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Background: Cortical atrophy is a common manifestation in behavioral variant frontotemporal degeneration (bvFTD), exhibiting spatial heterogeneity across various genetic subgroups, which may be driven by distinct biological mechanisms. Methods: We employed an integrative imaging transcriptomics approach to identify both disparate and shared transcriptomic signatures associated with cortical thickness in bvFTD with C9orf72 repeat expansions or pathogenic variants in GRN or MAPT. Functional enrichment analyses were conducted on each gene list significantly associated with cortical thickness. Additionally, we mapped neurotransmitter receptor/transporter density maps to the cortical thickness maps, to uncover different correlation patterns for each genetic form. Furthermore, we examined whether the identified genes were enriched for pathology-related genes by using previously identified genes linked to TDP-43 positive neurons and genes associated with tau pathology. Results: For each genetic form of bvFTD, we identified cortical thickness signatures and gene sets associated with them. The cortical thickness associated genes for GRN-bvFTD were significantly involved in neurotransmitter system and circadian entrainment. The different patterns of spatial correlations between synaptic density and cortical thinning, further confirmed the critical role of neurotransmission and synaptic signaling in shaping brain structure, especially in the GRN-bvFTD group. Furthermore, we observed significant overlap between genes linked to TDP-43 pathology and the gene sets associated with cortical thickness in C9orf72-bvFTD and GRN-bvFTD but not the MAPT-bvFTD group providing specificity for our associations. C9orf72-bvFTD and GRN-bvFTD also shared genes displaying consistent directionality, with those exhibiting either positive or negative correlations with cortical thickness in C9orf72-bvFTD showing the same direction (positive or negative) in GRN-bvFTD. MAPT-bvFTD displayed more pronounced differences in transcriptomic signatures compared to the other two genetic forms. The genes that exhibited significantly positive or negative correlations with cortical thickness in MAPT-bvFTD showed opposing directionality in C9orf72-bvFTD and GRN-bvFTD. Conclusions: Overall, this integrative transcriptomic approach identified several new shared and disparate genes associated with regional vulnerability with increased biological interpretation including overlap with synaptic density maps and pathologically-specific gene expression. These findings illuminated the intricate molecular underpinnings contributing to the heterogeneous nature of disease distribution in bvFTD with distinct genetic backgrounds. [ABSTRACT FROM AUTHOR]

[Display omitted] • Surface brain morphometry was explored in type 1 diabetes and neuropathic phenotypes. • Cortical thickness was reduced in diabetes and neuropathic pain. • Reduced postcentral gyrus sulcus depth associated with neuropathic pain. • Brain morphometry may offer deeper insights into diabetes and neuropathic pain. This study explored surface brain morphometry in type 1 diabetes including focus on painful diabetic peripheral neuropathy (DPN). Brain MRI was obtained from 56 individuals with diabetes (18 without DPN, 19 with painless DPN, 19 with painful DPN) and 20 healthy controls. Cortical thickness, sulcus depth, and gyrification were analysed globally and regionally in each group and in the combined diabetes group. Associations with clinical characteristics and pain were assessed. Globally, cortical thickness was reduced in the combined diabetes group and in painful DPN compared to healthy controls. No differences in sulcus depth and gyrification were found. Several regions, including the middle frontal gyrus showed reduced cortical thickness in the combined diabetes- and painful DPN group. The postcentral gyrus exhibited reduced cortical thickness in painful DPN compared to healthy controls, and reduced sulcus depth compared to painless DPN correlating with higher pain intensity. Cortical thinning manifested across the brain cortex in diabetes, especially for painful DPN. Altered postcentral gyrus morphometry may be associated with neuropathic pain. Assessing cortical morphometry may be critical for comprehending central neuropathy and the manifestation of painful DPN in diabetes. [ABSTRACT FROM AUTHOR]

Background: Memory decline is common in multiple sclerosis (MS), although pathophysiological mechanisms are not fully understood. Objective: The objective was to investigate the relationship of changes in structural and functional neuroimaging markers to memory decline over 3-year follow-up. Methods: Participants with MS underwent cognitive evaluation and structural, diffusion, and functional 3T magnetic resonance imaging (MRI) scans at baseline and 3-year follow-up. Changes in neuroimaging metrics from baseline to follow-up were compared between memory stable and memory decline groups. Our hypothesis that structural and functional connectivity changes mediate the association of atrophy to memory decline was tested. Results: A total of 249 MS patients completed baseline visit; 169 (67.8%) returned at 3-year follow-up. Based on ⩾10% decline, memory decline was observed in 44.4% (n = 75). Those with memory decline showed marginally greater whole-brain volume loss over time compared with those with stable memory performance (p = 0.08). In those with memory decline, changes in white matter tract integrity were related to regional cortical thinning (p < 0.01). Exploratory mediation analysis revealed structural and functional connectivity to mediate the relationship of atrophy to verbal and visual memory decline. Conclusion: Further work is needed to characterize complex interrelationships of atrophy and structural/functional connectivity changes to memory decline in MS. [ABSTRACT FROM AUTHOR]

Osteoporosis in postmenopausal women is one of the causes of femoral fractures and is prevented by the administration of bisphosphonates. Individual morphologies are considered to increase the risk of atypical fractures associated with long‐term administration. To evaluate cortical bone morphology quantitatively, we established a method to measure the distance from the center point of a cross‐section to the external and internal borders based on CT images. Using this method, 44 sides of a female femoral skeleton specimen were examined and areas of protrusion and thickening in the medial anterior and lateral posterior regions just below the lesser trochanter were identified. These positions strongly correlated with the anteversion angle, suggesting the involvement of the distribution of the load received from body weight defined by the angle. The finite element method was used to examine the relationships between the positions of these areas with compressive and tensile stress distribution areas in the one‐legged standing condition. The medial anterior region and lateral posterior region protruded and thickened in response to compressive and tensile stress, respectively. In addition, a hierarchical relationship was observed between the anteversion angle, tensile stress distribution, protrusion, and thickening in femurs with thinning of cortical bone, indicating that morphogenesis occurs adaptively to loading. The present results demonstrate the usefulness of this method in considering the formation mechanism and function of the femoral diaphysis and suggest that bone remodeling is necessary to maintain adaptability. [ABSTRACT FROM AUTHOR]

Dopamine (DA) signaling is critical for optimal cognitive aging, especially in prefrontal-parietal and fronto-striatal networks. Single nucleotide polymorphisms associated with dopamine regulation, COMT Val158Met and DRD2 C957T , stand to exert influence on executive function performance via neural properties. The current study investigated whether longitudinal thinning of mesocortical regions is related to COMT and DRD2 genetic predisposition and associated with decline in executive function over four-years. N =235 healthy adults aged 20–94 years were recruited, with n =124 returning 4-years later. Latent mixed effects modeling revealed dopamine-related thinning in several frontal, parietal, and cingulate regions as well as decline in verbal fluency category switching across 4-years. Mesocortical thinning was also related to switching performance. Greater cortical thinning interacted with DA-genotype risk for lower DA-availability to predict poorer switching performance in parietal and posterior cingulate cortex. These findings lend support to the notion that early-life factors, such as genetic influence on neurotransmitter function, play a role in cognitive and brain aging and their linked association. • Dopamine signaling decreases significantly with aging and predicts poorer cognition. • Genetic polymorphisms regulating dopamine availability predict cognitive performance. • Greater cortical thinning seen in genotypes at risk for lower synaptic availability. • Dopamine-related thinning was associated with poorer executive function performance. • Genetic predisposition to lower dopamine availability impacts neurocognitive aging. [ABSTRACT FROM AUTHOR]

Cherubism is a rare autosomal dominant skeletal dysplasia, affecting the maxilla and/or mandible. The condition typically has childhood onset, followed by progression until puberty, with subsequent regression. Cherubism lesions share histological features with giant cell tumor of bone, where high-dose monthly denosumab is an effective medical treatment. Therefore, high-dose denosumab has also been trialed in children with cherubism with positive outcomes. However, the role of denosumab in adult cherubism, particularly a lower dose and frequency, has not been established. We present the case of a 60-year-old man with cherubism, reviewed for a new 39 × 21 mm left mandibular lesion. The patient had multiple surgeries up to the age of 30 for tumors in the right maxilla and mandible. Given the impact of further surgery on his appearance and quality of life, the patient was referred to Endocrinology for consideration of medical therapy. His bone turnover markers were slightly elevated with normal calcium, phosphate, 25-OH vitamin D, and parathyroid hormone levels. A bone density scan showed lumbar spine osteopenia. He was commenced on 60 mg denosumab 6-monthly with excellent clinical and radiological responses over the next 30 months. The most recent CT mandible showed a sustained reduction in the lesion size, measuring 36 × 18 mm, with osteoid formation and improvement in cortical thinning. Surgery is no longer indicated. No adverse effects from denosumab were reported in the patient. This is the first study to report the efficacy and safety of a low-dose denosumab regimen in the management of cherubism. This treatment approach was able to prevent major surgery and minimize denosumab-related adverse effects. While the optimal treatment duration remains unclear, the patient will continue with 60 mg denosumab 6-monthly in the short-term given the favorable response. In summary, a low-dose denosumab regimen should be considered for patients with cherubism, particularly those with contraindications or preferences to avoid surgery. [ABSTRACT FROM AUTHOR]

Introduction: Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons, resulting in muscle atrophy, spasticity, hyperreflexia, and paralysis. Inflammation plays an important role in the development of ALS, and associated with rapid disease progression. Current observational studies indicate the thinning of cortical thickness in patients with ALS is associated with rapid disease progression and cognitive changes. However, the effects of inflammatory cytokines on cortical thickness in patients with ALS are unclear. Here, we investigated the relationship between inflammatory cytokines and cortical thickness in patients with ALS. Methods: We evaluated 51 patients with ALS for inflammatory cytokines including interleukin (IL)-4, interferon (IFN)-α, IL-1β, IL-2, IL-5, IL-12, tumor necrosis factor (TNF)-α, IL-6, IL-10, IL-8, IL-17, and IFN-γ and analyzed the correlation between these indicators and the ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (ΔFS score). Twenty-six patients with ALS and 26 controls were studied using whole-cortex analysis, and post-hoc analyses were performed to examine the correlation between brain cortical thickness and ALSFRS-R or ΔFS scores. Results: IL-4, IFN-α, IL-1β, and IL-2 levels were significantly correlated with ALSFRS-R scores, and the IL-2 level was significantly correlated with ΔFS scores. After controlling for age and sex, the ALS group had thinner cortexes in multiple clusters across the brain than the control group. Further analyses revealed that cortical thickness in the right superior temporal and lingual gyrus regions was inversely correlated with ΔFS scores. There was a significant positive correlation between the clusters in the right lingual cortex and IL-2 level. Conclusion: These results suggest cortical thickness was reduced in patients with ALS in motor and non-motor cortical areas. Inflammatory factors (especially IL-2) were correlated with cortical thickness, and both were related to the disease progression rate, suggesting IL-2 plays an important role in ALS. [ABSTRACT FROM AUTHOR]

Background: Accumulation of β-amyloid (Aβ) in the brain is a hallmark of Alzheimer's Disease (AD). Cerebral deposition of Aβ initiates deteriorating pathways which eventually can lead to AD. However, the exact mechanisms are not known. A possible pathway could be that Aβ affects the cerebral vessels, causing inadequate cerebrovascular function. In the present study, we examined if Aβ accumulation is associated with a reduced cerebral blood flow response (CBF) to neuronal activation by visual stimulation (ΔCBFVis.Act.) in cognitively normal subjects from the Metropolit Danish Male Birth Cohort. Methods: 64 subjects participated in the present study. ΔCBFVis.Act. was measured using arterial spin labelling (ASL) combined with blood-oxygen-level-dependent (BOLD) MRI. Neuronal activation was obtained by visual stimulation by a flickering checkerboard presented on a screen in the MRI-scanner. Brain Aβ accumulation and cerebral glucose metabolism were assessed by PET imaging using the radiotracers [11C]Pittsburgh Compound-B (PiB) and [18F]Fluorodeoxyglucose (FDG), respectively. Cortical thickness was measured from structural MRI. Results: ΔCBFVis.Act. correlated negatively (β = -32.1 [95% confidence interval (CI): -60.2; -4.1], r = -0.30, p = 0.025) with PiB standardized uptake value ratio (SUVr) in the brain regions activated by visual stimulation. ΔCBFVis.Act. did not correlate with FDG SUVr (β = 1.9 [CI: -23.8; 27.6], r = 0.02, p = 0.88) or cortical thickness (β = 10.3 [CI: -8.4; 29.0], r = 0.15, p = 0.27) in the activated brain regions. Resting CBF did not correlate with PiB SUVr neither in the regions activated by visual stimulation (β = -17.8 [CI:-71.9; 36.2], r =- 0.09, p = 0.51) nor in the remaining cortex (β = 5.2 [CI:-3.9; 14.2], r = 0.15, p = 0.26). Conclusion: We found a correlation between high PiB SUVr and reduced CBF response to neuronal activation, indicating a link between Aβ accumulation and impaired cerebrovascular function. The impairment was not associated with cortical thinning or hypometabolism, suggesting that Aβ accumulation affecting brain vessel function could be a very early pathology leading to neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Establishing a mature and reliable cortical bone drilling temperature model is the basis for predicting the size of the danger zone for bone thermal damage (Z Temperature ≥ 47 °C) during drilling. In this paper, the temperature field of cortical bone drilling process is comprehensively analyzed, and proposes a drilling temperature model by considering the heterogeneous structure of cortical bone and combining empirical and analytical methods. The cortical bone drilling temperature model is verified by cortical bone drilling experiments. The hole wall temperature and thermal damage area during drilling with a common drill and a developed chisel-edge thinning drill are compared. The experimental results show that the prediction error of the drilling temperature model considering the heterogeneous tissue structure of cortical bone is within 10 %, and the temperature changes of the tissue structure at different positions away from the periosteum of the cortical bone can be predicted more accurately during the drilling process. Compared with ordinary drill bits, chisel edge thinning drill bits have higher drilling efficiency and excellent chip removal ability. The hole wall temperature and thermal damage area during drilling are reduced by 5.1 %–17.2 % and 10.3 %–42.8 %, respectively. This study is helpful to help surgeons develop strategies for reducing temperature and damage. • An empirical model of friction temperature rise between drill bit and hole wall is established by RSM. • A drilling temperature model considering the heterogeneous structure of cortical bone is proposed. • Compared with common drills, the drilling temperature and thermal damage of chisel-thinning drills are lower. [ABSTRACT FROM AUTHOR]

Around 30% of people with schizophrenia are refractory to antipsychotic treatment (treatment-resistant schizophrenia). Abnormal structural neuroimaging findings, in particular volume and thickness reductions, are often described in schizophrenia. Novel biomarkers of active brain pathology such as neurofilament light chain protein are now expected to improve current understanding of psychiatric disorders, including schizophrenia. This study explored whether treatment-resistant schizophrenia individuals exhibit different associations between plasma neurofilament light chain protein levels and regional cortical thickness reductions compared with controls.Plasma neurofilament light chain protein levels were measured, and T1-weighted magnetic resonance imaging sequences were obtained and processed via FreeSurfer for each participant. General linear models adjusting for age and body mass index were estimated to determine whether the interaction between diagnostic group and plasma neurofilament light chain protein level predicted lower cortical thickness across frontotemporal structures and the insula.A total of 79 participants were included: 37 treatment-resistant schizophrenia and 42 healthy controls. Significant (false discovery rate-corrected) cortical thinning of the left (p = 0.005, η2 p = 0.100) and right (p = 0.002, η2 p = 0.149) insula, and left inferior temporal gyrus (p < 0.001, η2 p = 0.143) was associated with higher levels of plasma neurofilament light chain protein in treatment-resistant schizophrenia, but not in healthy controls.The association between regional thickness reduction of the bilateral insula and left inferior temporal gyrus with plasma neurofilament light chain protein may reflect a neuroprogressive component to schizophrenia, which is not observed in the normal population. [ABSTRACT FROM AUTHOR]