Cortical Thickness Research Articles

Three-dimensional assessment of alveolar bone changes and root resorption in extraction patients after fixed orthodontic treatment: A prospective study

The aim of this study was to evaluate the alveolar crestal bone height, alveolar bone thickness, and root resorption in mandibular incisors after fixed orthodontic treatment. A total of 35 patients (mean age 17.02 ± 3.24 years) with moderate to severe mandibular anterior crowding requiring first premolar extraction were included. Cone beam computed tomography scans of the mandibular anterior region were obtained from the patients before and after orthodontic treatment. The alveolar crestal bone height, cortical bone thickness (CBT) (at apex and midroot level), labial and lingual alveolar bone thickness, and root resorption were assessed for all mandibular incisors. Paired Student's t test was used to compare pretreatment and post-treatment alveolar bone changes and root resorption. A significant decrease in lingual crestal bone height was observed in all mandibular incisors after orthodontic treatment (P < 0.001). Lingual CBT decreased at the midroot level significantly for all mandibular incisors after completion of orthodontic treatment (P < 0.001). A significant decrease in total lingual bone thickness was observed in all mandibular incisors (P < 0.001). Root lengths of mandibular incisors decreased significantly in the sagittal and coronal sections after orthodontic treatment (P < 0.001). Fixed orthodontic treatment with premolar extraction results in a significant reduction of alveolar crestal bone height, CBT (at midroot level), and alveolar bone thickness on the lingual aspect of mandibular incisors. Significant orthodontically induced inflammatory root resorption was observed in all mandibular incisors after orthodontic treatment.

Piezo1 expression in mature osteocytes is dispensable for the skeletal response to mechanical loading

Mechanical loading is essential for bone growth and homeostasis, with osteocytes considered the primary mechanosensors. Deleting the mechanosensitive ion channel Piezo1 from Dmp1-Cre-targeted cells, which include both osteoblasts and osteocytes, resulted in reduced bone mass and impaired skeletal responses to mechanical stimuli. To specifically isolate Piezo1's role in osteocytes, we used Sost-Cre mice to generate mice with Piezo1 deletion exclusively in mature osteocytes. These mice exhibited lower bone mineral density, decreased cancellous bone mass, and reduced cortical thickness with decrease periosteal expansion. However, unlike mice lacking Piezo1 in both osteoblasts and osteocytes, those with Piezo1 deletion in mature osteocytes responded normally to mechanical loading. These findings suggest that Piezo1 expression in mature osteocytes contributes to bone maintenance under normal physiological condition, but is dispensable for the skeletal response to mechanical loading.

Cerebral cortex changes in FD, IBS, and GERD: A Mendelian randomization study

BackgroundProspective and cross-sectional studies have reported an association between functional gastrointestinal disorders and anxiety and depression. However, the causal relationship is unclear. Therefore, we used Mendelian randomization (MR) to determine the causal effects of common gastrointestinal disorders on cortical structures. MethodsGenome-wide association study (GWAS) data for functional dyspepsia (FD), irritable bowel syndrome (IBS), and gastroesophageal reflux disease (GERD) were obtained from 329,262, 16,792, and 602,604 Europeans, respectively. GWAS cerebral cortical architecture data for cortical thickness (TH) and surface area (SA) were obtained from 51,665 MRI scans. MR was used to analyze the casual relationship between FD, IBS, GERD, and cortical structures. Inverse-variance weighted, weighted median, and MR–Egger tests were performed as assessment indicators. We also evaluated heterogeneity and pleiotropy. ResultsThe results revealed that FD significantly decreases the TH in the rostral anterior cingulate cortex (βTH = −0.022 mm; 95%CI: −0.035 mm to −0.009 mm2; PTH = 6.89 × 10−4), and IBS significantly decreases the SA of the pars triangularis (βSA = −21.91 mm2; 95%CI: −32.99 mm to −10.83 mm2; PSA = 1.06 × 10−4), precuneus (βSA = −47.53 mm2; 95%CI: −73.57 mm to-21.48 mm2; PSA = 3.48 × 10−4) and superior frontal regions (βSA = −78.70 mm2; 95%CI: −122.61 mm to −34.78 mm2; PSA = 4.4 × 10−4). At the local functional level, GERD significantly increases the SA of the inferior temporal region (βSA = −113.58 mm2, 95%CI: −113.58 mm to −39.01 mm2, PSA = 6.05 × 10−5). ConclusionsFD, IBS and GERD can affect the cerebral cortex architecture through the brain-gut axis, thus increasing the risks of mental illness and cognitive dysfunction.

Development of white matter in young adulthood: The speed of brain aging and its relationship with changes in fractional anisotropy

White matter (WM) development has been studied extensively, but most studies used cross-sectional data, and to the best of our knowledge, none of them considered the possible effects of biological (vs. chronological) age. Therefore, we conducted a longitudinal multimodal study of WM development and studied changes in fractional anisotropy (FA) in the different WM tracts and their relationship with cortical thickness-based measures of brain aging in young adulthood. A total of 105 participants from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort underwent magnetic resonance imaging (MRI) at the age of 23-24, and the age of 28-30 years. At both time points, FA in the different WM tracts was extracted using the JHU atlas, and brain age gap estimate (BrainAGE) was calculated using the Neuroanatomical Age Prediction using R (NAPR) model based on cortical thickness maps. Changes in FA and the speed of cortical brain aging were calculated as the difference between the respective variables in the late vs. early 20s. We demonstrated tract-specific increases as well as decreases in FA, which indicate that the WM microstructure continues to develop in the third decade of life. Moreover, the significant interaction between the speed of cortical brain aging, tract, and sex on mean FA revealed that a greater speed of cortical brain aging in young adulthood predicted greater decreases in FA in the bilateral cingulum and left superior longitudinal fasciculus in young adult men. Overall, these changes in FA in the WM tracts in young adulthood point out the protracted development of WM microstructure, particularly in men.

Evaluation of mandibular bone structure changes in phenylketonuria patients using fractal analysis and radiomorphometric indices

ObjectivesThe aim of this study was to evaluate the effect of phenylketonuria (PKU) on mandibular bone structure by comparing the bone of PKU patients with healthy controls using fractal analysis and the radiomorphometric indices of mandibular cortical width (MCW) and mandibular cortical index (MCI). Study DesignIn total, 32 patients with PKU were analyzed and compared with the control patients. Regions of interest in panoramic radiographs were selected and the fractal dimension (FD) obtained from fractal analysis was calculated. MCW was defined as the cortical thickness of the inferior border of the mandible at the level of the mental foramen. MCI classified the endosteal edge of the mandibular cortex as C1: straight and sharp, C2: the presence lacunar resorption spaces, and C3: distinctly porous and severely eroded. The significance level was P<0.05. ResultsAll FD and MCW values were significantly lower in the PKU patients. The prevalence of C1 was significantly lower and prevalence of C2 was significantly higher in the PKU group. ConclusionThe differences in fractal dimension and radiomorphometric indices between patients with PKU and healthy controls may indicate a potential impact of PKU on mandibular bone structure.

The Douglas-Bell Canada Brain Bank Post-mortem Brain Imaging Protocol

Magnetic resonance imaging (MRI) is a valuable non-invasive tool that has been widely used for in vivo investigations of brain morphometry and microstructural characteristics. Post-mortem MRIs can provide complementary anatomical and microstructural information to in vivo imaging and ex vivo neuropathological assessments without compromising the sample for future investigations. We have developed a post-mortem MRI protocol for the brain specimens of the Douglas-Bell Canada Brain Bank (DBCBB), the largest brain bank in Canada housing over 3000 neurotypical and diseased brain specimens, that allows for acquisition of high-resolution 3T and 7T MRIs. Our protocol can be used to scan DBCBB specimens with minimal tissue manipulation, allowing for feasibly scanning large numbers of post-mortem specimens while retaining the quality of the tissue for downstream histology and immunohistochemistry assessments. We demonstrate the robustness of this protocol despite the dependency of image quality on fixation by acquiring data on the first day of extraction and fixation, to over twenty years post fixation. The acquired images can be used to perform volumetric segmentations, cortical thickness measurements, and quantitative analyses which can be potentially used to link MRI-derived and ex vivo histological measures, assaying both the normative organization of the brain and ex vivo measures of pathology.

Total Hip Arthroplasty in Hip Osteoarthritis with Subtrochanteric Localized Periosteal Thickening: Preoperative Planning Using Finite Element Analysis to Determine the Optimal Stem Length

Background: Owing to the risk of atypical femoral fractures, total hip arthroplasty presents unique challenges for patients with ipsilateral osteoarthritis and localized periosteal thickening in the femoral subtrochanteric region. Stem length selection is critical for minimizing stress concentration in the thickened cortex to avoid such fractures. Herein, we report the case of a 78-year-old woman with ipsilateral hip osteoarthritis and localized subtrochanteric periosteal thickening. Methods: Preoperative planning included a finite element analysis to assess the stress distribution across various stem lengths. A simulation was conducted to determine the optimal stem length to span the cortical thickening and reduce the risk of postoperative complications. Results: The finite element analysis indicated that a stem length of &gt;150 mm was required to effectively reduce the stress at the site of cortical thickening. A 175 mm stem was selected for total hip arthroplasty, which provided a favorable stress distribution and avoided the risk of stress concentration. Conclusions: In cases of ipsilateral osteoarthritis with localized subtrochanteric periosteal thickening, finite element analysis can be valuable for preoperative planning to determine the optimal stem length, thereby reducing the risk of atypical femoral fractures. Further studies with multiple cases are recommended to validate these findings and improve surgical outcomes.

Sex Differences in Cortical Thickness and Neuropsychiatric Symptom Burden Based on APOE4 Homozygosity in Alzheimer's Disease.

Sex differences in patterns of cortical thickness and neuropsychiatric symptom (NPS) burden were examined among individuals with Alzheimer's disease (AD) and two copies (homozygote carriers) of the e4 allele of the apolipoprotein gene (APOE). A total of 752 participants with a clinical etiologic diagnosis of AD were selected from the National Alzheimer's Coordinating Center (NACC) database. Bayesian multilevel regression was used to examine both the within- and between-sex differences in gray-matter cortical thickness and total NPS burden associated with APOE homozygosity. Female homozygote carriers displayed a high probability of having reduced cortical thickness primarily in medial-lateral temporal regions and a greater burden of NPS, relative to both non-homozygous females and homozygous males. These findings support the notion that APOE4 status affects cortical thickness and symptom burden in men and women with AD differentially, with females showing more pronounced effects in brain areas known to be vulnerable in early AD. Future investigations should attempt to elucidate the proposed pattern of decline longitudinally.

Associations between structural neuroimaging markers of Alzheimer's risk and scam susceptibility.

Older adults with greater scam susceptibility are at greater risk for mild cognitive impairment and incident Alzheimer's dementia, regardless of baseline cognition. This, combined with documented associations between scam susceptibility and beta amyloid at death suggests that scam susceptibility may be an earlier indicator of pathological aging than cognition. Little, however, is known about whether in vivo neuroimaging markers of early-stage risk for Alzheimer's dementia are also related to scam susceptibility; such knowledge will inform upon the associations of neurodegenerative processes with scam susceptibility and may help identify vulnerable individuals. Participants were 472 community-based adults without dementia (age ~ 81y; 75% women) from the Rush Memory and Aging Project. Baseline 3T MRI T1-weighted structural and T2-weighted FLAIR data were used to assess the cortical thickness 'signature' of Alzheimer's disease (AD-CT) and white matter hyperintensity (WMH) burden, respectively. Scam susceptibility was measured using a questionnaire that assessed behaviors associated with vulnerability to fraud and scams. Demographically-adjusted linear effects regression models determined the relationship of each neuroimaging measure, first separately and then combined, with scam susceptibility. Reduced AD-CT was associated with higher levels of scam susceptibility (estimate=-0.10, standard error = 0.03, p = 0.002). WMH burden was not associated with scam susceptibility either alone or when combined in the same model as AD-CT (p-values ≥ 0.14). Results for AD-CT persisted after the inclusion of WMH burden. AD-CT was associated with scam susceptibility in older adults without dementia possibly signaling an in vivo profile of this behavior.

Posttraumatic Stress Disorder in Children: A Narrative Review

Method: This narrative review summarizes research from the years 2019-2024 on posttraumatic stress disorder (PTSD) and posttraumatic stress symptoms (PTSS) in children. Results: This research suggests that prevalence rates have been highly variable as a function of the stress experienced, for example, post-surgery (15%), following exposure to war (28%) and following head injury (34%). The negative effects have included cognitive dysfunction, aggression and other behavioral difficulties and the comorbidities include sleep disorders, somatic symptoms and depression. Predictors/risk factors have been the primary focus in this literature and have included parent risk factors including exposure to intimate partner violence, sexual and emotional abuse. Sensory modulation and cognitive processes have been implicated as, for example, negative attention bias and subjective threat. Injuries and hospitalizations have been predictors as has been exposure to explosions and earthquakes. The most frequently studied intervention has been cognitive behavioral therapy which has consistently reduced the symptoms of PTSD. Potential underlying biological mechanisms have included parent PTSD, pregnancy inflammation, and autonomic dysregulation including low cortisol and heartrate, although reduced cortical thickness (volume) in several areas of the brain has been the most frequently studied potential mechanism. Discussion: The studies in this review highlight the prevalence and severity of posttraumatic stress disorder in children. However, they have been primarily based on mixed-age child and adolescent samples and the results have varied by the type of stress experienced and the severity of the stress.

Three-Dimensional Evaluation of Impacted Mandibular Third Molar Angulation and its Impact on Lingual Cortical Bone Thickness: A Retrospective Cone-Beam Computed Tomography Study

Background: The removal of impacted lower third molars surgically can cause complications, and the lingual cortical bone thickness in this region becomes a determining factor in the risk of perforation and injury to the lingual nerve (LN). This study was conducted to assess the relationship between different angulations of impacted lower third molars based on Winter’s classification and the thickness of the lingual cortical bone. Variations in lingual cortical bone thickness among the genders were evaluated as well. Methods: Cone-beam computed tomography (CBCT) scans of 50 impacted lower third molar teeth of 50 patients (26 men and 24 women) were evaluated in this study. The lingual bone thickness surrounding impacted lower mandibular teeth was measured at three key points, namely, the cemento-enamel junction of the second mandibular molar, the mid-root of the impacted third molar, and the root apex of the impacted third molar. Mesiodistal angulation and buccolingual angulations of the impacted mandibular third molars underwent investigation. Statistical analysis was conducted using SPSS 23. Data were analyzed using the independent sample t test, one-way ANOVA, multiple linear regression analysis, and Fisher’s exact test. Results: There was a statistically significant relationship between the means of lingual cortical bone thickness surrounding the third molars based on Winter’s classification of third molars impacted at mesiodistal angulation (P=0.00). Regarding gender, buccolingual angulation demonstrated a statistically significant relationship among the means of lingual bone thickness around the third molars (P=0.022). Conclusion: In our study, the thickness of the lingual cortical bone was notably affected in the middle and apical areas of the impacted third molar region. The variable position of the LN near the mandible third molar region was significant in dental procedures due to its proximity. Three-dimensional (3D) imaging CBCT provides preoperative risk assessment that reduces preventable complications that cannot be answered by 2D imaging.

Combined cognitive assessment and automated MRI volumetry improves the diagnostic accuracy of detecting MCI due to Alzheimer's disease

BackgroundMild cognitive impairment (MCI) confers a high annual risk of 10–15 % of conversion to Alzheimer's disease (AD) dementia. MRI atrophy patterns derived from automated ROI analysis, particularly hippocampal subfield volumes, were reported to be useful in diagnosing early clinical stages of Alzheimer's disease. ObjectiveThe aim of the present study was to combine automated ROI MRI morphometry of hippocampal subfield volumes and cortical thickness estimates using FreeSurfer 6.0 with cognitive measures to predict disease progression and time to conversion from MCI to AD dementia. MethodsBaseline (Neuropsychology, MRI) and clinical follow-up data from 62 MCI patients were analysed retrospectively. Individual cortical thickness and volumetric measures were obtained from T1-weighted MRI. Linear discriminant analysis (LDA) of both, cognitive measures and MRI measures (hippocampal subfields, temporal and parietal lobe volumes), were performed to differentiate MCI converters from stable MCI patients. ResultsOut of 62 MCI patients 21 (34 %) converted to AD dementia within a mean follow-up time of 74.7 ± 36.8 months (mean ± SD, range 12 to 130 months). LDA identified temporal lobe atrophy and hippocampal subfield volumes in combination with cognitive measures of verbal memory, verbal fluency and executive functions to correctly classify 71.4.% of MCI subjects converting to AD dementia and 92.7 % with stable MCI. Lower baseline GM volume of the subiculum and the superior temporal gyrus was associated with faster disease progression of MCI converters. ConclusionCombining cognitive assessment with automated ROI MRI morphometry is superior to using a single test in order to distinguish MCI due to AD from non converting MCI patients.

Jaw bone changes in panoramic radiography in patients with hyperparathyroidism

Background and aims: The current investigation aimed to evaluate jaw bone changes, and compare the presence of gonial cortex bone thickness, mental index (MI), lamina dura (LD), lower dental canal, and bone density in panoramic radiography, in patients with hyperparathyroidism. Methods: The present cross-sectional descriptive-analytical study was performed on 17 healthy individuals and 17 patients who suffered from resorptive hypercalciuria in the dialysis center of Shahid Beheshti hospital in Babol in 2018. If patients had two or more decayed teeth, they were referred to a specialized maxillofacial clinic by the dentist for free panoramic imaging. Mandibular cortical index, LD, bone change, mandibular resorption (MR), and general cortical indices underwent examination. Results: The mean age of the control and case groups was 36.58±11.81 years and 40.23±14.32 years, respectively (P=0.424). In addition, the mean MI was 4.27±0.87 and 2.98±0.75 in the control and case groups, respectively (P&lt;0.001). Based on the results, the mean gonion region’s cortical bone thickness was 0.93±0.23 and 1.09±0.24 in the case and control groups, respectively (P&lt;0.001). Further, bone changes (P=0.036) and MR (P=0.017) were significantly different in the case and control groups. However, LD vision showed no significant difference in the hyperparathyroidism and the control groups (P=0.141). Conclusion: The results demonstrated a decrease in the thickness of the cortical bone in the guinea pig, mental region, and lack of dental canal in resorptive hypercalciuria compared to healthy individuals.

Maternal high-fat high-sugar diet impairs bone quality and strength but not cartilage in aging mice.

Osteoarthritis (OA) is a prevalent aging disorder of synovial joints and recent work suggests that a parental high-fat diet increases OA severity following joint injury in offspring. We hypothesized that a maternal high-fat high-sugar (HFHS) diet would promote spontaneous osteoarthritis-related cartilage and bone changes in 1-year-old offspring. Female C57BL/6 J mice were placed on either a chow control or HFHS diet for 6 weeks before mating to a chow-fed C57BL/6 J male and maintained on their assigned diets throughout pregnancy and lactation. Male and female offspring were weaned onto a chow diet, raised to 1 year of age, and evaluated for cartilage and bone changes indicative of OA. However, offspring did not show early signs of OA as measured by histological Mankin scoring, mechanical testing of the pericellular matrix, histological synovitis scoring, or subchondral bone thickening as measured by microcomputed Tomography. On the other hand, male offspring from HFHS-fed dams had reduced trabecular bone quality in the tibial metaphysis and decreased cortical thickness. Although maternal HFHS diet did not impact trabecular or cortical bone quality in tibias of female offspring, the radii of these animals had decreased cortical thickness, increased medullary area, and impaired breaking strength compared to those of control-fed dams. Finally, we evaluated bone quality and strength in male and female F2 offspring and found that the grandmaternal diet modestly impacted radial bone geometry but not strength. Together these results suggest that maternal HFHS diet impairs F1 offspring skeletal integrity in a sex and bone site-specific manner.

Quantitative evaluation of Scout Accelerated Motion Estimation and Reduction (SAMER) MPRAGE for morphometric analysis of brain tissue in patients undergoing evaluation for memory loss

BackgroundThree-dimensional (3D) T1-weighted MRI sequences such as the magnetization prepared rapid gradient echo (MPRAGE) sequence are important for assessing regional cortical atrophy in the clinical evaluation of dementia but have long acquisition times and are prone to motion artifact. The recently developed Scout Accelerated Motion Estimation and Reduction (SAMER) retrospective motion correction method addresses motion artifact within clinically-acceptable computation times and has been validated through qualitative evaluation in inpatient and emergency settings. MethodsWe evaluated the quantitative accuracy of morphometric analysis of SAMER motion-corrected compared to non-motion-corrected MPRAGE images by estimating cortical volume and thickness across neuroanatomical regions in two subject groups: (1) healthy volunteers and (2) patients undergoing evaluation for dementia. In part (1), we used a set of 108 MPRAGE reconstructed images derived from 12 healthy volunteers to systematically assess the effectiveness of SAMER in correcting varying degrees of motion corruption, ranging from mild to severe. In part (2), 29 patients who were scheduled for brain MRI with memory loss protocol and had motion corruption on their clinical MPRAGE scans were prospectively enrolled. ResultsIn part (1), SAMER resulted in effective correction of motion-induced cortical volume and thickness reductions. We observed systematic increases in the estimated cortical volume and thickness across all neuroanatomical regions and a relative reduction in percent error values compared to reference standard scans of up to 66 % for the cerebral white matter volume. In part (2), SAMER resulted in statistically significant volume increases across anatomical regions, with the most pronounced increases seen in the parietal and temporal lobes, and general reductions in percent error relative to reference standard clinical scans. ConclusionSAMER improves the accuracy of morphometry through systematic increases and recovery of the estimated cortical volume and cortical thickness following motion correction, which may affect the evaluation of regional cortical atrophy in patients undergoing evaluation for dementia.

Effect of Fibroblast Growth Factor (FGF) 19 and 21 on Hip Geometry and Strength in Post-menopausal Osteoporosis (PMO)

Fibroblast Growth Factor (FGF) receptor signalling is important for skeletal development. The FGF19 subfamily which includes FGF19 and FGF21 are involved in bone metabolism, although their effects on bone mineral density (BMD) and bone strength remain unclear. To further characterise the influence of these two factors on the skeleton, we studied the association between circulating concentrations of FGF19 and 21 with BMD and parameters of hip geometry and strength in post-menopausal osteoporosis (PMO). The study cohort consisted of 374 women aged (mean [SD]) 68.7[12.3] years with PMO. FGF19 and FGF21 were measured in serum by ELISA. BMD was measured at the lumbar spine (LS), total hip (TH) and femoral neck (FN) (n = 277) by dual energy X-ray absorptiometry (DXA) and hip structural analysis (HSA) parameters (n = 263) at the narrow neck of the femur (NN), Intertrochanter (IT) and Femoral shaft (FS) were derived from DXA scans. FGF19 and 21 were not associated with prevalent fractures or BMD when corrected for covariates; age, BMI, smoking habits and alcohol intake. Log-transformed FGF 21 was negatively associated with HSA parameters including Outer Diameter (OD) (p = 0.019), Cross-sectional area (CSA) (p = 0.01), cross-sectional moment of inertia (CSMI) (p = 0.011), Section modulus (Z) (p = 0.002) and cortical thickness (Co Th) (p = 0.026) at the IT only. CSA, CSMI, Z and Co Th were significantly lower (p < 0.05) in women with FGF21 concentrations greater than the median (> 103.5 pg/ml). Our data suggest that FGF 21 may have potentially adverse effects on the skeleton. Further characterisation is needed, particularly as FGF 21 analogues or agonists may be used to treat obesity-related metabolic disorders.

Association between large neutral amino acids and white matter hyperintensities in middle-aged adults at varying metabolic risk.

This investigation delves into the interplay between large neutral amino acids (LNAA) and metabolic syndrome (MetS) in midlife adults, examining their collective influence on brain structure. While LNAA, such as tryptophan and phenylalanine, are known to bolster cognition in youth, these relationships often reverse later in life. Our study hypothesized an earlier reversal of these benefits in middle-aged adults with MetS, potentially signaling premature brain aging. Eighty participants between 40-61years underwent MetS component quantification, LNAA measurement via high-performance liquid chromatography, and brain imaging to evaluate white matter hyperintensities (WMH) volume and medial temporal lobe (MTL) cortical thickness. Our linear regression analyses, adjusting for sex, age, and education, revealed that phenylalanine levels moderated the relationship between MetS and WMH volume (F(6, 69) = 3.134, p < 0.05, R2 = 0.214), suggesting the brain impact of MetS may be partly due to phenylalanine catabolism byproducts. LNAA metabolites did not significantly modulate the MetS-MTL cortical thickness relationship. These findings suggest that better understanding of the role of phenylalanine in the pathogenesis of cerebrovascular disease in midlife may be essential to developing early interventions to protect cognitive health. Further research is crucial to elucidate the longitudinal influence of LNAA and MetS on brain health, thereby informing strategies to mitigate cognitive decline.

Inactivation of spermine synthase in mice causes osteopenia due to reduced osteoblast activity.

Spermine synthase, encoded by the SMS gene, is involved in polyamine metabolism, as it is required for the synthesis of spermine from its precursor molecule spermidine. Pathogenic variants of SMS are known to cause Snyder-Robinson syndrome (SRS), an X-linked recessive disorder causing various symptoms, including intellectual disability, muscular hypotonia, infertility, but also skeletal abnormalities, such as facial dysmorphisms and osteoporosis. Since the impact of a murine SMS deficiency has so far only been analysed in Gy mice, where a large genomic deletion also includes the neighbouring Phex gene, there is only limited knowledge about the potential role of SMS in bone cell regulation. In the present manuscript we describe two patients carrying distinct SMS variants, both diagnosed with osteoporosis. Whereas the first patient displayed all characteristic hallmarks of SRS, the second patient was initially diagnosed, based on laboratory findings, as a case of adult-onset hypophosphatasia. In order to study the impact of SMS inactivation on bone remodelling we took advantage of a newly developed mouse model carrying a pathogenic SMS variant (p.G56S). Compared to their wildtype littermates 12-week-old male SmsG56S/0 mice displayed reduced trabecular bone mass and cortical thickness, as assessed by μCT analysis of the femur. This phenotype was histologically confirmed by the analysis of spine and tibia sections, where we also observed a moderate enrichment of non-mineralized osteoid in SmsG56S/0 mice. Cellular and dynamic histomorphometry further identified a reduced bone formation rate as a main cause of the low bone mass phenotype. Likewise, primary bone marrow cells from SmsG56S/0 mice displayed reduced capacity to form a mineralized matrix ex vivo, thereby suggesting a cell-autonomous mechanism. Taken together, our data identify SMS as an enzyme with physiological relevance for osteoblast activity, thereby demonstrating an important role of polyamine metabolism in the control of bone remodeling.

CRISPR activation of Tfeb , a master regulator of autophagy and lysosomal biogenesis, in osteoblast lineage cells increases bone mass and strength.

Autophagy is a recycling pathway in which damaged or dysfunctional proteins, protein aggregates, and organelles are delivered to lysosomes for degradation. Insufficiency of autophagy is thought to contribute to several age-related diseases including osteoporosis. Consistent with this, elimination of autophagy from the osteoblast lineage reduces bone formation and causes low bone mass. However, whether increasing autophagy would benefit bone health is unknown. Here, we increased expression of the endogenous Transcription Factor EB gene ( Tfeb ) in osteoblast lineage cells in vivo via CRISPR activation. Tfeb overexpression stimulated autophagy and lysosomal biogenesis in osteoblasts. Tfeb overexpressing male mice displayed a robust increase in femoral and vertebral cortical thickness at 4.5 months of age. Histomorphometric analysis revealed that the increase in femoral cortical thickness was due to increased bone formation at the periosteal surface. Tfeb overexpression also increased femoral trabecular bone volume. Consistent with these results, bone strength was increased in Tfeb overexpressing mice. Female Tfeb overexpressing mice also displayed a progressive increase in bone mass over time and at 12 months of age had high cortical thickness and trabecular bone volume. This increase in vertebral trabecular bone volume was due to elevated bone formation. Osteoblastic cultures showed that Tfeb overexpression increased proliferation and osteoblast formation. Overall, these results demonstrate that stimulation of autophagy in osteoblast lineage cells promotes bone formation and strength and may represent an effective approach to combat osteoporosis.

Causal effect of air pollution on the risk of brain health and potential mediation by gut microbiota

ObjectiveEpidemiologic investigations have examined the correlation between air pollution and neurologic disorders and neuroanatomic structures. Increasing evidence underscores the profound influence of the gut microbiota on brain health. However, the existing evidence is equivocal, and a causal link remains uncertain. This study aimed: to determine if there is a causal connection between four key air pollutants, and 42 neurologic diseases, and 1325 distinct brain structures; and to explore the potential role of the gut microbiota in mediating these associations. MethodsUnivariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) models were deployed to estimate the causal impact of air pollutants (including particulate matter [PM] with aerodynamic diameters <2.5 μm [PM2.5], and <10 μm [PM10]; PM2.5 absorbance; and nitrogen oxides [NOx]) on brain health through various Mendelian randomization methodologies. Lastly, the mediating role of the gut microbiome in the connections between the identified pollutants and neurologic diseases and brain structures was systematically examined. ResultsThe potential causal associations of PM2.5, PM2.5 absorbance, PM10, and exposure to NOx, with the risks of intracerebral hemorrhage, hippocampal perivascular spaces, large artery strokes, generalized epilepsy with tonic-clonic seizures, Alzheimer’s disease, multiple sclerosis, anorexia nervosa, post-traumatic stress disorder (PTSD), and 420 brain structures, were investigated by UVMR analysis. Following adjustment for air pollutants by MVMR analysis, the genetic correlations between PM10 exposure and PTSD and multiple sclerosis remained significant and robust. Importantly, we observed that phylum Lentisphaerae may mediate the association between PM10 and multiple sclerosis. Additionally, PM2.5 absorbance with a greater risk of reduced thickness in the left anterior transverse temporal gyrus of Heschl and a decreased area in the right sulcus intermedius primus of Jensen, mediated by genus Senegalimassilia and genus Lachnospiraceae UCG010, respectively. Finally, we provided evidence that Clostridium innocuum and genus Ruminococcus2 may partly mediate the causal effect of NOx on altered thickness in the left transverse temporal cortex and area in the right sulcus intermedius primus of Jensen, respectively. ConclusionThis study established a genetic connection between air pollution and brain health, implicating the gut microbiota as a potential mediator in the relationship between air pollution, neurologic disorders, and altered brain structures.