Gray Matter Volume Reduction Research Articles

Etiology of Antisocial Personality Disorder: A Review of Brain Function and Childhood Experiences

Antisocial Personality Disorder (ASPD) is a psychological disorder in which an individual engages exclusively or significantly in the deliberate violating of, scamming, as well as violence against other people for their gain. This review aims to provide a comprehensive account of the recent developments regarding biological, neurocognitive, and neuropsychological factors and environmental risks related to ASPD. Neuroimaging studies have been conducted to assess brain function using voxel-based morphometry (VBM) and imaging of functional magnetic resonance (fMRI) to determine structural and functional changes that occur. Previous studies have recognized marked grey matter volume (GMV) disruptions in the prefrontal cortex, temporal lobes, parietal regions, and aberrant functional connectivity profiles — particularly between attention and default mode networks. Of the environmental factor, childhood trauma is crucial for leading to necessary support of ASPD phenotype with emotional or physical abuse during infancy, significantly contributing to risk-prediction capacity—the systematic review methodology involved six critical evaluations of the study on neurobiology and childhood ASPD risk factors. Consistent neuroimaging data on brain structure (grey matter volume reductions) and functional connectivity and the critical role of early life experiences in susceptibility to this disorder are shown throughout. In conclusion, ASPD's etiology is multifactorial, involving a complex interaction of biological and environmental factors. Understanding the neurological underpinnings and developmental experiences leading to ASPD can inform more targeted interventions and treatment strategies for at-risk individuals, highlighting the need for early detection and therapeutic approaches to address brain function deficits and childhood adversities.

Voxel-based morphometry in the assessment of brain condition in patients after breast cancer treatment (Part 2)

Background. Breast cancer is one of the most common malignancies in women. Modern treatment methods, such as chemotherapy, can cause adverse effects on the central nervous system, including cognitive impairment known as “chemobrain”. Brain imaging techniques, such as voxel-based morphometry (VBM), are essential for diagnosing these changes. Objective. The study aimed to assess changes in brain structure volumes in breast cancer survivors using voxel-based morphometry. Design and Methods. The study included 86 patients (mean age 43.27 ± 4.38 years) who underwent breast cancer treatment and 26 healthy volunteers (mean age 44 ± 5.68 years). MRI of the brain was performed using the MPRAGE sequence to exclude organic pathology and analyze brain structure volumes. Data analysis was conducted using the VolBrain platform. Results. Morphometric analysis revealed a statistically significant reduction in gray and white matter volumes in breast cancer patients after chemotherapy compared to the control group. This reduction was accompanied by complaints of cognitive decline, including memory and attention deficits, which correlated with decreased brain structure volumes. Conclusion. Voxel-based morphometry enables the detection of subtle changes in brain structure in breast cancer survivors. The results confirm the significant impact of chemotherapy on the central nervous system and highlight the need for early diagnosis and rehabilitation of cognitive impairments.

Voxel-based morphometry in the assessment of brain condition in patients after breast cancer treatment (Part 1)

Background. Breast cancer is one of the most common malignancies in women. Modern treatment methods, such as chemotherapy, can cause adverse effects on the central nervous system, including cognitive impairment known as “chemobrain”. Brain imaging techniques, such as voxel-based morphometry (VBM), are essential for diagnosing these changes. Objective. The study aimed to assess changes in brain structure volumes in breast cancer survivors using voxel-based morphometry. Design and Methods. The study included 86 patients (mean age 43.27 ± 4.38 years) who underwent breast cancer treatment and 26 healthy volunteers (mean age 44 ± 5.68 years). MRI of the brain was performed using the MPRAGE sequence to exclude organic pathology and analyze brain structure volumes. Data analysis was conducted using the VolBrain platform. Results. Morphometric analysis revealed a statistically significant reduction in gray and white matter volumes in breast cancer patients after chemotherapy compared to the control group. This reduction was accompanied by complaints of cognitive decline, including memory and attention deficits, which correlated with decreased brain structure volumes. Conclusion. Voxel-based morphometry enables the detection of subtle changes in brain structure in breast cancer survivors. The results confirm the significant impact of chemotherapy on the central nervous system and highlight the need for early diagnosis and rehabilitation of cognitive impairments.

Short-Term Restriction of Physical and Social Activities Effects on Brain Structure and Connectivity

Background: Prolonged confinement in enclosed environments has raised concerns about its effects on both physical and mental health. Although increased rates of depression or anxiety during COVID-19 lockdowns have been reported, the effects of short-term restrictions on social activities and physical on brain function and structure remain poorly known. Methods: This study explored longitudinal changes in brain gray matter volume (GMV) and functional connectivity (FC) immediately after and four months following a short-term lockdown in comparison to pre-lockdown conditions. MRI data were collected from 20 participants before the lockdown, from 29 participants (14 original, 15 new) two months post-lockdown, and from 27 out of the 29 participants four months post-lifting of the lockdown. Results: Results showed significant GMV reductions in the right gyrus rectus and cuneus post-lockdown, with further reductions observed four months after lifting the restrictions, affecting additional brain regions. Longitudinal FC trajectories revealed decreased connectivity between the default mode network (DMN) and sensorimotor/attention networks post-lockdown, and recovery after four months post-lifting of the lockdown. Conclusions: The observed plasticity in brain FC indicates substantial recovery potential with the potential long-term effect of structural changes. Our findings offer insights into the effects of isolation on the human brain, potentially informing rehabilitation mechanisms and interventions for individuals in similar conditions.

Repeated exposure to high-dose nicotine induces prefrontal gray matter atrophy in adolescent male rats

Incidences of seizure after e-cigarette use in adolescents and young adults have been reported, raising the concern about the risk of nicotine overconsumption. Few previous studies have investigated the effects of nicotine at high doses on brain and behavior in adolescent animals. In this study, the effects of a 15-day repeated nicotine treatment at a daily dose of 2 mg/kg body weight were investigated in adolescent and adult male rats. Nicotine treatment abolished body weight gain in the adults, but did not affect the body weight significantly in the adolescents. Only the nicotine-treated adolescents showed significant changes in brain anatomy 1 day post-treatment, which manifested as a significant reduction of whole-brain gray matter (GM) volume, a further reduction of regional GM volume in the medial prefrontal cortex (mPFC) and altered GM volume covariations between the mPFC and a number of brain regions. The mPFC of nicotine-treated adolescent rats did not exhibit evident signs of neuronal degeneration and reactive astrocytosis, but showed a significantly decreased expression of presynaptic marker synaptophysin (SYN), along with a significantly increased oxidative stress and a significantly elevated expressions of microglial marker ionized calcium binding adaptor molecule 1 (IBA1). Together, these results suggested that repeated nicotine overdosing may shift regional redox, modulate microglia-mediated pruning, and give rise to structural/connectivity deficits in the mPFC of adolescent male rats.

Deficits in prosodic speech-in-noise recognition in schizophrenia patients and its association with psychiatric symptoms

BackgroundUncertainty in speech perception and emotional disturbances are intertwined with psychiatric symptoms. How prosody embedded in target speech affects speech-in-noise recognition (SR) and is related to psychiatric symptoms in patients with schizophrenia (SCHs) remains unclear. This study aimed to examine the neural substrates of prosodic SR deficits and their associations with psychiatric symptom dimensions in patients with schizophrenia.MethodsFifty-four SCHs and 59 healthy control participants (HCs) completed the SR task (participants were required to identify the contents of the target pseudo-sentences expressed in neutral, happy, sad, angry, fearful, and disgusted prosody by actors), positive and negative syndrome scale (PANSS) assessment, and magnetic resonance imaging scanning. We examined the deficits of the six prosodic SRs in schizophrenia patients and their associations with brain gray matter volume (GMV) and psychiatric symptoms.ResultsNegative emotional (sad, angry, fearful, and disgusted) prosodies of the target sentences worsened SR across groups. Both participant groups had equal SR between the neutral and happy prosody conditions. Compared to the anger and disgusted conditions, SCHs and HCs had better SR under sad and fearful conditions. Better prosodic SR was associated with shorter duration and lower local shimmer of target sentences. A partial least squares (PLS) component of GMV (covering 47 brain regions with group differences) was associated with six prosodic SRs. The happy SR was associated with the PANSS total, negative, and general scores, adjusting for covariates.ConclusionsNegative emotional prosodies of the target sentences dampened the recognition of the target sentences. The prosodic SR abnormalities in SCHs were associated with not only brain GMV reductions in the regions involved in the processing of sensorimotor, speech, and emotion but also with negative and general psychiatric symptoms. These findings suggest the possibility of improving negative symptoms by improving a happy SR in schizophrenia patients based on neuroplasticity.

Gene expression is associated with brain function of insomnia disorder, rather than brain structure

Previous research has found brain structural and functional abnormalities in patients with insomnia disorder (ID). However, the relationship between brain abnormalities in ID and brain gene expression is unclear. This study explored the relationship between gene expression and brain structural or functional abnormalities in ID, and we validated the reliability of the results with two independent datasets (discover dataset: healthy control (HC) = 129, ID = 264; validation dataset: HC = 160, ID = 115). Brain imaging results show that ID has abnormal resting-state spontaneous activity, regional homogeneity, and widespread gray matter volume reduction compared to HC. The association analysis results with gene expression further revealed that brain function abnormalities in ID were significantly associated with gene expression, but structural abnormalities were not. This study establishes a link between transcriptional changes and brain functional abnormalities in ID, revealing a genetic basis that may involve several biological pathways. Specifically, these pathways include hormonal regulation of the hypothalamic-pituitary-adrenal (HPA) axis, which plays a crucial role in stress response and sleep regulation; ion transport across membranes, vital for neuronal communication; and inhibitory neuronal regulation, essential for maintaining normal brain function. Furthermore, the ID-related genes are enriched for brain tissue and cortical cells, emphasizing their relevance in understanding the biological underpinnings of ID.

Volumetric MRI correlates of persistent auditory verbal hallucinations and olfactory identification impairment in chronic schizophrenia: A cross-sectional study

BackgroundOlfactory impairments are often observed in schizophrenia (SCZ) patients experiencing persistent auditory verbal hallucinations (pAVHs), yet it remains unclear whether these symptoms share a common neural mechanism with specific brain regions' gray matter volume (GMV) abnormalities. This study aimed to preliminarily elucidate olfactory impairment differences between SCZ patients with and without pAVHs and their correlation with GMV abnormalities in relevant brain regions. MethodsA total of 75 SCZ patients with pAVHs (pAVH group), 56 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group) were examined. Voxel-based morphometry is useful for comparing and analyzing the differences in GMV among three groups. The Odor Stick Identification Test for Japanese (OSIT-J) was harnessed to gauge olfactory abilities. ResultsOlfactory impairments are notably significant across entire SCZ patients compared to HC, with no significant differences in olfactory performance among SCZ subgroups. Notably, the pAVH group demonstrated a significant GMV diminution in the frontal-temporal cortex, starkly contrasting with the non-pAVH and HC groups. Intriguingly, stepwise regression analysis confirmed a strong positive relation between OSIT-J scores and a GMV reduction in the right medial orbitofrontal cortex (mOFC), although this correlation was only observed in the overall SCZ patient group (P < 0.0036, Bonferroni correction). ConclusionsThe GMV perturbations within the mOFC, distinctive to SCZ, may underpin the neuroimaging substrates linked to heightened vulnerability to olfactory impairments in this population. This exploration underscores the imperative of delving into the neural underpinnings of sensory impairments within SCZ, propelling a nuanced understanding of its heterogeneity.

Characterization of Morphological Brain Changes in Generalized Epilepsy Using Region-based Morphometry

Magnetic Resonance Imaging has been widely involved in detecting morphological brain changes in generalized epilepsy at voxel level. It is believed that region-based morphometry could provide better characterizations for macro structural changes in the brain with comparative advantages than voxel-based morphometry. The aim of this study is to detect regional brain changes associated with generalized epilepsy and to test the potential of regional brain changes in classification of patients with generalized epilepsy and non-epileptic subjects. 45 patients and 46 non-epileptic subjects were scanned using a 3 Tesla MRI scanner and 3D T1 weighted images were obtained. Images were pre-processed and region based structural metrics (grey matter volumes, white matter volumes, cerebrospinal fluid volumes, cortical gyrification, and sulcus depth) were developed using Computational Anatomical Toolbox (CAT12). Two sample t-tests were used to perform the univariate analyses and results were corrected for multiple comparisons (FDR corrected, p &lt; 0.05). Grey matter volume reductions were detected in cerebellum, frontal lobe, temporal lobe, thalamus, and hippocampal region while bilateral white matter volume reductions were reported in cerebellum. In contrast, cerebrospinal fluid volume increments in left lateral ventricle were also detected. Reduced regional gyrification was detected in left posterior ramus of the lateral sulcus and reduced sulcal depths were detected in occipital pole, cuneus, and posterior ramus of the lateral sulcus in patients. Furthermore, pattern analysis revealed that each metric shows different discriminative abilities to distinguish patients with generalized epilepsy and non-epileptic subjects (Classification accuracy: 61.1%, 62.2%, 58.8%, 61.1% and 60% for GMV, WMV, CSFV, Cortical gyrification and sulcal depth respectively). In conclusion, this study provides a comprehensive understanding about regional structural changes (cortical and subcortical) associated with generalized epilepsy under region-based morphometry. However, pattern analyses do not provide adequate discriminative power and therefore the clinical utility of findings is limited.

Multimodal investigations of structural and functional brain alterations in anorexia and bulimia nervosa and their relationships to psychopathology

BackgroundNeurobiological understanding of eating disorders (EDs) is limited. This study presents the first comparative multi-modal magnetic resonance imaging (MRI) assessments of anorexia nervosa (AN) and bulimia nervosa (BN), uncovering neurobiological differences associated with these disorders. MethodsThis female case-control study included 57 healthy controls (HC) and 130 participants with EDs (BN and AN subtypes). Structural and functional MRI assessed gray matter volume (GMV), cortical thickness (CT), and task-based activities related to reward processing, social-emotional functioning, and response inhibition. Whole-brain group differences were correlated to ED psychopathology. ResultsSignificant structural differences were observed in the ED group compared to HCs, including reduced GMV in the left lateral orbitofrontal cortex and lower CT in the left rostral middle frontal gyrus and precuneus, after adjusting for BMI. Specific structural alterations were only evident in AN subgroups. GMV reductions in the orbitofrontal cortex were linked to impulsivity, while lower CT in the frontal gyrus correlated with cognitive restraint in eating, suggesting these regions may play key roles in ED psychopathology. Functional MRI also revealed notable differences. During reward anticipation, participants with EDs exhibited deactivations in the cerebellum and right superior frontal gyrus, alongside reduced activation in the left lingual gyrus. These functional changes were associated with heightened neuroticism. Mediation analyses suggested that starvation-related GMV reductions in EDs disrupt reward-related brain function, increase neuroticism, and reinforce cognitive restraint, likely contributing to the persistence of ED symptoms. ConclusionsThese findings illuminate key neurobehavioral mechanisms underlying EDs, pointing to potential brain-based targets for developing specialized treatment.

Cytokines and Madness: A Unifying Hypothesis of Schizophrenia Involving Interleukin-22.

Schizophrenia is a severe neuropsychiatric illness of uncertain etiopathogenesis in which antipsychotic drugs can attenuate the symptoms, but patients rarely return to the premorbid level of functioning. In fact, with each relapse, people living with schizophrenia progress toward disability and cognitive impairment. Moreover, our patients desire to live normal lives, to manage their daily affairs independently, date, get married, and raise and support a family. Those of us who work daily with schizophrenia patients know that these objectives are rarely met despite the novel and allegedly improved dopamine blockers. We hypothesize that poor outcomes in schizophrenia reflect the gray matter volume reduction, which continues despite antipsychotic treatment. We hypothesize further that increased gut barrier permeability, due to dysfunctional aryl hydrocarbon receptor (AhR), downregulates the gut barrier protectors, brain-derived neurotrophic factor (BDNF), and interleukin-22 (IL-22), facilitating microbial translocation into the systemic circulation, eventually reaching the brain. Recombinant human IL-22 could ameliorate the outcome of schizophrenia by limiting bacterial translocation and by initiating tissue repair. This short review examines the signal transducer and transcription-three (STAT3)/AhR axis and downregulation of IL-22 and BDNF with subsequent increase in gut barrier permeability. Based on the hypothesis presented here, we discuss alternative schizophrenia interventions, including AhR antagonists, mitochondrial transplant, membrane lipid replacement, and recombinant human IL-22.

Depressive symptoms are linked to age-specific neuroanatomical and cognitive variations

Depression is a heterogeneous disorder, both in terms of patient symptomatology and in patient sociodemographic factors. Here, we examine the contribution of age to this heterogeneity, by characterizing the associations of depressive symptoms with cognitive performance and brain structure across the lifespan. We analyzed data from the Cambridge Centre for Aging Neuroscience (Cam-CAN) cohort (N = 2591, age 18–99). A subset of this cohort (N = 647) underwent structural MRI. Depressive symptoms were measured using the Hospital Anxiety and Depression Scale. Cognitive assessments were performed using The Addenbrooke's Cognitive Examination Revised. Generalized linear models were employed to examine the relationship between depressive symptoms and cognitive performance. Statistical parametric mapping explored age-dependent associations between depressive symptoms and grey matter volume. Cognitive performance was associated with a significant age by depression by cognitive domain interaction, indicating that older individuals with more depressive symptoms had a lower cognitive performance, particularly in the fluency domain. Structural MRI revealed preferential depression-related reduction in grey matter volume in the left and right hippocampi in older adults. By contrast, in younger adults, depressive symptoms were more strongly associated with grey matter volume reduction in the left superior frontal gyrus and left middle frontal gyrus. Collectively, these findings indicate that the associations of depression with cognitive performance and brain structure are age-dependent, suggesting that the pathophysiological mechanisms underlying depression may differ between young and older adults. Recognizing these differences will support the development of better diagnostic tools and therapeutic interventions for depression across the lifespan.

The Effect of Segmentation Method on Medial Temporal Lobe Subregion Volumes in Aging.

Early stages of Alzheimer's disease (AD) are associated with volume reductions in specific subregions of the medial temporal lobe (MTL). Using a manual segmentation method-the Olsen-Amaral-Palombo (OAP) protocol-previous work in healthy older adults showed that reductions in grey matter volumes in MTL subregions were associated with lower scores on the Montreal Cognitive Assessment (MoCA), suggesting atrophy may occur prior to diagnosis of mild cognitive impairment, a condition that often progresses to AD. However, current "gold standard" manual segmentation methods are labour intensive and time consuming. Here, we examined the utility of Automatic Segmentation of Hippocampal Subfields (ASHS) to detect volumetric differences in MTL subregions of healthy older adults who varied in cognitive status as determined by the MoCA. We trained ASHS on the OAP protocol to create the ASHS-OAP atlas and then examined how well automated segmentation replicated manual segmentation. Volumetric measures obtained from the ASHS-OAP atlas were also contrasted against those from the ASHS-PMC atlas, a widely used atlas provided by the ASHS team. The pattern of volumetric results was similar between the ASHS-OAP atlas and manual segmentation for anterolateral entorhinal cortex and perirhinal cortex, suggesting that ASHS-OAP is a viable alternative to current manual segmentation methods for detecting group differences based on cognitive status. Although ASHS-OAP and ASHS-PMC produced varying volumes for most regions of interest, they both identified early signs of neurodegeneration in CA2/CA3/DG and identified marginal differences in entorhinal cortex. Our findings highlight the utility of automated segmentation methods but still underscore the need for a unified and harmonized MTL segmentation atlas.

Abnormal changes in neuropsychological function, brain structure and cerebral perfusion in patients with unruptured intracranial aneurysms.

Patients with unruptured intracranial aneurysms (UIAs) often experience emotional changes and cognitive impairments. However, the specific mechanisms underlying these impairments are still not fully understood. In the present study, voxel-based morphometry (VBM) and surface-based morphometry (SBM) were employed to investigate structural alterations in 49 patients diagnosed with UIAs compared with 50 healthy controls. Additionally, this study aimed to analyze the correlations among cortical morphological indices, cerebral blood perfusion values and neuropsychological test results. Compared with control group, UIA patients exhibited increased gray matter volume in the right anterior orbitofrontal cortex and decreased gray matter volume in the left thalamus pulvinar and hippocampus. Furthermore, the fractal dimension was lower in the right postcentral gyrus and entorhinal cortex. The cerebral perfusion values in the abnormal brain regions demonstrated a downward trend, which was associated with a reduction in gray matter volume in the left thalamus pulvinar and hippocampus, elevated anxiety levels and impaired executive function. UIA patients are prone to cognitive impairment and emotional dysregulation, which are accompanied by subtle changes in local gray matter volume and decreases in fractal dimension and cerebral blood flow. These findings provide new insights into the potential mechanisms underlying the cognitive impairment observed in UIA patients.

Gray matter volumetric changes in tinnitus: The impact of hearing loss and severity

Tinnitus is a phantom auditory sensation that commonly co-occurs with hearing loss. Both tinnitus and hearing loss can impact the quality of life, emotional well-being, and cognitive functioning of the affected individuals. While previous studies have highlighted structural alterations in hearing loss and/or tinnitus, the fundamental neural mechanisms underpinning tinnitus severity remain poorly understood. In this study, we conducted a voxel-based morphometry to investigate gray matter (GM) volume differences among groups of participants with varying tinnitus severity and hearing status, and controls within a large sample. We observed reduced GM volume in the left anterior insula and right planum polare in participants with hearing loss, regardless of their tinnitus status, compared to normal hearing controls. We noted decreased GM volume in the bilateral anterior and posterior insula for those with tinnitus and normal hearing compared to a normal hearing control group. Further, the tinnitus with hearing loss group showed decreased GM volume in the left planum polare, left inferior temporal gyrus, bilateral anterior temporal gyri, and right superior frontal gyrus compared to the normal hearing control group, suggesting a combined effect of hearing loss and tinnitus. While tinnitus severity did not show a significant overall effect, there was a significant positive correlation between tinnitus distress and GM volume in bilateral planum polare. Our findings enhance the understanding of structural brain changes related to hearing loss and tinnitus, and advance the overall knowledge of tinnitus pathophysiology, which can contribute to the development of more effective treatments for tinnitus.

Posthospitalization COVID-19 cognitive deficits at 1 year are global and associated with elevated brain injury markers and gray matter volume reduction.

The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies.

How to detect affect recognition alterations in amyotrophic lateral sclerosis.

To define the clinical usability of an affect recognition (AR) battery-the Comprehensive Affect Testing System (CATS)-in an Italian sample of patients with amyotrophic lateral sclerosis (ALS). 96 ALS patients and 116 healthy controls underwent a neuropsychological assessment including the AR subtests of the abbreviated version of the CATS (CATS-A). CATS-A AR subtests and their global score (CATS-A AR Quotient, ARQ) were assessed for their factorial, convergent, and divergent validity. The diagnostic accuracy of each CATS-A AR measure in discriminating ALS patients with cognitive impairment from cognitively normal controls and patients was tested via receiver-operating characteristics analyses. Optimal cut-offs were identified for CATS-A AR measures yielding an acceptable AUC value (≥ .70). The ability of CATS-A ARQ to discriminate between different ALS cognitive phenotypes was also tested. Gray-matter (GM) volumes of controls, ALS with normal (ALS-nARQ), and impaired ARQ score (ALS-iARQ) were compared using ANCOVA models. CATS-A AR subtests and ARQ proved to have moderate-to-strong convergent and divergent validity. Almost all considered CATS-A measures reached acceptable accuracy and diagnostic power (AUC range = .79-.83). ARQ showed to be the best diagnostic measure (sensitivity = .80; specificity = .75) and discriminated between different ALS cognitive phenotypes. Compared to ALS-nARQ, ALS-iARQ patients showed reduced GM volumes in the right anterior cingulate, right middle frontal, left inferior temporal, and superior occipital regions. The AR subtests of the CATS-A, and in particular the CATS-A ARQ, are sound measures of AR in ALS. AR deficits may be a valid marker of frontotemporal involvement in these patients.

The effect of alemtuzumab on neurodegeneration in relapsing-remitting multiple sclerosis: A five-year prospective mono-center study

BackgroundRelapsing-remitting multiple sclerosis (RRMS) is an inflammatory and neurodegenerative disease. After two or more short courses of alemtuzumab (ALZ), an immune reconstitution is achieved, which long-term results in reduced disease activity. We aimed to investigate the effect of ALZ on measures of neurodegeneration (i.e., brain atrophy, and retinal layer thinning). MethodsWe designed an observational prospective mono-center study in RRMS patients initiating ALZ treatment. Patients were assessed at baseline (month 0) and thereafter annually for five years with clinical measures, synthetic magnetic resonance imaging (SyMRI) and optical coherence tomography (OCT), with a re-baseline SyMRI scan and an OCT exam 24 months after initiating ALZ. Persons with neurological symptoms but without evidence of neurological disease served as symptomatic controls (SCs, n = 27). ResultsForty-nine RRMS patients were included. Baseline median expanded disability status scale [2.0 (IQR 1.5)] was unchanged during follow-up, 71 % were progression-free, 33 % achieved no evidence of disease activity-3 (NEDA-3). Between baseline and month 60, SyMRI showed a reduction of brain parenchymal fraction (BPF) and grey matter (GM) volume in patients. The BPF reduction was greater in RRMS patients than in SCs (p < 0.05), and more pronounced in patients with high pre-baseline disease activity than in those without (p < 0.01). OCT showed significant thinning of macular ganglion cell and inner plexiform layers (mGCIPL) and in peripapillary retinal nerve fiber layer (pRNFL) in patients. In contrast, absolute values of white matter (WM) volume and myelin content (MyC) quantified by SyMRI, were stable or increased after re-baseline (month 24) and up to month 60, and this increase appeared limited to patients without high pre-baseline disease activity and to patients with NEDA-3 or disability worsening during follow-up. A strong positive correlation between WM volume and GM volume at baseline was lost after ALZ intervention for their delta values, i.e., change from re-baseline (month 24) to month 60. While the positive baseline correlation between WM volume and MyC increased for their delta values, the positive baseline correlation between GM volume and MyC changed to negative for their delta values. ConclusionWe showed that neurodegeneration continued in RRMS patients under ALZ treatment, but it appeared to be limited to BPF and GM, and more pronounced in patients with disease activity. Our data suggest that patients who respond to ALZ treatment show signs of remyelination. OCT and SyMRI have potential to quantify measures of neurodegeneration that is affected by treatment intervention in RRMS.

Associations between Parenting and Cognitive and Language Abilities at 2 Years of Age Depend on Prenatal Exposure to Disadvantage

To investigate whether parenting or neonatal brain volumes mediate associations between prenatal social disadvantage (PSD) and cognitive/language abilities and whether these mechanisms vary by level of disadvantage. Pregnant women were recruited prospectively from obstetric clinics in St Louis, Missouri. PSD encompassed access to social (eg, education) and material (eg, income to needs, health insurance, area deprivation, and nutrition) resources during pregnancy. Neonates underwent brain magnetic resonance imaging. Mother-child dyads (n=202) returned at age 1 year for parenting observations and at age 2 years for cognition/language assessments (Bayley Scales of Infant and Toddler Development, Third Edition). Generalized additive and mediation models tested hypotheses. Greater PSD associated nonlinearly with poorer cognitive/language scores. Associations between parenting and cognition/language were moderated by disadvantage, such that supportive and nonsupportive parenting behaviors related only to cognition/language in children with lesser PSD. Parenting mediation effects differed by level of disadvantage: both supportive and nonsupportive parenting mediated PSD-cognition/language associations in children with lesser disadvantage, but not in children with greater disadvantage. PSD-associated reductions in neonatal subcortical grey matter (β=0.19; q=0.03), white matter (β=0.23; q=0.02), and total brain volume (β=0.18; q=0.03) were associated with lower cognition, but did not mediate the associations between PSD and cognition. Parenting moderates and mediates associations between PSD and early cognition and language, but only in families with less social disadvantage. These findings, although correlational, suggest that there may be a critical threshold of disadvantage, below which mediating or moderating factors become less effective, highlighting the importance of reducing disadvantage as primary prevention.

Cortical lobar volume reductions associated with homocysteine-related subcortical brain atrophy and poorer cognition in healthy aging.

Homocysteine (Hcy) is a cardiovascular risk factor implicated in cognitive impairment and cerebrovascular disease but has also been associated with Alzheimer's disease. In 160 healthy older adults (mean age = 69.66 ± 9.95 years), we sought to investigate the association of cortical brain volume with white matter hyperintensity (WMH) burden and a previously identified Hcy-related multivariate network pattern showing reductions in subcortical gray matter (SGM) volumes of hippocampus and nucleus accumbens with relative preservation of basal ganglia. We additionally evaluated the potential role of these brain imaging markers as a series of mediators in a vascular brain pathway leading to age-related cognitive dysfunction in healthy aging. We found reductions in parietal lobar gray matter associated with the Hcy-SGM pattern, which was further associated with WMH burden. Mediation analyses revealed that slowed processing speed related to aging, but not executive functioning or memory, was mediated sequentially through increased WMH lesion volume, greater Hcy-SGM pattern expression, and then smaller parietal lobe volume. Together, these findings suggest that volume reductions in parietal gray matter associated with a pattern of Hcy-related SGM volume differences may be indicative of slowed processing speed in cognitive aging, potentially linking cardiovascular risk to an important aspect of cognitive dysfunction in healthy aging.