Newborn insula gray matter volume is prospectively associated with early life adiposity gain

The importance of energy homeostasis brain circuitry in the context of obesity is well established, however, the developmental ontogeny of this circuitry in humans is currently unknown. Here, we investigate the prospective association between newborn gray matter (GM) volume in the insula, a key brain region underlying energy homeostasis, and change in percent body fat accrual over the first six months of postnatal life, an outcome that represents among the most reliable infant predictors of childhood obesity risk

Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals

Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia

Impulsivity and body fat accumulation are linked to cortical and subcortical brain volumes among adolescents and adults

Obesity is associated not only with metabolic and physical health conditions, but with individual variations in cognition and brain health. This study examined the association between body fat (an index of excess weight severity), impulsivity (a vulnerability factor for obesity), and brain structure among adolescents and adults across the body mass index (BMI) spectrum. We used 3D T1 weighted anatomic magnetic resonance imaging scans to map the association between body fat and volumes in regions associated with obesity and impulsivity. Participants were 127 individuals (BMI: 18–40 kg/m2; M = 25.69 ± 5.15), aged 14 to 45 years (M = 24.79 ± 9.60; female = 64). Body fat was measured with bioelectric impendence technology, while impulsivity was measured with the UPPS-P Impulsive Behaviour Scale. Results showed that higher body fat was associated with larger cerebellar white matter, medial orbitofrontal cortex (OFC), and nucleus accumbens volume, although the latter finding was specific to adolescents. The relationship between body fat and medial OFC volume was moderated by impulsivity. Elevated impulsivity was also associated with smaller amygdala and larger frontal pole volumes. Our findings link vulnerability and severity markers of obesity with neuroanatomical measures of frontal, limbic and cerebellar structures, and unravel specific links between body fat and striatal volume in adolescence

Diagnosis of bipolar disorders and body mass index predict clustering based on similarities in cortical thickness-ENIGMA study in 2436 individuals

AIMS: Rates of obesity have reached epidemic proportions, especially among people with psychiatric disorders. While the effects of obesity on the brain are of major interest in medicine, they remain markedly under-researched in psychiatry. METHODS: We obtained body mass index (BMI) and magnetic resonance imaging-derived regional cortical thickness, surface area from 836 bipolar disorders (BD) and 1600 control individuals from 14 sites within the ENIGMA-BD Working Group. We identified regionally specific profiles of cortical thickness using K-means clustering and studied clinical characteristics associated with individual cortical profiles. RESULTS: We detected two clusters based on similarities among participants in cortical thickness. The lower thickness cluster (46.8% of the sample) showed thinner cortex, especially in the frontal and temporal lobes and was associated with diagnosis of BD, higher BMI, and older age. BD individuals in the low thickness cluster were more likely to have the diagnosis of bipolar disorder I and less likely to be treated with lithium. In contrast, clustering based on similarities in the cortical surface area was unrelated to BD or BMI and only tracked age and sex. CONCLUSIONS: We provide evidence that both BD and obesity are associated with similar alterations in cortical thickness, but not surface area. The fact that obesity increased the chance of having low cortical thickness could explain differences in cortical measures among people with BD. The thinner cortex in individuals with higher BMI, which was additive and similar to the BD-associated alterations, may suggest that treating obesity could lower the extent of cortical thinning in BD

Cardiovascular risk factors in secondary progressive multiple sclerosis: A cross-sectional analysis from the MS-STAT2 randomized controlled trial

BACKGROUND AND PURPOSE: There is increasing evidence that cardiovascular risk (CVR) contributes to disability progression in multiple sclerosis (MS). CVR is particularly prevalent in secondary progressive MS (SPMS) and can be quantified through validated composite CVR scores. The aim was to examine the cross-sectional relationships between excess modifiable CVR, whole and regional brain atrophy on magnetic resonance imaging, and disability in patients with SPMS. METHODS: Participants had SPMS, and data were collected at enrolment into the MS-STAT2 trial. Composite CVR scores were calculated using the QRISK3 software. Prematurely achieved CVR due to modifiable risk factors was expressed as QRISK3 premature CVR, derived through reference to the normative QRISK3 dataset and expressed in years. Associations were determined with multiple linear regressions. RESULTS: For the 218 participants, mean age was 54 years and median Expanded Disability Status Scale was 6.0. Each additional year of prematurely achieved CVR was associated with a 2.7 mL (beta coefficient; 95% confidence interval 0.8-4.7; p = 0.006) smaller normalized whole brain volume. The strongest relationship was seen for the cortical grey matter (beta coefficient 1.6 mL per year; 95% confidence interval 0.5-2.7; p = 0.003), and associations were also found with poorer verbal working memory performance. Body mass index demonstrated the strongest relationships with normalized brain volumes, whilst serum lipid ratios demonstrated strong relationships with verbal and visuospatial working memory performance. CONCLUSIONS: Prematurely achieved CVR is associated with lower normalized brain volumes in SPMS. Future longitudinal analyses of this clinical trial dataset will be important to determine whether CVR predicts future disease worsening

Epigenetic and transcriptional control of the microglial inflammatory response: potential insights into neuro-inflammaging

Inflammation is an evolutionarily conserved host defense response during infection or injury that seeks to remove the causal agent that led to its initiation, repair the damaged tissue(s) and restore homeostasis. Thus, transient inflammation in response to an adequate threat with a quick return to a basal resting state is beneficial. However, when inflammation becomes inappropriately increased or prolonged it can have severe pathophysiological consequences. During aging, the immune system shifts to a proinflammatory state characterized by low-grade, chronic, sterile inflammation that has been termed ‘inflammaging’. The proinflammatory state largely results from chronic activation of the innate immune system and includes elevated circulating levels of inflammatory mediators including the immune cell signaling molecules (cytokines) Interleukin (IL)-1, IL-6, IL-8, IL-13, IL-18, tumor necrosis factor (TNFα) and antivirals (the type I interferons (IFN-I). Numerous factors are thought to contribute to inflammaging and amongst potential mechanisms high fat feeding/obesity and associated increases in gut permeability to bacterial endotoxins, as well as, cellular senescence have emerged as key contributors. Importantly, inflammaging is tightly correlated to global indicators of poor health status, multimorbidity, impairment in day-to-day living activities and is thought to underlie or accelerate most age-dependent chronic diseases (e.g. cardiovascular disease, diabetes, cancer, as well as, neurodegenerative conditions like Parkinson’s disease (PD) and Alzheimer’s disease (AD)).While mechanisms driving peripheral inflammaging are beginning to be understood, the etiology of neuro-inflammaging is a crucially unresolved issue. An important source of inflammation in the brain are the non-neuronal cell populations (glia) which provide structural, trophic, and other physiological support for neurons, and especially, the activity of microglia–the brain’s own resident innate immune cells. Microglia are essential for brain development, maintenance and protection throughout the life of an organism. As innate immune cells, however, they can also mount a full inflammatory response to infection or environmental challenge to restore brain health.Environmental factors, for example, changes in peripheral levels of fatty acids, bacterial endotoxins or proinflammatory mediators resulting from high fat feeding or gut permeabilization can cause microglia to undergo changes that signal activation. Most importantly, microglia lose their homeostatic function during aging, becoming less neuroprotective and increasingly neurotoxic. Microglia-mediated inflammation, for example, is strongly linked to age-induced cognitive impairment, is a common hallmark of both PD and AD, and is believed to be mechanistically important in driving pathogenesis. Thus, there is great interest in discovering factors that regulate age-related changes in microglial inflammatory function.Although inflammation is a complex and multicomponent response, a key point of its control occurs at the level of gene transcription and involves several classes of transcription factors, transcriptional co-regulators and chromatin modifications. A recent 2017 study by Soreq et al., identified a relatively unknown gene, PHD finger protein 15 (PHF15) as one of the top 25 differentially expressed genes in microglia during non-pathological aging in humans, with PHF15 levels increasing with age. Sequence and structural similarity to other members of the PHF family suggest that PHF15 might function as a putative chromatin-mediated gene regulator. I first sought to determine whether PHF15 could repress inflammatory function in microglia. If so, I wanted to investigate whether factors known to be causal in inflammaging (e.g. high fat feeding/obesity or cellular senescence) lead to age-dependent cognitive impairment via modulation of microglial PHF15. A major hallmark of senescent cells is the secretion of inflammatory mediators including various cytokines (lL-6, IL-1β, IL-8), chemoattractant cytokines (chemokines; for example C-X-C motif chemokine 10 (CXCL10), C-C motif chemokine ligand (CCL-) 5 (CCL5) and CCL20), antivirals (IFN-I), growth factors and extracellular matrix proteases termed the senescence-associated secretory phenotype (SASP). Secretion of the SASP is partially controlled by the Cyclic GMP-AMP (cGAMP) synthase (cGAS)-Stimulator of interferon genes (STING) (cGAS-STING) cytosolic DNA sensing pathway at the molecular level. Thus, peripheral changes induced by high fat feeding/obesity or the SASP could lead to increased neuroinflammation via inhibition of microglial PHF15.I show that Phf15 significantly represses proinflammatory gene expression in mouse microglia, modulating both the magnitude and duration of the inflammatory response. Importantly, Phf15 regulates both basal expression and signal-dependent upregulation of proinflammatory genes—which constitute different phases of the transcriptional inflammatory response and are controlled by distinct molecular mechanisms. Global transcriptional changes after Phf15 knockout in a microglial cell line further revealed that Phf15 may specifically regulate the antiviral response, as well as, proinflammatory factor production and secretion. Interestingly, loss of Phf15 resulted in increased IFN-I-dependent and inflammatory gene expression profiles that closely mimic transcriptional changes in aged microglia. Together, my data indicate that Phf15 is an important novel repressor of microglial inflammatory function which might counteract age-induced inflammation in the healthy, aging brain.Interestingly, I found decreased expression levels of Il-6, a key proinflammatory cytokine expressed by senescent cells in the hippocampus–an area which mediates various memory-related process–of aged (27-month old) STING-deficient mice. However, this decrease did not translate to improved working memory or differences in Phf15 mRNA expression in the brain, suggesting that expression of SASP-related inflammatory factors by the cGAS-STING pathway does not proceed via inhibition of Phf15. Similarly, prolonged treatment with a high fat diet/obesity did not affect working memory or levels of Phf15 in the mouse brain, suggesting that brain inflammation resulting from a HFD or obesity is likewise not a result of Phf15 downregulation.Overall, my results suggest that Phf15 could function as an immune regulatory checkpoint, restraining the transition from a homeostatic phenotype towards the chronic, proinflammatory, IFN-I responsive state seen in microglia in the aged brain. Further understanding of its exact mechanism of action could lend insight into possible future therapeutic intervention

Neuroreceptor availability and cerebral morphology in human obesity

Obesity is a major challenge to human health worldwide. Little is known about the brain mechanisms that are associated with overeating and obesity in humans. In this project, multimodal neuroimaging techniques were utilized to study brain neurotransmission and anatomy in obesity. Bariatric surgery was used as an experimental method for assessing whether the possible differences between obese and non-obese individuals change following the weight loss. This could indicate whether obesity-related altered neurotransmission and cerebral atrophy are recoverable or whether they represent stable individual characteristics. Morbidly obese subjects (BMI ≥ 35 kg/m2) and non-obese control subjects (mean BMI 23 kg/m2) were studied with positron emission tomography (PET) and magnetic resonance imaging (MRI). In the PET studies, focus was put on dopaminergic and opioidergic systems, both of which are crucial in the reward processing. Brain dopamine D2 receptor (D2R) availability was measured using [11C]raclopride and µ-opioid receptor (MOR) availability using [11C]carfentanil. In the MRI studies, voxel-based morphometry (VBM) of T1-weighted MRI images was used, coupled with diffusion tensor imaging (DTI). Obese subjects underwent bariatric surgery as their standard clinical treatment during the study. Preoperatively, morbidly obese subjects had significantly lower MOR availability but unaltered D2R availability in several brain regions involved in reward processing, including striatum, insula, and thalamus. Moreover, obesity disrupted the interaction between the MOR and D2R systems in ventral striatum. Bariatric surgery and concomitant weight loss normalized MOR availability in the obese, but did not influence D2R availability in any brain region. Morbidly obese subjects had also significantly lower grey and white matter densities globally in the brain, but more focal changes were located in the areas associated with inhibitory control, reward processing, and appetite. DTI revealed also signs of axonal damage in the obese in corticospinal tracts and occipito-frontal fascicles. Surgery-induced weight loss resulted in global recovery of white matter density as well as more focal recovery of grey matter density among obese subjects. Altogether these results show that the endogenous opioid system is fundamentally linked to obesity. Lowered MOR availability is likely a consequence of obesity and may mediate maintenance of excessive energy uptake. In addition, obesity has adverse effects on brain structure. Bariatric surgery however reverses MOR dysfunction and recovers cerebral atrophy. Understanding the opioidergic contribution to overeating and obesity is critical for developing new psychological or pharmacological treatments for obesity. The actual molecular mechanisms behind the positive change in structure and neurotransmitter function still remain unclear and should be addressed in the future research.Neuroreseptorit ja aivojen rakenne lihavuudessa Lihavuudesta on tullut yksi maailman suurimmista terveysongelmista. Lihavuuteen liittyvistä aivojen toiminnan ja rakenteen muutoksista tiedetään kuitenkin toistaiseksi melko vähän. Tässä tutkimuksessa selvitettiin aivojen välittäjäainetoiminnan ja rakenteen eroja lihavien ja normaalipainoisten henkilöiden välillä. Lihavuusleikkauksen ja sitä seuraavan laihtumisen aiheuttamia aivojen välittäjäainetoiminnan ja tiheyden muutoksia arvioimalla voitiin päätellä, ovatko aivomuutokset jo olemassa ennen lihavuuden syntyä vai ovatko ne lihavuuden aiheuttamia. Vaikeasti lihavien henkilöiden (BMI ≥ 35 kg/m2) aivoja verrattiin normaalipainoisten henkilöiden (BMI:n keskiarvo 23 kg/m2) aivoihin käyttämällä positroniemissiotomografiaa (PET) ja magneettiresonanssikuvantamismenetelmiä (MRI). PET-tutkimuksissa käytettiin kahta radioisotoopilla leimattua merkkiainetta, joista [11C]raklopriidi sitoutuu dopamiinin D2-reseptoreihin ja [11C]karfentaniili µ-opioidireseptoreihin. Kummatkin reseptorit ovat keskeisessä asemassa aivojen mielihyväjärjestelmän toiminnassa. MRI-tutkimuksissa käytettiin analyysimenetelminä vokselipohjaista morfometriaa (voxel-based morphometry, VBM) sekä diffuusiotensorikuvantamista (diffusion tensor imaging, DTI). Lihaville tutkittaville tehtiin tutkimuksen aikana lihavuusleikkaus aiemman hoitosuunnitelman mukaisesti. Ennen lihavuusleikkausta lihavilla tutkittavilla oli selvästi vähemmän µ-opioidireseptoreja mielihyväjärjestelmän keskeisissä osissa, kuten tyvitumakkeissa, insulassa ja talamuksessa, mutta dopamiinin D2-reseptorien määrä oli sama kuin normaalipainoisilla tutkittavilla. Lisäksi näiden reseptorijärjestelmien välinen yhteys oli häiriintynyt lihavilla tutkittavilla aivojuovion etuosassa. Lihavuusleikkauksen aiheuttaman laihtumisen jälkeen µ-opioidireseptorien määrä palautui samalle tasolle kuin normaalipainoisilla. Dopamiinireseptorien määrässä ei tapahtunut muutosta. Magneettitutkimuksissa kävi ilmi, että lihavilla tutkittavilla aivojen harmaan ja valkean aineen tiheydet olivat pienemmät kuin normaalipainoisilla tutkittavilla. Eroa löytyi erityisesti mielihyvään ja ruokahaluun liittyvillä alueilla. Myös valkean aineen radastoissa oli vaurion merkkejä. Leikkauksen jälkeen tapahtui palautumista laajasti valkean aineen alueilla mutta myös selvästi pienemmillä harmaan aineen alueilla. Tulokset osoittavat, että opioidijärjestelmä liittyy keskeisesti lihavuuteen ja liikasyömiseen. Opioidijärjestelmän poikkeava toiminta on todennäköisesti lihavuuden aiheuttamaa ja saattaa ylläpitää haitallista syömiskäyttäytymistä. Lisäksi lihavuudella on haitallisia vaikutuksia aivojen rakenteeseen. Lihavuusleikkaus palauttaa opioidijärjestelmän ennalleen ja korjaa lihavuuden aiheuttamaa aivokudoksen harventumaa. Opioidijärjestelmän merkityksen ymmärtäminen on välttämätöntä lihavuuden uusien psykologisten ja farmakologisten hoitomuotojen kehittämisessä. Solutason mekanismit leikkauksen aiheuttamien muutosten taustalla ovat kuitenkin edelleen epäselvät, ja niihin tulisi keskittyä jatkotutkimuksissa.Siirretty Doriast

Modifying Diet and Exercise in Multiple Sclerosis: A Pilot Study

Title from PDF of title page viewed June 10, 2022Thesis advisor: Jared M. BruceVitaIncludes bibliographical references (pages 67-95)Thesis (M.A.)--Department of Psychology. University of Missouri--Kansas City, 2021Background: Modest weight loss can have significant health benefits and reduce the risk of developing chronic health comorbidities (Van Gaal et al., 1997). It remains unclear whether weight loss in individuals with multiple sclerosis (MS) can aid in reducing disease burden. Purpose: The three aims of this single arm non-randomized study include, (1) Develop and assess the feasibility and acceptability of a six-month telehealth, behavioral weight loss program for people with MS; (2) Examine the primary outcome variable, percent weight loss, from baseline to six-month follow-up; and (3) Assess minutes of physical activity and servings of fruits and vegetables eaten daily in people with MS. Methods: Participants were provided with a Fitbit device, Fitbit Aria Scale, and a premium subscription to the Lose It! application. Program recommendations included eating 1200 – 1500 calories a day and working up to 150 minutes of moderate intensity physical activity per week over six months. Group members met weekly to discuss topics related to healthy living in MS and attended two individual calls with the group leader. Qualitative and quantitative data were used to examine facilitators and barriers to behavior change, perceived benefits of weight loss and healthy lifestyle practices, and patient satisfaction with the program. Changes in diet and physical activity routines were monitored via questionnaires at baseline and follow-up. Percent weight loss was calculated at follow-up. Results: Eight people were consented and enrolled in the program. On average, participants attended 17 of the 24 weekly sessions (SD = 7.15). Average percent weight loss was 10.57% (SD = 7.20). Nearly all participants strongly agreed the program helped them live a healthier lifestyle (3.87 ± 0.35 on 0 to 4 Likert scale). Activity scores increased from insufficiently active (M = 13.0, SD = 14.98) to active at follow-up (M = 43.50, SD = 21.31; t(7) = -3.33, p = 0.013). Self-reported fruit and vegetable servings increased overall but fruit consumption was the only variable that was significantly increased (M = -0.54, SD = 0.59; t(7) = -2.61, p = 0.035). Discussion: Taken together, results from this pilot trial will be used to inform future study directions. Weight loss interventions tailored to people with MS could potentially improve the health and quality of life for hundreds of thousands of patients.Introduction -- Methods -- Appendi