Frontal White Matter Volume Research Articles

Inflammatory protein associations with brain MRI measures: Framingham Offspring Cohort.

Brain magnetic resonance imaging (MRI) and inflammatory biomarkers are crucial for investigating preclinical neurocognitive disorders. Current investigations focus on a few inflammatory markers. The study aims to investigate the associations between inflammatory biomarkers and MRI measures and to examine sex differences among the associations in the Framingham Heart Study. Dementia and stroke-free participants underwent OLINK Proteomics profiling and MRI measurements within 5 years. Pairwise cross-sectional analysis assessed 68 biomarkers with 13 brain MRI volumes, adjusting for covariates and familial correlations. Elevated CDCP1, IL6, OPG, and 4E.BP1 were related to smaller total cerebral brain volume (TCBV), whereas higher HGF, IL8, and MMP10 were associated with smaller TCBV, total and frontal white matter volumes. Higher SCF and TWEAK were associated with larger TCBV. In sex-stratified analyses, associations were observed exclusively among males. We report several associations between inflammatory biomarkers and brain volumes, highlighting different associations within sex subgroups. Higher CDCP1, IL6, OPG, and 4E.BP1 levels were associated with smaller TCBV. Higher levels of HGF, IL8 and MMP10 were associated with smaller TCBV, CWV and FWV. Higher levels of SCF and TWEAK, were associated with larger TCBV. Significance diminished in models adjusting for CVD risk factors. Associations were observed exclusively in males.

Structural and Functional Brain Patterns Predict Formal Thought Disorder’s Severity and Its Persistence in Recent-Onset Psychosis: Results From the PRONIA Study

BackgroundFormal thought disorder (FThD) is a core feature of psychosis, and its severity and long-term persistence relates to poor clinical outcomes. However, advances in developing early recognition and management tools for FThD are hindered by a lack of insight into the brain-level predictors of FThD states and progression at the individual level. MethodsTwo hundred thirty-three individuals with recent-onset psychosis were drawn from the multisite European Prognostic Tools for Early Psychosis Management study. Support vector machine classifiers were trained within a cross-validation framework to separate two FThD symptom-based subgroups (high vs. low FThD severity), using cross-sectional whole-brain multiband fractional amplitude of low frequency fluctuations, gray matter volume and white matter volume data. Moreover, we trained machine learning models on these neuroimaging readouts to predict the persistence of high FThD subgroup membership from baseline to 1-year follow-up. ResultsCross-sectionally, multivariate patterns of gray matter volume within the salience, dorsal attention, visual, and ventral attention networks separated the FThD severity subgroups (balanced accuracy [BAC] = 60.8%). Longitudinally, distributed activations/deactivations within all fractional amplitude of low frequency fluctuation sub-bands (BACslow-5 = 73.2%, BACslow-4 = 72.9%, BACslow-3 = 68.0%), gray matter volume patterns overlapping with the cross-sectional ones (BAC = 62.7%), and smaller frontal white matter volume (BAC = 73.1%) predicted the persistence of high FThD severity from baseline to follow-up, with a combined multimodal balanced accuracy of BAC = 77%. ConclusionsWe report the first evidence of brain structural and functional patterns predictive of FThD severity and persistence in early psychosis. These findings open up avenues for the development of neuroimaging-based diagnostic, prognostic, and treatment options for the early recognition and management of FThD and associated poor outcomes.

Diagnostic Application of Automated Brain MRI Volumetry in Comparing Alzheimer Disease, Behavioral Variant Frontotemporal Dementia and Traumatic Brain Injury (P12-6.005)

<h3>Objective:</h3> To evaluate if application of automated brain MRI volumetry can improve delineation of neurocognitive disorders. <h3>Background:</h3> Assessment of regional structural differences with brain MRI volumetric quantification can improve diagnostic separation of multiple neurodegenerative and non-neurodegenerative disorders. <h3>Design/Methods:</h3> We utilized 136 participants with traumatic brain injury (TBI; n=40), early (EOAD; n=45) and late onset Alzheimer disease (LOAD; n=31) and behavioral variant frontotemporal dementia (bvFTD; n=20). Participants had brain MRI including 3D T1 and analyzed with an FDA cleared software program, Neuroreader. At the time of analysis, Mini-Mental State Exam (MMSE) scores were available on majority of participants (n=125). One-way ANOVA compared mean age, MMSE, and brain volumes across all four groups with Bonferroni correction for multiple comparisons. Volumes were adjusted for total intracranial volume (TIV). Discriminant analysis was done with leave-one-out cross validation on measured brain volumes to determine diagnostic delineation. Automated linear regression identified predictive features. <h3>Results:</h3> LOAD was the oldest compared to other groups (p&lt;.001). There were no statistically significant differences in sex (p=.58) with 54.4% women. EOAD and LOAD had the lowest MMSE scores compared to TBI (p=.04 for EOAD and p=.01 for LOAD). Regional volume difference across groups showed lowest hippocampal volumes in LOAD (p=.005), low white matter volume in TBI (p=.007), lower parietal lobe volumes in EOAD (p&lt;.01), and lower frontal lobe volumes in bvFTD (p&lt;.001). Regional volume differences resulted in a correct classification of 89%, 79.4% after cross validation. Predictive features included caudate, amygdala, frontal, parietal, temporal lobar and total white matter volumes. <h3>Conclusions:</h3> Lower parietal lobe volumes in EOAD and hippocampal volumes in LOAD as well as frontal atrophy of bvFTD reflect known anatomical distribution of pathology in those conditions. White matter volume loss in TBI has been noted with that condition. Brain MRI volumetry may be beneficial in clinical practice. <b>Disclosure:</b> Dr. Meysami has nothing to disclose. Prof. Raji has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Brainreader ApS. Prof. Raji has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Apollo Health . Prof. Raji has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Neurevolution Medicine. Dr. Porter has nothing to disclose. David Merrill has nothing to disclose. Dr. Mendez has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Medical Education Speakers’ Bureau. Dr. Mendez has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for UpToDate. The institution of Dr. Mendez has received research support from NIH. Dr. Mendez has received publishing royalties from a publication relating to health care.

Effect of schizophrenia common variants on infant brain volumes: cross-sectional study in 207 term neonates in developing Human Connectome Project

Increasing lines of evidence suggest deviations from the normal early developmental trajectory could give rise to the onset of schizophrenia during adolescence and young adulthood, but few studies have investigated brain imaging changes associated with schizophrenia common variants in neonates. This study compared the brain volumes of both grey and white matter regions with schizophrenia polygenic risk scores (PRS) for 207 healthy term-born infants of European ancestry. Linear regression was used to estimate the relationship between PRS and brain volumes, with gestational age at birth, postmenstrual age at scan, ancestral principal components, sex and intracranial volumes as covariates. The schizophrenia PRS were negatively associated with the grey (β = −0.08, p = 4.2 × 10−3) and white (β = −0.13, p = 9.4 × 10−3) matter superior temporal gyrus volumes, white frontal lobe volume (β = −0.09, p = 1.5 × 10−3) and the total white matter volume (β = −0.062, p = 1.66 × 10−2). This result also remained robust when incorporating individuals of Asian ancestry. Explorative functional analysis of the schizophrenia risk variants associated with the right frontal lobe white matter volume found enrichment in neurodevelopmental pathways. This preliminary result suggests possible involvement of schizophrenia risk genes in early brain growth, and potential early life structural alterations long before the average age of onset of the disease.

Maternal Immune Activation during Pregnancy Alters Postnatal Brain Growth and Cognitive Development in Nonhuman Primate Offspring.

Human epidemiological studies implicate exposure to infection during gestation in the etiology of neurodevelopmental disorders. Animal models of maternal immune activation (MIA) have identified the maternal immune response as the critical link between maternal infection and aberrant offspring brain and behavior development. Here we evaluate neurodevelopment of male rhesus monkeys (Macaca mulatta) born to MIA-treated dams (n = 14) injected with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the same gestational time points (n = 10) or were untreated (n = 4). MIA-treated dams exhibited a strong immune response as indexed by transient increases in sickness behavior, temperature, and inflammatory cytokines. Although offspring born to control or MIA-treated dams did not differ on measures of physical growth and early developmental milestones, the MIA-treated animals exhibited subtle changes in cognitive development and deviated from species-typical brain growth trajectories. Longitudinal MRI revealed significant gray matter volume reductions in the prefrontal and frontal cortices of MIA-treated offspring at 6 months that persisted through the final time point at 45 months along with smaller frontal white matter volumes in MIA-treated animals at 36 and 45 months. These findings provide the first evidence of early postnatal changes in brain development in MIA-exposed nonhuman primates and establish a translationally relevant model system to explore the neurodevelopmental trajectory of risk associated with prenatal immune challenge from birth through late adolescence.SIGNIFICANCE STATEMENT Women exposed to infection during pregnancy have an increased risk of giving birth to a child who will later be diagnosed with a neurodevelopmental disorder. Preclinical maternal immune activation (MIA) models have demonstrated that the effects of maternal infection on fetal brain development are mediated by maternal immune response. Since the majority of MIA models are conducted in rodents, the nonhuman primate provides a unique system to evaluate the MIA hypothesis in a species closely related to humans. Here we report the first longitudinal study conducted in a nonhuman primate MIA model. MIA-exposed offspring demonstrate subtle changes in cognitive development paired with marked reductions in frontal gray and white matter, further supporting the association between prenatal immune challenge and alterations in offspring neurodevelopment.

Left frontal white matter atrophy links to timing mechanisms relevant for apraxia of speech

AbstractBackgroundIn patients with apraxia of speech (AOS), we observed impaired perceptual timing abilities, which lead us to propose a shared mechanism of impaired timing processing underlying both impaired perceptual processing and motor speech output [1]. Given that white matter damage is often observed in AOS, we here investigate whether white matter changes are related to impaired perceptual timing as one possible mechanism underlying AOS.MethodA psychoacoustic and multimodal neuroimaging analysis was performed in 12 patients with the nonfluent variant (NFV) of Primary Progressive Aphasia (PPA) with AOS, 11 patients with the semantic variant and 24 controls. During the four perceptual timing tasks (r1‐r4, [1]), participants had to detect the longer gap in pairs of tones (r1) or in a sequence of tones (r2) or discriminate between rhythmic sequences with a strongly (r3) or weakly (r4) metrical beat. Speech rhythm was quantified in connected speech by means of the normalized pairwise variability index (PVI). Deformation‐based morphometry (DBM) and diffusion tensor imaging (DTI) were acquired on a 3T MRI and processed using CAT12 and MRTRIX3, respectively. We determined Fractional Anisotropy (FA) and Mean Diffusivity (MD) values for the left Aslant tract, which is typically damaged in NFV.ResultSeventy‐five percent of NFV patients displayed impaired perceptual timing, specifically when discriminating between rhythmic sequences (r3‐r4, transformed to z‐scores, Figure 1). Impaired perceptual timing correlated with abnormal vowel lengthening (correlation of r3 and PVI of strong‐weak words: r = 0.65, P = 0.029). Moreover, left frontal white matter volume loss adjacent to the supplementary motor area (SMA) correlated with impaired perceptual timing (r3) in NFV (Figure 2, cluster‐level FWE‐corr. P&lt;.05). MD in the left Aslant tract also correlated with perceptual timing in NFV (correlation with r3: r = 0.82, P = 0.026).ConclusionA shared white matter substrate adjacent to the SMA links impaired perceptual timing and motor speech impairment. Our data indicates that impaired timing may be one of the neurocomputational mechanisms underlying AOS. Moreover, regional variations in left frontal lobe atrophy explain part of phenotypical heterogeneity in NFV. Resource: (1) Grube, Bruffaerts, Schaeverbeke et al., Brain 2016.

The Effects of Lutein and Zeaxanthin Supplementation on Brain Morphology in Older Adults: A Randomized, Controlled Trial.

A growing literature emphasizes the importance of lifestyle factors such as nutrition in successful aging. The current study examined if one year of supplementation with lutein (L) and zeaxanthin (Z), two nutrients with known antioxidative properties and cognitive benefits, impacted structural brain outcomes in older adults using a double-blind, randomized, placebo-controlled trial design. Community-dwelling older adults (20 males and 27 females) aged 65–87 years (M = 71.8 years, SD = 6.04 years) were randomized into supplement (N = 33) and placebo groups (N = 14) using simple randomization. The supplement group received 10 mg L + 2 mg Z daily for 12 months while the placebo group received a visually identical, inert placebo. L and Z were measured via retinal concentrations (macular pigment optical density or MPOD). Structural brain outcomes, focusing on global and frontal-temporal lobe regions, were acquired using both T1-weighted and DTI MRI sequences. We hypothesized that the supplement group would increase, maintain, or show attenuated loss in hypothesized regions-of-interest (ROIs) while the placebo group would show age-related declines in brain structural integrity over the course of the trial. While results showed age-related declines for frontal and temporal gray and white matter volumes, as well as fornix white matter microstructure across both groups, only minimal differences were found between the supplement and placebo groups. However, exploratory analyses showed that individuals who responded better to supplementation (i.e., showed greater increases in MPOD) showed less decline in global and prefrontal gray matter volume than supplement “nonresponders.” While results suggest that one year of L and Z supplementation may have limited effects on structural brain outcomes overall, there may be a subsample of individuals for whom supplementation of L and Z provides greater benefits. ClinicalTrials.gov number, NCT02023645.

Methanol Poisoning as an Acute Toxicological Basal Ganglia Lesion Model: Evidence from Brain Volumetry and Cognition.

Acute methanol poisoning leads to optic neuropathy and necrotic lesions of basal ganglia (BG) and subcortical white matter. Survivors of methanol poisoning exhibit long-term executive and memory deficits. Associations between brain volumetry parameters and cognitive sequelae of methanol poisoning are not known. The aim of our study was to identify long-term associations between the cognitive performance of survivors of methanol poisoning and the volume of the brain structures that are selectively vulnerable to methanol. We conducted a cross-sectional follow-up study on a sample of patients (n=33, age 50±14 years, 82% males) who survived acute methanol poisoning during methanol mass poisoning outbreak from September 2012 till January 2013 in the Czech Republic. A battery of neuropsychological tests and brain magnetic resonance imaging were included in the clinical examination protocol. Specific brain structures (putamen, globus pallidus, nucleus caudatus, and frontal white matter) were selected as regions of interest, and their volumes were estimated using the MorphoBox prototype software. In robust multiple regression models, sustained visual attention performance (as assessed by Trail Making Test and Prague Stroop Test) was positively associated with BG structures and frontal white matter volumes (Wald=9.03 to 85.50, p<0.01), sensitivity to interference (as assessed by Frontal Battery Assessment) was negatively associated with frontal white matter volume (Wald=35.44 to 42.25, p<0.001), and motor performance (as assessed by Finger Tapping Test) was positively associated with globus pallidus and frontal white matter volumes (Wald=9.66 to 13.29, p<0.01). Our results demonstrate that smaller volumes of elements of BG-thalamocortical circuitry, namely the BG and frontal white matter, relate to attention and motor performance in methanol poisoning from a long-term perspective. Disruption of those functional circuits may underlie specific cognitive deficits observed in methanol poisoning.

Executive control deficits correlate with reduced frontal white matter volume in multiple sclerosis

ABSTRACTIntroduction: Executive control deficits are frequently reported in patients with multiple sclerosis (MS). We have previously proposed that in the context of competing automatic and volitional processes, such deficits may in part reflect poor resolution of response conflict. This study aimed to investigate the neuropathological underpinnings of executive control deficits in MS, focusing on the frontostriatal system proposed to mediate executive control.Method: Forty-one MS patients and 25 healthy controls completed measures of executive control that have previously been used to characterize deficit in MS: antisaccade and endogenously cued saccade paradigms, and the Stroop color and word test. Relationships between task performance and volumetric measures of frontal white matter, frontal gray matter, striatum, and pallidum were investigated.Results: MS participants performed significantly more poorly on the Stroop and antisaccade tasks than controls. For MS patients, higher erroneous responding on the antisaccade task was related to reduced frontal white matter volume.Conclusion: These findings suggest that loss of frontal white matter may underlie executive control deficits in MS, and provides information that may inform the development of targeted cognitive training strategies in MS.

Longitudinal association between brain volume change and gait speed in a general population.

To determine the association between brain structural changes and gait speed in a four-year longitudinal prospective cohort study. A total of 767 well-functioning community-dwelling participants, free of arthritis, silent infarct, stroke, dementia, head injury, and cancer, completed baseline brain magnetic resonance imaging scan and gait speed tests between 2011 and 2014, and follow-up tests between 2015 and 2017. The gait test consisted of measuring the elapsed time to walk four meters at usual speed. To estimate whether brain volume changes predict gait speed decline at follow-up, a generalized linear regression model was used after adjusting for potential confounding factors including gait speed at baseline. Participants who experienced ≥0.05 m/s gait speed decline, previously defined as a clinically meaningful decline, were more likely to be women, less likely to be smokers, and had lower physical activity scores (p = 0.003, p = 0.025, and p = 0.006, respectively), as compared to those who did not experience the decline. Also, they demonstrated smaller volumes of hippocampus, total gray matter, parietal gray matter, temporal gray matter, and temporal white matter (p = 0.004, p = 0.042, p = 0.021, p = 0.001, and p = 0.004, respectively). Even after correcting the significance level due to multiple comparisons, overall gray matter and overall white matter volume changes during four-year follow-up period showed significant associations with gait speed at follow-up (p < 0.001 and p = 0.002). Regarding region-specific volumes, frontal white matter and parietal gray matter volume changes demonstrated significant associations with gait speed (p = 0.002, p = 0.004, respectively). In a four-year longitudinal study among 767 well-functioning community-dwelling healthy participants from a general population, we observed a significant association between brain volume changes and gait speed.

Characterisation of brain volume and microstructure at term-equivalent age in infants born across the gestational age spectrum.

BackgroundRisk of morbidity differs between very preterm (VP; <32 weeks' gestational age (GA)), moderate preterm (MP; 32–33 weeks' GA), late preterm (LP; 34–36 weeks' GA), and full-term (FT; ≥37 weeks' GA) infants. However, brain structure at term-equivalent age (TEA; 38–44 weeks) remains to be characterised in all clinically important GA groups. We aimed to compare global and regional brain volumes, and regional white matter microstructure, between VP, MP, LP and FT groups at TEA, in order to establish the magnitude and anatomical locations of between-group differences.MethodsStructural images from 328 infants (91 VP, 63 MP, 104 LP and 70 FT) were segmented into white matter, cortical grey matter, cerebrospinal fluid (CSF), subcortical grey matter, brainstem and cerebellum. Global tissue volumes were analysed, and additionally, cortical grey matter and white matter volumes were analysed at the regional level using voxel-based morphometry. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) images from 361 infants (92 VP, 69 MP, 120 LP and 80 FT) were analysed using Tract-Based Spatial Statistics. Statistical analyses involved examining the overall effect of GA group on global volumes (using linear regressions) and regional volumes and microstructure (using non-parametric permutation testing), as well performing post-hoc comparisons between the GA sub-groups.ResultsOn global analysis, cerebrospinal fluid (CSF) volume was larger in all preterm sub-groups compared with the FT group. On regional analysis, volume was smaller in parts of the temporal cortical grey matter, and parts of the temporal white matter and corpus callosum, in all preterm sub-groups compared with the FT group. FA was lower, and RD and MD were higher in voxels located in much of the white matter in all preterm sub-groups compared with the FT group. The anatomical locations of group differences were similar for each preterm vs. FT comparison, but the magnitude and spatial extent of group differences was largest for the VP, followed by the MP, and then the LP comparison. Comparing within the preterm groups, the VP sub-group had smaller frontal and temporal grey and white matter volume, and lower FA and higher MD and RD within voxels in the approximate location of the corpus callosum compared with the MP sub-group. There were few volume and microstructural differences between the MP and LP sub-groups.ConclusionAll preterm sub-groups had atypical brain volume and microstructure at TEA when compared with a FT group, particularly for the CSF, temporal grey and white matter, and corpus callosum. In general, the groups followed a gradient, where the differences were most pronounced for the VP group, less pronounced for the MP group, and least pronounced for the LP group. The VP sub-group was particularly vulnerable compared with the MP and LP sub-groups.

Age-Modulated Associations between KIBRA, Brain Volume, and Verbal Memory among Healthy Older Adults.

The resource modulation hypothesis suggests that the influence of genes on cognitive functioning increases with age. The KIBRA single nucleotide polymorphism rs17070145, associated with episodic memory and working memory, has been suggested to follow such a pattern, but few studies have tested this assertion directly. The present study investigated the relationship between KIBRA alleles (T carriers vs. CC homozygotes), cognitive performance, and brain volumes in three groups of cognitively healthy adults—middle aged (ages 52–64, n = 38), young old (ages 65–72, n = 45), and older old (ages 73–92, n = 62)—who were carefully matched on potentially confounding variables including apolipoprotein ε4 status and hypertension. Consistent with our prediction, T carriers maintained verbal memory performance with increasing age while CC homozygotes declined. Voxel-based morphometric analysis of magnetic resonance images showed an advantage for T carriers in frontal white matter volume that increased with age. Focusing on the older old group, this advantage for T carriers was also evident in left lingual gyrus gray matter and several additional frontal white matter regions. Contrary to expectations, neither KIBRA nor the interaction between KIBRA and age predicted hippocampal volumes. None of the brain regions investigated showed a CC homozygote advantage. Taken together, these data suggest that KIBRA results in decreased verbal memory performance and lower brain volumes in CC homozygotes compared to T carriers, particularly among the oldest old, consistent with the resource modulation hypothesis.

Disrupted development and integrity of frontal white matter in patients treated for pediatric medulloblastoma.

Treatment of pediatric medulloblastoma is associated with known neurocognitive deficits that we hypothesize are caused by microstructural damage to frontal white matter (WM). Longitudinal MRI examinations were collected from baseline (after surgery but before therapy) to 36 months in 146 patients and at 3 time points in 72 controls. Regional analyses of frontal WM volume and diffusion tensor imaging metrics were performed and verified with tract-based spatial statistics. Age-adjusted, linear mixed-effects models were used to compare patient and control images and to associate imaging changes with Woodcock-Johnson Tests of Cognitive Abilities. At baseline, WM volumes in patients were similar to those in controls; fractional anisotropy (FA) was lower bilaterally (P < 0.001) and was associated with decreased Processing Speed (P = 0.014) and Broad Attention (P = 0.025) performance at 36 months. During follow-up, WM volumes increased in controls but decreased in patients (P < 0.001) bilaterally. Smaller WM volumes in patients at 36 months were associated with concurrent decreased Working Memory (P = 0.026) performance. Lower FA in patients with pediatric medulloblastoma compared with age-similar controls indicated that patients suffer substantial acute microstructural damage to supratentorial frontal WM following surgery but before radiation therapy or chemotherapy. Additionally, this damage to the frontal WM was associated with decreased cognitive performance in executive function 36 months later. This early damage also likely contributed to posttherapeutic failure of age-appropriate WM development and to the known association between decreased WM volumes and decreased cognitive performance.

Influence of diabetes mellitus on longitudinal atrophy and cognition in Parkinson's disease

ObjectiveTo investigate the impact of diabetes mellitus (DM) on cognitive performance and longitudinal volumetric brain changes in a cohort of cognitively normal mild PD patients. MethodsProspective study of idiopathic PD subjects who underwent baseline and follow-up MRI imaging and neuropsychological assessments at 6month intervals for 3years. Subjects were classified based on the presence (PD-DM) or absence of DM (PD-No DM) at baseline. Volumetric analysis was performed using FreeSurfer 5.3 image analysis suite. Brain volume and cognition were compared and analyzed cross-sectionally and longitudinally. Analyses were corrected for intracranial volume. ResultsThere were 65 PD-no DM and 12 PD-DM subjects at baseline with comparable global cognition at baseline. PD-DM subjects had lower cortical grey matter (GM), amygdala, frontal white matter and temporal white matter volumes and higher total white matter hyperintensity and periventricular hyperintensities. After mean follow-up of 29.08months, there were 51 PD-no DM and 11 PD-DM subjects. PD-DM subjects demonstrated greater decline in MMSE and MOCA scores compared to PD-No DM. PD-DM subjects had a higher rate of atrophy in the cortical WM, particularly in the parietal and occipital white matter. ConclusionMild PD patients with DM have lower GM and WM volumes at baseline and higher WMH volumes, despite comparable cognitive scores. Longitudinally, DM in PD results in greater rate of cognitive decline, associated with higher WM atrophy.

Brain structure, working memory and response inhibition in childhood leukemia survivors

IntroductionSurvival rates for children with acute lymphoblastic leukemia (ALL) approach 95%. At the same time, there is growing concern that chemotherapy causes alterations in brain development and cognitive abilities. We performed MRI measurements of white and gray matter volume to explore how variation in brain structure may be related to cognitive abilities in ALL survivors and healthy controls.MethodsThe sample included 24 male ALL survivors who had completed contemporary treatment 3–11 years prior, and 21 age‐ and sex‐matched controls. Participants were between 8 and 18 years old. Working memory and motor response inhibition were measured with the N‐Back and Stop Signal Tasks (SST), respectively. Participants underwent 3T structural MRI to assess white and gray matter volumes overall, lobe‐wise, and in cortical and atlas‐identified subcortical structures. Mental health was assessed with the Child Behavioral Checklist.Results ALL survivors performed more poorly on measures of working memory and response inhibition than controls. Frontal and parietal white matter, temporal and occipital gray matter volume, and volumes of subcortical white and gray matter structures were significantly reduced in ALL survivors compared with controls. Significant structure‐function correlations were observed between working memory performance and volume of the amygdala, thalamus, striatum, and corpus callosum. Response inhibition was correlated with frontal white matter volume. No differences were found in psychopathology.ConclusionsCompared with controls, a reduction in volume across brain regions and tissue types, was detectable in ALL survivors years after completion of therapy. These structural alterations were correlated with neurocognitive performance, particularly in working memory. Confirming these observations in a larger, more representative sample of the population is necessary. Additionally, establishing the time course of these changes—and the treatment, genetic, and environmental factors that influence them—may provide opportunities to identify at‐risk patients, inform the design of treatment modifications, and minimize adverse cognitive outcomes.

From neuroleptics to neuroscience and from Pavlov to psychotherapy: more than just the "emperor's new treatments" for mental illnesses?

“The drugs don't work” was one of the hit singles from The Verve's album Urban Hymns , released in 1997. The song was written by lead singer Richard Ashcroft relating to his drug abuse, but it might well relate to the modern treatments for mental illnesses. More than half a century after neuroleptics, antidepressants, benzodiazepines, antipsychotics, behavior therapy, and cognitive treatment were introduced, it is prudent to ask whether “the drugs don't work”. During the past 50 years, the industrialized world has seen a dichotomy between loudly proclaimed therapeutic breakthroughs and rapidly rising numbers of people on disability payments because of mental illness. We hear that antipsychotic, antidepressant, and anti‐anxiety drugs as well as behavior therapy and newer treatments have radically improved what was described as a dismal fate of people suffering from mental disorders. Simultaneously, the percentage of disabled mentally ill patients in the USA has risen by more than 600% since the 1950s (Whitaker, 2010) and similar rates are seen in European countries. Most epidemiologists agree that this “epidemic” is not caused by increased incidence. Moreover, the once rapid succession of new therapeutic developments seems to have halted, at least in pharmacology, as big companies are withdrawing from research on mental disorders. How can this apparent contradiction be explained? Could it be that therapeutic progress is much less than we think or are being told? Could it be that the course of depression, anxiety, schizophrenia, or ADHD has been altered for the worse? Could it be that we cannot make therapeutic progress because the concept of mental illness and its treatment is deeply flawed? There are strong reasons to assume that all three suspicions are in fact true. So, what do we know about the efficiency of pharmacological and psychological treatments? In regard to short‐term outcomes, pharmacotherapy is clearly …

Regional brain volume changes in alcohol-dependent individuals during early abstinence: associations with relapse following treatment

Cross-sectional structural magnetic resonance (MR) imaging studies of individuals with an alcohol use disorder (AUD) report that those who relapse after treatment, relative to individuals who maintain a period of extended abstinence, show greater morphological abnormalities in multiple brain regions near the inception of treatment, particularly in the frontal lobe. However, given the cross-sectional design of previous studies, it is unclear if the baseline morphological differences between future abstainers and relapsers were maintained over the course of early recovery. The primary goal of this study was to determine if frontal lobe tissue volume recovery during early abstinence is associated with long-term abstinence from alcohol. We compared frontal, parietal, temporal and occipital grey matter (GM) and white matter (WM) volumes, at 1 and 4 weeks of abstinence, among individuals who resumed alcohol consumption within 12 months of treatment (Relapsers) and those who showed sustained abstinence over 12 months following treatment (Abstainers). At 1 and 4 weeks of sobriety, both Abstainers and Relapsers demonstrated significantly smaller GM volumes than Controls in the majority of ROIs, but Relapsers exhibited significantly smaller bilateral frontal GM volumes than Abstainers. No significant group differences were observed for any WM region of interest. The persistent bilateral frontal GM volume deficits in Relapsers over 4 weeks from last alcohol use may represent an endophenotype that differentiates those who respond more favorably to the typical psychosocial and pharmacological interventions provided for AUD.

Abstract P063: Cigarette Smoking and Neuroimaging Indices of Cerebrovascular Health in a Population-based Cohort of Middle-aged Adults

Introduction: Several studies report an association between cigarette smoking and dementia. One proposed hypothesis is that smoking leads to adverse cognitive and brain changes through vascular pathways. To date, few data exist on the link between smoking and vascular brain measures. We examined, in a population-based middle-aged cohort, the association of history of cigarette smoking with three indicators of cerebrovascular health: (i) white matter (WM) integrity measured using WM-fractional anisotropy, (ii) abnormal WM volume, and (iii) cerebral blood flow (CBF) in the gray matter. We focused on lobar measures of these indicators to detect whether specific regional cerebrovascular indicators are differently related to smoking. Hypothesis: We assessed the hypothesis that smoking history is associated with more adverse cerebrovascular measures (lower fractional anisotropy, larger abnormal WM volumes, and lower CBF). Methods: Data come from the Coronary Artery Risk Development in Young Adults CARDIA-brain magnetic resonance imaging sub-study (n=538). Brain measures and self-reported smoking history were obtained at the 25th year follow-up (mean age=50). We used linear (for CBF and WM-fractional anisotropy) and multinomial logistic (for abnormal WM volume) regression models, adjusted for potential confounders (including vascular and lifestyle risk factors and medical conditions). Results: Compared to never-smokers, current smokers had lower WM-fractional anisotropy in all brain lobes (-0.005 lower fractional anisotropy in the occipital lobe and -0.006 in the other lobes; p&lt;0.05). Smoking history was also associated with larger abnormal WM volumes: Compared to never-smokers, smokers and/or former-smokers had patterns of larger abnormal WM volumes in all lobes, with pronounced associations observed in the frontal lobe wherein smokers and former-smokers had up to twice the risk of having larger abnormal frontal WM volumes as never-smokers (p&lt;0.05). Smoking history was associated with lower CBF in the occipital (-2.89 ml/100g/min (95%CI=-5.43, -0.36); p=0.03) and parietal lobes (-3.31 (95%CI=-5.91, -0.71); p=0.01). Conclusions: In this cohort of middle-aged adults, associations between smoking and adverse WM measures were observed in all brain lobes, whereas associations of smoking with CBF were localized in the occipital and parietal lobes. This localization may reflect a link between smoking and blood flow processes related to sensory-cognitive networks. In conclusion, results suggest that smoking is associated with three early-indicators of cerebrovascular burden (WM-fractional anisotropy, WM abnormal volume, and CBF) across the brain and that it may be differentially related to different regional cerebrovascular indicators.

NeuN+ neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure

Increased neuronal densities in subcortical white matter have been reported for some cases with schizophrenia. The underlying cellular and molecular mechanisms remain unresolved.We exposed 26 young adult macaque monkeys for 6months to either clozapine, haloperidol or placebo and measured by structural MRI frontal gray and white matter volumes before and after treatment, followed by observer-independent, flow-cytometry-based quantification of neuronal and non-neuronal nuclei and molecular fingerprinting of cell-type specific transcripts.After clozapine exposure, the proportion of nuclei expressing the neuronal marker NeuN increased by approximately 50% in subcortical white matter, in conjunction with a more subtle and non-significant increase in overlying gray matter. Numbers and proportions of nuclei expressing the oligodendrocyte lineage marker, OLIG2, and cell-type specific RNA expression patterns, were maintained after antipsychotic drug exposure. Frontal lobe gray and white matter volumes remained indistinguishable between antipsychotic-drug-exposed and control groups.Chronic clozapine exposure increases the proportion of NeuN+ nuclei in frontal subcortical white matter, without alterations in frontal lobe volumes or cell type-specific gene expression. Further exploration of neurochemical plasticity in non-human primate brain exposed to antipsychotic drugs is warranted.

Reduced frontal white matter volume in children with early onset of adrenarche

While there is growing evidence that puberty affects brain development, very little is known about the structural brain changes associated with dehydroepiandrosterone (DHEA), an adrenal hormone that exhibits dramatic increases during adrenarche, the earliest phase of puberty. Moreover, no research has investigated whether relatively early exposure to DHEA (i.e., early adrenarche) during this period is associated with differences in brain structure. We ran a whole-brain voxel-based morphometry analysis on T1-weighted magnetic resonance imaging brain scans to compare gray (GMV) and white matter volumes (WMV) between children experiencing relatively early (n=41) vs. relatively late (n=44) adrenarche. We also investigated the correlations between GMV or WMV and DHEA levels, and finally, tested for sex differences in group and correlation analyses. We observed reduced frontal WMV in a cluster located on the left corona radiata in children experiencing earlier adrenarche. In addition, WMV in this area was negatively correlated with DHEA levels. We did not observe any effect of gender in both the group and the correlation analyses. Early onset of adrenarche (as defined by relatively early exposure to DHEA) may be associated with differences in the development of frontal white matter tracts.