significantly younger (mean age: 70.1) compared to both HC cohorts (ADNI-HC: 76.0, p&lt;0.001, HAB-HC: 73.8, p &lt; 0.001), and to patients with AD (75.5, p &lt; 0.001). Despite being younger, patients with CAA presented significantly lower global WMV (28% ± 2.6) than both ADNI-HC (29.2% ± 2.2, p &lt; 0.001), HAB-HC (29.0% ± 2.5, p = 0.001), and patients with AD (28.7% ± 2.2, p = 0.02) [Figure]. The association persisted after correcting for age, gender and WMHv. Within the CAA cohort, there was a negative correlation between WMV and lobar MB counts (rho = -0.26, p = 0.03), it remained significant after correcting for age, gender, WMHv (p=0.016). There were no significant associations however between WMV and neither WMHv, nor cortical thickness (both p&gt;0.2). Conclusions: Patients with CAA show WMA when compared to older HC and AD. WMA independently correlates with MBs, a marker of CAA severity. Consistent spatial patterns of atrophy especially in posterior regions when compared to both HC and AD [Figure] might represent the “WMA signature of CAA”.

Abstract WMP85: Significance of Cerebral Small Vessel Disease in Acute Intracerebral Hemorrhage: The INTERACT2 Study

Background: Uncertainty exists over the significance of structural changes arising from cerebral small vessel disease (CSVD), including white matter lesions (WML), lacunes and atrophy, for outcome after acute intracerebral hemorrhage (ICH). We determined associations of CT markers of CSVD and outcomes among participants of the INTERACT2 study. Methods: We graded WML (van Swieten scale), brain atrophy (two linear measurements, frontal ratio [FR] and third ventricle Sylvian fissure distance [TSD]) and the presence of lacunes for 2069/2839 patients with available baseline brain CT (&lt;6hr ICH onset) by three independent neurologists blind to clinical data. Results: WML and brain atrophy were independently associated with death or disability (modified Rankin Scale score 3-6) at 90 days: adjusted odds ratios for WML (grade 3 and 4 vs. 1), FR and TSD (most vs. least severe atrophy quartile) were 1.42 (95% confidence interval 1.02-0.98), 1.47 (1.08-1.99) and 1.64 (1.21-2.22), respectively (all P for trend &lt;0.05). There was no association between lacunes or any CSVD biomarkers and absolute ICH growth, and no significant differences in the effects of intensive BP lowering in each subgroup of CSVD. Conclusions: CSVD manifestations of WML and brain atrophy have prognostic value in acute ICH but they do not appear to influence ICH growth. Intensive BP lowering provided similar treatment effects irrespective of degree of CSVD.

Minocycline Transiently Reduces Microglia/Macrophage Activation but Exacerbates Cognitive Deficits Following Repetitive Traumatic Brain Injury in the Neonatal Rat.

Elevated microglial/macrophage-associated biomarkers in the cerebrospinal fluid of infant victims of abusive head trauma (AHT) suggest that these cells play a role in the pathophysiology of the injury. In a model of AHT in 11-day-old rats, 3 impacts (24 hours apart) resulted in spatial learning and memory deficits and increased brain microglial/macrophage reactivity, traumatic axonal injury, neuronal degeneration, and cortical and white-matter atrophy. The antibiotic minocycline has been effective in decreasing injury-induced microglial/macrophage activation while simultaneously attenuating cellular and functional deficits in models of neonatal hypoxic ischemia, but the potential for this compound to rescue deficits after impact-based trauma to the immature brain remains unexplored. Acute minocycline administration in this model of AHT decreased microglial/macrophage reactivity in the corpus callosum of brain-injured animals at 3 days postinjury, but this effect was lost by 7 days postinjury. Additionally, minocycline treatment had no effect on traumatic axonal injury, neurodegeneration, tissue atrophy, or spatial learning deficits. Interestingly, minocycline-treated animals demonstrated exacerbated injury-induced spatial memory deficits. These results contrast with previous findings in other models of brain injury and suggest that minocycline is ineffective in reducing microglial/macrophage activation and ameliorating injury-induced deficits following repetitive neonatal traumatic brain injury.

Time-course of myelination and atrophy on cerebral imaging in 35 patients with PLP1-related disorders.

Brain magnetic resonance imaging (MRI) motor development score (MDS) correlations were used to analyze the natural time-course of hypomyelinating PLP1-related disorders (Pelizaeus-Merzbacher disease [PMD] and spastic paraplegia type 2). Thirty-five male patients (ranging from 0.7-43.5y at the first MRI) with PLP1-related disorder were prospectively followed over 7 years. Patients were classified according to best motor function acquired before 5 years (MDS) into five categories (from PMD0 without motor acquisition to PMD4 with autonomous walking). We determined myelination and atrophy scores and measured corpus callosum area, volume of cerebellum, white matter and grey matter on 63 MRI. Age-adjusted multivariate analysis revealed that patients with PMD0-1 had higher-severity atrophy scores and smaller corpus callosum area than did patients with PMD2 and PMD3-4. Myelination score increased until 12 years. There was evidence that the mean myelination differed in frontal white matter, arcuate fibres, and internal capsules among the groups. Most patients showed worsening atrophy (brain, cerebellum, corpus callosum), whereas grey matter and white matter proportions did not change. Brain atrophy and myelination of anterior cerebral regions appear to be pertinent biomarkers of motor development. The time-course of inter- and intra-individual cerebral white matter and grey matter atrophy suggests that both oligodendrocytes and neurons are involved in the physiopathology of PLP1-related disorders.

Hereditary diffuse leukoencephalopathy with spheroids – a volumetric and radiological comparison with multiple sclerosis patients and healthy controls

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder caused by colony-stimulating factor 1 receptor (CSF1R) gene mutations, resulting in demyelination and axonal degeneration with spheroids. The clinical expression is variable, including behavioral changes, cognitive impairment, motor symptoms and parkinsonism. Magnetic resonance imaging (MRI) reveals white matter (WM) changes and atrophy. The indistinct phenotype has led to misdiagnoses. This study's aim was to compare brain volumetry and radiological ratings in HDLS with multiple sclerosis (MS) patients and controls. Five HDLS patients with c.2562T>A p.Asn854Lys CSF1R mutation, five age- and gender-matched MS patients and five healthy controls were cross-sectionally studied. All patients were examined neurologically. HDLS patients underwent Mini-Mental State Examination (MMSE). Brain MRI scans were analyzed volumetrically with FreeSurfer and Lesion Segmentation Toolbox and neuroradiologically with the brain MRI scoring system for HDLS. Patients with HDLS had lower brain, grey matter and WM fractions (66.3%; 37.9%; 27.6%) compared with controls (78.5%, P = 0.008; 44.4%, P = 0.008; 32.0%, P = 0.008), but not compared with MS patients (65.7%, P = 0.7; 36.8%, P = 0.4; 27.3%, P = 0.7). Cerebellar WM changes and atrophy were not seen in the HDLS group. The HDLS lesion volume fraction correlated with MMSE scores (r = -0.90, P = 0.04). Brain volume fractions in HDLS were lower than in controls and similar to those seen in MS. The cerebellum was relatively spared in HDLS, which may help in differentiating HDLS WM changes from MS. The strong relationship of HDLS lesions with MMSE scores indicates that accumulating WM pathology in HDLS is associated with cognitive decline.

Tobacco Smoke-Induced Brain White Matter Myelin Dysfunction: Potential Co-Factor Role of Smoking in Neurodegeneration.

Meta-analysis studies showed that smokers have increased risk for developing Alzheimer's disease (AD) compared with non-smokers, and neuroimaging studies revealed that smoking damages white matter structural integrity. The present study characterizes the effects of side-stream (second hand) cigarette smoke (CS) exposures on the expression of genes that regulate oligodendrocyte myelin-synthesis, maturation, and maintenance and neuroglial functions. Adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). The frontal lobes were used for histology and qRT-PCR analysis. Luxol fast blue, Hematoxylin and Eosin stained histological sections revealed CS-associated reductions in myelin staining intensity and narrowing of the corpus callosum. CS exposures broadly decreased mRNA levels of immature and mature oligodendrocyte myelin-associated, neuroglial, and oligodendrocyte-related transcription factors. These effects were more prominent in the CS8 compared with CS4 group, suggesting that molecular abnormalities linked to white matter atrophy and myelin loss worsen with duration of CS exposure. Recovery normalized or upregulated less than 25% of the suppressed genes; in most cases, inhibition of gene expression was either sustained or exacerbated. CS exposures broadly inhibit expression of genes needed for myelin synthesis and maintenance. These adverse effects often were not reversed by short-term CS withdrawal. The results support the hypothesis that smoking contributes to white matter degeneration, and therefore could be a key risk factor for a number of neurodegenerative diseases, including AD.

Longitudinal magnetic resonance imaging study shows progressive pyramidal and callosal damage in Friedreich's ataxia

Spinal cord and peripheral nerves are classically known to be damaged in Friedreich's ataxia, but the extent of cerebral involvement in the disease and its progression over time are not yet characterized. The aim of this study was to evaluate longitudinally cerebral damage in Friedreich's ataxia. We enrolled 31 patients and 40 controls, which were evaluated at baseline and after 1 and 2 years. To assess gray matter, we employed voxel-based morphometry and cortical thickness measurements. White matter was evaluated using diffusion tensor imaging. Statistical analyses were both cross-sectional and longitudinal (corrected for multiple comparisons). Group comparison between patients and controls revealed widespread macrostructural differences at baseline: gray matter atrophy in the dentate nuclei, brainstem, and precentral gyri; and white matter atrophy in the cerebellum and superior cerebellar peduncles, brainstem, and periventricular areas. We did not identify any longitudinal volumetric change over time. There were extensive microstructural alterations, including superior cerebellar peduncles, corpus callosum, and pyramidal tracts. Longitudinal analyses identified progressive microstructural abnormalities at the corpus callosum, pyramidal tracts, and superior cerebellar peduncles after 1 year of follow-up. Patients with Friedreich's ataxia present more widespread gray and white matter damage than previously reported, including not only infratentorial areas, but also supratentorial structures. Furthermore, patients with Friedreich's ataxia have progressive microstructural abnormalities amenable to detection in a short-term follow-up.

Pontine and cerebral atrophy in Lennox–Gastaut syndrome

ObjectivesLennox–Gastaut syndrome (LGS) is a severe epilepsy of childhood onset associated with intellectual disability and multiple seizure types. Characteristic interictal electrographic discharges include generalized paroxysmal fast activity and slow spike and wave, which we have previously shown recruit widespread areas of association cortex. We wished to determine whether patients with Lennox–Gastaut syndrome (LGS) have changes in cerebral volumes that match this pattern of cortical recruitment. MethodsHigh resolution T1 weighted structural MRI was collected from 10 patients with LGS and 10 age and sex matched controls. Voxel-based morphometry (VBM) was used to compare tissue volumes across the whole brain (grey matter, white matter and CSF) and pontine volume between patients and controls, as well as to identify other regions of maximal tissue loss. ResultsLGS patients showed a significant decrease in whole brain volume compared to controls. Cortical atrophy was prominent in the mesial frontal region and bilateral anterior temporal poles. White matter atrophy was widespread and included peri-central and premotor regions. Atrophy was prominent in the pons, particularly in the region of the reticular formation. Grey matter atrophy trended to progress with age. SignificanceGrey and white matter atrophy are a feature of Lennox–Gastaut syndrome. Grey matter atrophy is apparent in the mesial frontal lobe suggesting this region may be an important node in the epilepsy network of LGS. Atrophy maximal in the pons and cerebellum mimics the patterns of seizure spread that has been previously observed during tonic seizures. This supports the idea that the pons is a key part of the epilepsy network in LGS.

Differential Sphingolipid and Phospholipid Profiles in Alcohol and Nicotine-Derived Nitrosamine Ketone-Associated White Matter Degeneration.

Alcohol-mediated neurodegeneration is associated with white matter (WM) atrophy due to targeting of myelin and oligodendrocytes. However, variability in disease severity suggests cofactors contribute to WM degeneration. We examined the potential cofactor role of the tobacco-specific nitrosamine, nicotine-derived nitrosamine ketone (NNK), because smoking causes WM atrophy and most heavy drinkers consume tobacco products. This 8-week study of Long Evans rats had 4 treatment groups: control; NNK-2mg/kg, 3×/wk in weeks 3 to 8; ethanol (EtOH) (chronic-26% caloric+binge-2g/kg, 3×/wk in weeks 7 to 8); and EtOH+NNK. Exposure effects on WM lipid biochemical profiles and insitu distributions were examined using matrix-assisted laser desorption/ionization imaging mass spectrometry and tandem mass spectrometry. NNK mainly caused WM fiber degeneration and fiber loss, EtOH caused demyelination, and dual exposures had additive effects. EtOH and EtOH+NNK decreased WM (including corpus callosum) and/or gray matter (hypothalamus, cortex, medial temporal) levels of several phosphatidylserine, phosphatidylinositol, and sphingolipid (sulfatide [ST]) species, while NNK increased or had minimal effect on these lipids. EtOH+NNK had broader and larger inhibitory effects on phospholipids and ST than EtOH or NNK alone. Principal component analysis clustered control with NNK, and EtOH with EtOH+NNK groups, highlighting the independent EtOH- rather than NNK-driven responses. Chronic EtOH exposures decreased several phospholipid and sphingolipid species in brain, while concomitant NNK exposures exacerbated these effects. These findings support our hypothesis that tobacco smoking is a pathogenic cofactor in alcohol-mediated WM degeneration.

Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).

Long-Term Effects of Resistance Exercise Training on Cognition and Brain Volume in Older Women: Results from a Randomized Controlled Trial.

Aerobic exercise training has been shown to attenuate cognitive decline and reduce brain atrophy with advancing age. The extent to which resistance exercise training improves cognition and prevents brain atrophy is less known, and few studies include long-term follow-up cognitive and neuroimaging assessments. We report data from a randomized controlled trial of 155 older women, who engaged in 52 weeks of resistance training (either once- or twice-weekly) or balance-and-toning (twice-weekly). Executive functioning and memory were assessed at baseline, 1-year follow-up (i.e., immediately post-intervention), and 2-year follow-up. A subset underwent structural magnetic resonance imaging scans at those time points. At 2-year follow-up, both frequencies of resistance training promoted executive function compared to balance-and-toning (standardized difference [d]=.31-.48). Additionally, twice-weekly resistance training promoted memory (d=.45), reduced cortical white matter atrophy (d=.45), and increased peak muscle power (d=.27) at 2-year follow-up relative to balance-and-toning. These effects were independent of one another. These findings suggest resistance training may have a long-term impact on cognition and white matter volume in older women.