Greater cortical thinning and microstructural integrity loss in myotonic dystrophy type 1 compared to myotonic dystrophy type 2.

BACKGROUND: Myotonic dystrophy is a multisystem disorder characterized by widespread organic involvement including central nervous system symptoms. Although myotonic dystrophy disease types 1 (DM1) and 2 (DM2) cover a similar spectrum of symptoms, more pronounced clinical and brain alterations have been described in DM1. Here, we investigated brain volumetric and white matter alterations in both disease types and compared to healthy controls (HC). METHODS: MRI scans were obtained from 29 DM1, 27 DM2, and 56 HC. We assessed macro- and microstructural brain changes by surface-based analysis of cortical thickness of anatomical images and tract-based spatial statistics of fractional anisotropy (FA) obtained by diffusion-weighted imaging, respectively. Global MRI measures were related to clinical and neuropsychological scores to evaluate their clinical relevance. RESULTS: Cortical thickness was reduced in both patient groups compared to HC, showing similar patterns of regional distribution in DM1 and DM2 (occipital, temporal, frontal) but more pronounced cortical thinning for DM1. Similarly, FA values showed a widespread decrease in DM1 and DM2 compared to HC. Interestingly, FA was significantly lower in DM1 compared to DM2 within most parts of the brain. CONCLUSION: Comparisons between DM1 and DM2 indicate a more pronounced cortical thinning of grey matter and a widespread reduction in microstructural integrity of white matter in DM1. Future studies are required to unravel the underlying and separating mechanisms for the disease courses of the two types and their neuropsychological symptoms.

The hippocampus as a structural and functional network epicentre for distant cortical thinning in neurocognitive aging.

Alterations in grey matter (GM) and white matter (WM) are associated with memory impairment across the neurocognitive aging spectrum and theorised to spread throughout brain networks. Functional and structural connectivity (FC,SC) may explain widespread atrophy. We tested the effect of SC and FC to the hippocampus on cortical thickness (CT) of connected areas. In 419 (223 F) participants (agemean=73 ±â€¯8) from the Alzheimer's Disease Neuroimaging Initiative, cortical regions associated with memory (Rey Auditory Verbal Learning Test) were identified using Lasso regression. Two structural equation models (SEM), for SC and resting-state FC, were fitted including CT areas, and SC and FC to the left and right hippocampus (LHIP,RHIP). LHIP (ß=-0.150,p=<.001) and RHIP (ß=-0.139,p=<.001) SC predicted left temporopolar/rhinal CT; RHIP SC predicted right temporopolar/rhinal CT (ß=-0.191,p=<.001). LHIP SC predicted right fusiform/parahippocampal (ß=-0.104,p=.011) and intraparietal sulcus/superior parietal CT (ß=0.101,p=.028). Increased RHIP FC predicted higher left inferior parietal CT (ß=0.132,p=.042) while increased LHIP FC predicted lower right fusiform/parahippocampal CT (ß=-0.97; p=.023). The hippocampi may be epicentres for cortical thinning through disrupted connectivity.

Linking white matter hyperintensities to regional cortical thinning, amyloid deposition, and synaptic density loss in Alzheimer's disease.

INTRODUCTION: We investigated the association between white matter hyperintensities (WMH) and regional cortical thickness, amyloid and tau deposition, and synaptic density in the WMH-connected cortex using multimodal images. METHODS: We included 107 participants (59 with Alzheimer's disease [AD]; 27 with mild cognitive impairment; 21 cognitively normal controls) with amyloid beta (Aß) positivity on amyloid positron emission tomography (PET). The cortex connected to WMH was identified using probabilistic tractography. RESULTS: We found that WMH connected to the cortex with more severe regional degeneration as measured by cortical thickness, Aß and tau deposition, and synaptic vesicle glycoprotein 2 A (SV2A) density using 18F-SynVesT-1 PET. In addition, higher ratios of Aß in the deep WMH-connected versus WMH-unconnected cortex were significantly related to lower cognitive scores. Last, the cortical thickness of WMH-connected cortex reduced more than WMH-unconnected cortex over 12 months. DISCUSSION: Our results suggest that WMH may be associated with AD-intrinsic processes of degeneration, in addition to vascular mechanisms. HIGHLIGHTS: We studied white matter hyperintensities (WMHs) and WMH-connected cortical changes. WMHs are associated with more severe regional cortical degeneration. Findings suggest WMHs may be associated with Alzheimer's disease-intrinsic processes of degeneration.

Examining the interaction between prenatal stress and polygenic risk for attention-deficit/hyperactivity disorder on brain growth in childhood: Findings from the DREAM BIG consortium.

This study explored the interactions among prenatal stress, child sex, and polygenic risk scores (PGS) for attention-deficit/hyperactivity disorder (ADHD) on structural developmental changes of brain regions implicated in ADHD. We used data from two population-based birth cohorts: Growing Up in Singapore Towards healthy Outcomes (GUSTO) from Singapore (n = 113) and Generation R from Rotterdam, the Netherlands (n = 433). Prenatal stress was assessed using questionnaires. We obtained latent constructs of prenatal adversity and prenatal mood problems using confirmatory factor analyses. The participants were genotyped using genome-wide single nucleotide polymorphism arrays, and ADHD PGSs were computed. Magnetic resonance imaging scans were acquired at 4.5 and 6 years (GUSTO), and at 10 and 14 years (Generation R). We estimated the age-related rate of change for brain outcomes related to ADHD and performed (1) prenatal stress by sex interaction models, (2) prenatal stress by ADHD PGS interaction models, and (3) 3-way interaction models, including prenatal stress, sex, and ADHD PGS. We observed an interaction between prenatal stress and ADHD PGS on mean cortical thickness annual rate of change in Generation R (i.e., in individuals with higher ADHD PGS, higher prenatal stress was associated with a lower rate of cortical thinning, whereas in individuals with lower ADHD PGS, higher prenatal stress was associated with a higher rate of cortical thinning). None of the other tested interactions were statistically significant. Higher prenatal stress may promote a slower brain developmental rate during adolescence in individuals with higher ADHD genetic vulnerability, whereas it may promote a faster brain developmental rate in individuals with lower ADHD genetic vulnerability.

Accelerated Cortical Thinning in Schizophrenia Is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental Disorders.

BACKGROUND: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. Studies have reported a shared genetic basis between schizophrenia and cortical thickness. However, no genes whose expression is related to abnormal cortical thinning in schizophrenia have been identified. METHODS: We conducted linear mixed models to estimate the rates of accelerated cortical thinning across 68 regions from the Desikan-Killiany atlas in individuals with schizophrenia compared with healthy control participants from a large longitudinal sample (ncases = 169 and ncontrols = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning. RESULTS: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit this accelerated thinning were downregulated in several psychiatric disorders and were enriched for both common and rare disrupting variation for schizophrenia and neurodevelopmental disorders. In contrast, none of these enrichments were observed for baseline cross-sectional cortical thickness differences. CONCLUSIONS: Our findings suggest that accelerated cortical thinning, rather than cortical thickness alone, serves as an informative phenotype for neurodevelopmental disruptions in schizophrenia. We highlight the genetic and transcriptomic correlates of this accelerated cortical thinning, emphasizing the need for future longitudinal studies to elucidate the role of genetic variation and the temporal-spatial dynamics of gene expression in brain development and aging in schizophrenia.

Distinct spatiotemporal patterns of cortical thinning in Alzheimer's disease-type cognitive impairment and subcortical vascular cognitive impairment.

Previous studies on Alzheimer's disease-type cognitive impairment (ADCI) and subcortical vascular cognitive impairment (SVCI) has rarely explored spatiotemporal heterogeneity. This study aims to identify distinct spatiotemporal cortical atrophy patterns in ADCI and SVCI. 1,338 participants (713 ADCI, 208 SVCI, and 417 cognitively unimpaired elders) underwent brain magnetic resonance imaging (MRI), amyloid positron emission tomography, and neuropsychological tests. Using MRI, this study measures cortical thickness in five brain regions (medial temporal, inferior temporal, posterior medial parietal, lateral parietal, and frontal areas) and utilizes the Subtype and Stage Inference (SuStaIn) model to predict the most probable subtype and stage for each participant. SuStaIn identifies two distinct cortical thinning patterns in ADCI (medial temporal: 65.8%, diffuse: 34.2%) and SVCI (frontotemporal: 47.1%, parietal: 52.9%) patients. The medial temporal subtype of ADCI shows a faster decline in attention, visuospatial, visual memory, and frontal/executive domains than the diffuse subtype (p-value < 0.01). However, there are no significant differences in longitudinal cognitive outcomes between the two subtypes of SVCI. Our study provides valuable insights into the distinct spatiotemporal patterns of cortical thinning in patients with ADCI and SVCI, suggesting the potential for individualized therapeutic and preventive strategies to improve clinical outcomes.

Gray matter biomarkers for major depressive disorder and manic disorder using logistic regression.

The study investigates morphometric changes using surface-based measures and logistic regression in Major depressive-disorder (MDD) and Manic-disorder patients as compared to controls. MDD (n = 21) and manic (n = 20) subjects were recruited from psychiatric clinics, along with 19 healthy-controls from local population, after structured and semi-structured clinical interview (DSM-IV, brief Psychotic-Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Hamilton depression rating scale (HDRS), cognitive function by postgraduate Institute Battery of Brain Dysfunction (PGIBBD)). Using 3D T1-weighted images, gray matter (GM) cortical thickness and GM-based morphometric signatures (using logistic regression) were compared among MDD, manic disorder and controls using analysis of covariance (ANCOVA). No significant difference was found between the MDD and manic disorder patients. When compared to controls, cortical thinning was observed in bilateral rostral middle frontal gyrus and parsopercularis, right lateral occipital cortex, right lingual gyrus in MDD; and bilateral rostral middle frontal and superior frontal gyrus, right middle temporal gyrus, left supramarginal and left precentral gyrus in Manic disorders. Logistic regression analysis exhibited GM cortical thinning in the bilateral parsopercularis, right lateral occipital cortex and lingual gyrus in MDD; and bilateral rostral middle, superior frontal gyri, right middle temporal gyrus in Manic with a sensitivity and specificity of 85.7 % and 94.7 % and 90.0 % and 94.7 %, respectively in comparison with controls. Both groups exhibited GM loss in bilateral rostral middle frontal gyrus brain regions compared to controls. Multivariate analysis revealed common changes in GM in MDD and manic disorders associated with mood temperament, but differences when compared to controls.

Longitudinal brain structure changes in Parkinson's disease: A replication study.

CONTEXT: An existing major challenge in Parkinson's disease (PD) research is the identification of biomarkers of disease progression. While magnetic resonance imaging is a potential source of PD biomarkers, none of the magnetic resonance imaging measures of PD are robust enough to warrant their adoption in clinical research. This study is part of a project that aims to replicate 11 PD studies reviewed in a recent survey (JAMA neurology, 78(10) 2021) to investigate the robustness of PD neuroimaging findings to data and analytical variations. OBJECTIVE: This study attempts to replicate the results in Hanganu et al. (Brain, 137(4) 2014) using data from the Parkinson's Progression Markers Initiative (PPMI). METHODS: Using 25 PD subjects and 18 healthy controls, we analyzed the rate of change of cortical thickness and of the volume of subcortical structures, and we measured the relationship between structural changes and cognitive decline. We compared our findings to the results in the original study. RESULTS: (1) Similarly to the original study, PD patients with mild cognitive impairment (MCI) exhibited increased cortical thinning over time compared to patients without MCI in the right middle temporal gyrus, insula, and precuneus. (2) The rate of cortical thinning in the left inferior temporal and precentral gyri in PD patients correlated with the change in cognitive performance. (3) There were no group differences in the change of subcortical volumes. (4) We did not find a relationship between the change in subcortical volumes and the change in cognitive performance. CONCLUSION: Despite important differences in the dataset used in this replication study, and despite differences in sample size, we were able to partially replicate the original results. We produced a publicly available reproducible notebook allowing researchers to further investigate the reproducibility of the results in Hanganu et al. (2014) when more data is added to PPMI.

Rates of cortical thinning in Alzheimer's disease signature regions associate with vascular burden but not with ß-amyloid status in cognitively normal adults at age 70.

BACKGROUND: Consistent patterns of reduced cortical thickness have been identified in early Alzheimer's disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear. METHODS: Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral ß-amyloid (Aß) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years). RESULTS: In a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aß status did not. Among Aß positive participants (n=56), there was some evidence that greater global Aß standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08). CONCLUSIONS: Cortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aß-positivity, robust Aß-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.

Structural connectome architecture shapes the maturation of cortical morphology from childhood to adolescence.

Cortical thinning is an important hallmark of the maturation of brain morphology during childhood and adolescence. However, the connectome-based wiring mechanism that underlies cortical maturation remains unclear. Here, we show cortical thinning patterns primarily located in the lateral frontal and parietal heteromodal nodes during childhood and adolescence, which are structurally constrained by white matter network architecture and are particularly represented using a network-based diffusion model. Furthermore, connectome-based constraints are regionally heterogeneous, with the largest constraints residing in frontoparietal nodes, and are associated with gene expression signatures of microstructural neurodevelopmental events. These results are highly reproducible in another independent dataset. These findings advance our understanding of network-level mechanisms and the associated genetic basis that underlies the maturational process of cortical morphology during childhood and adolescence.

Factors affecting stress shielding and osteolysis after reverse shoulder arthroplasty: A multicenter study in a Japanese population.

BACKGROUND: Stress shielding and osteolysis around the humeral stem after reverse shoulder arthroplasty causes loosening and periprosthetic fractures and reduces bone stock during revision surgery. In Japanese patients, who have relatively small bodies, different characteristics may exist regarding the occurrence of these changes compared with the characteristics of Westerners, who have relatively larger frames. The purpose of this multicenter study was to investigate the incidence and clarify the predictors of stress shielding and osteolysis in Japanese individuals who underwent reverse shoulder arthroplasty. METHODS: The occurrence of stress shielding and osteolysis was investigated in 135 shoulders that had undergone reverse shoulder arthroplasty at least 2 years prior in five Japanese hospitals. During post-surgical follow-up, which was conducted every 3 months, the locations of the stress shielding occurrences, such as cortical thinning and osteopenia (which primarily occurred in zones 1, 2, and 7, where 1 is the greater tuberosity and 7 is the calcar part), spot weld, and condensation lines, were recorded. Cases without any abnormal findings on radiographs obtained up to ≥2 years after surgery were regarded as having no abnormalities. Finally, the predictors of cortical thinning and proximal humeral osteolysis were assessed using univariate and multivariate regression analyses. RESULTS: Cortical thinning and osteopenia occurred in 68 shoulders, a condensation line occurred in 37 shoulders, and spot weld occurred in 23 shoulders. In particular, greater tuberosity and calcar osteolysis occurred in 40 and 47 shoulders, respectively. Long stem, cementless stem, and a larger proximal filling ratio were independent predictors of cortical thinning and osteopenia, whereas a cementless stem, larger metaphysis diameter, and a larger proximal filling ratio were associated with proximal humeral osteolysis. CONCLUSIONS: The predictors of stress shielding and osteolysis included the use of long stems, cementless stems, larger proximal filling ratios, and larger metaphysis diameters. LEVEL OF EVIDENCE: retrospective comparative study (Level III).

Regional Tau Deposition Reflects Different Pathways of Subsequent Neurodegeneration and Memory Decline in Cognitively Normal Older Adults.

OBJECTIVE: Tau pathology is recognized as a primary contributor to neurodegeneration and clinical symptoms in Alzheimer's disease (AD). This study aims to localize the early tau pathology in cognitively normal older people that is predictive of subsequent neurodegeneration and memory decline, and delineate factors underlying tau-related memory decline in individuals with and without ß-amyloid (Aß). METHODS: A total of 138 cognitively normal older individuals from the Berkeley Aging Cohort Study underwent 11 C-Pittsburgh Compound-B (PiB) positron emission tomography (PET) to determine Aß positivity and 18 F-Flortaucipir (FTP) PET to measure tau deposition, with prospective cognitive assessments and structural magnetic resonance imaging. Voxel-wise FTP analyses examined associations between baseline tau deposition and longitudinal memory decline, longitudinal hippocampal atrophy, and longitudinal cortical thinning in AD signature regions. We also examined whether hippocampal atrophy and cortical thinning mediate tau effects on future memory decline. RESULTS: We found Aß-dependent tau associations with memory decline in the entorhinal and temporoparietal regions, Aß-independent tau associations with hippocampal atrophy within the medial temporal lobe (MTL), and that widespread tau was associated with mean cortical thinning in AD signature regions. Tau-related memory decline was mediated by hippocampal atrophy in Aß- individuals and by mean cortical thinning in Aß+ individuals. INTERPRETATION: Our results suggest that tau may affect memory through different mechanisms in normal aging and AD. Early tau deposition independent of Aß predicts subsequent hippocampal atrophy that may lead to memory deficits in normal older individuals, whereas elevated cortical tau deposition is associated with cortical thinning that may lead to more severe memory decline in AD. ANN NEUROL 2024;95:249-259.

Neuroimaging Characteristics of Hearing Loss in the Mayo Clinic Study of Aging.

OBJECTIVE: To investigate the association between standard pure tone and speech audiometry with neuroimaging characteristics reflective of aging and dementia in older adults. STUDY DESIGN: Prospective population-based study. SETTING: Single tertiary care referral center. METHODS: Participants from the Mayo Clinic Study of aging 60 years old or older with normal cognition or mild cognitive impairment, baseline neuroimaging, and a behavioral audiogram associated with neuroimaging were eligible for study. Imaging modalities included structural MRI (sMRI) and fluid-attenuated inversion recovery MRI (FLAIR-MRI; N = 605), diffusion tensor imaging MRI (DTI-MRI; N = 444), and fluorodeoxyglucose-positron emission tomography (FDG-PET; N = 413). Multivariable logistic and linear regression models were used to evaluate associations with neuroimaging outcomes. RESULTS: Mean (SD) pure tone average (PTA) was 33 (15) dB HL and mean (SD) word recognition score (WRS) was 91% (14). There were no significant associations between audiometric performance and cortical thinning assessed by sMRI. Each 10-dB increase in PTA was associated with increased likelihood of abnormal white-matter hyperintensity (WMH) from FLAIR-MRI (odds ratio 1.26, P = .02). From DTI-MRI, participants with <100% WRSs had significantly lower fractional anisotropy in the genu of the corpus callosum (parameter estimate [PE] -0.012, P = .008) compared to those with perfect WRSs. From FDG-PET, each 10% decrease in WRSs was associated with decreased uptake in the anterior cingulate cortex (PE -0.013, P = .001). CONCLUSION: Poorer audiometric performance was not significantly associated with cortical thinning but was associated with white matter damage relevant to cerebrovascular disease (increased abnormal WMH, decreased corpus callosum diffusion). These neuroimaging results suggest a pathophysiologic link between hearing loss and cerebrovascular disease.

Associations Between Structural Covariance Network and Antipsychotic Treatment Response in Schizophrenia.

BACKGROUND AND HYPOTHESIS: Schizophrenia is associated with widespread cortical thinning and abnormality in the structural covariance network, which may reflect connectome alterations due to treatment effect or disease progression. Notably, patients with treatment-resistant schizophrenia (TRS) have stronger and more widespread cortical thinning, but it remains unclear whether structural covariance is associated with treatment response in schizophrenia. STUDY DESIGN: We organized a multicenter magnetic resonance imaging study to assess structural covariance in a large population of TRS and non-TRS, who had been resistant and responsive to non-clozapine antipsychotics, respectively. Whole-brain structural covariance for cortical thickness was assessed in 102 patients with TRS, 77 patients with non-TRS, and 79 healthy controls (HC). Network-based statistics were used to examine the difference in structural covariance networks among the 3 groups. Moreover, the relationship between altered individual differentiated structural covariance and clinico-demographics was also explored. STUDY RESULTS: Patients with non-TRS exhibited greater structural covariance compared with HC, mainly in the fronto-temporal and fronto-occipital regions, while there were no significant differences in structural covariance between TRS and non-TRS or HC. Higher individual differentiated structural covariance was associated with lower general scores of the Positive and Negative Syndrome Scale in the non-TRS group, but not in the TRS group. CONCLUSIONS: These findings suggest that reconfiguration of brain networks via coordinated cortical thinning is related to treatment response in schizophrenia. Further longitudinal studies are warranted to confirm if greater structural covariance could serve as a marker for treatment response in this disease.

Disease Progression Patterns of Brain Morphology in Schizophrenia: More Progressed Stages in Treatment Resistance.

BACKGROUND AND HYPOTHESIS: Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. STUDY DESIGN: In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning analysis. STUDY RESULTS: SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (P = .001). The GP-CX type presented earlier stages than the pure CX type (P = .009). CONCLUSIONS: The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker.

Personalized brain MRI revealed distinct functional and anatomical disruptions in Creutzfeldt-Jakob disease and Alzheimer's disease.

AIMS: Creutzfeldt-Jakob disease (CJD) is a lethal neurodegenerative disorder, which leads to a rapidly progressive dementia. This study aimed to examine the cortical alterations in CJD, changes in these brain characteristics over time, and the differences between CJD and Alzheimer's disease (AD) that show similar clinical manifestations. METHODS: To obtain reliable, subject-specific functional measures, we acquired 24 min of resting-state fMRI data from each subject. We applied an individual-based approach to characterize the functional brain organization of 10 patients with CJD, 8 matched patients with AD, and 8 normal controls. We measured cortical atrophy as well as disruption in resting-state functional connectivity (rsFC) and then investigated longitudinal brain changes in a subset of CJD patients. RESULTS: CJD was associated with widespread cortical thinning and weakened rsFC. Compared with AD, CJD showed distinct atrophy patterns and greater disruptions in rsFC. Moreover, the longitudinal data demonstrated that the progressive cortical thinning and disruption in rsFC mainly affected the association rather than the primary cortex in CJD. CONCLUSIONS: CJD shows unique anatomical and functional disruptions in the cerebral cortex, distinct from AD. Rapid progression of CJD affects both the cortical thickness and rsFC in the association cortex.

Improving prediction of psychosis in youth at clinical high-risk: pre-baseline symptom duration and cortical thinning as moderators of the NAPLS2 risk calculator.

BACKGROUND: Clinical implementation of risk calculator models in the clinical high-risk for psychosis (CHR-P) population has been hindered by heterogeneous risk distributions across study cohorts which could be attributed to pre-ascertainment illness progression. To examine this, we tested whether the duration of attenuated psychotic symptom (APS) worsening prior to baseline moderated performance of the North American prodrome longitudinal study 2 (NAPLS2) risk calculator. We also examined whether rates of cortical thinning, another marker of illness progression, bolstered clinical prediction models. METHODS: Participants from both the NAPLS2 and NAPLS3 samples were classified as either 'long' or 'short' symptom duration based on time since APS increase prior to baseline. The NAPLS2 risk calculator model was applied to each of these groups. In a subset of NAPLS3 participants who completed follow-up magnetic resonance imaging scans, change in cortical thickness was combined with the individual risk score to predict conversion to psychosis. RESULTS: The risk calculator models achieved similar performance across the combined NAPLS2/NAPLS3 sample [area under the curve (AUC) = 0.69], the long duration group (AUC = 0.71), and the short duration group (AUC = 0.71). The shorter duration group was younger and had higher baseline APS than the longer duration group. The addition of cortical thinning improved the prediction of conversion significantly for the short duration group (AUC = 0.84), with a moderate improvement in prediction for the longer duration group (AUC = 0.78). CONCLUSIONS: These results suggest that early illness progression differs among CHR-P patients, is detectable with both clinical and neuroimaging measures, and could play an essential role in the prediction of clinical outcomes.

The effect of inflammation markers on cortical thinning in major depressive disorder: A possible mediator of depression and cortical changes.

BACKGROUND: Major depressive disorder (MDD) is a prevalent mental health condition with significant societal impact. Owing to the intricate biological diversity of MDD, treatment efficacy remains limited. Immune biomarkers have emerged as potential predictors of treatment response, underscoring the interaction between the immune system and the brain. This study investigated the relationship between cytokine levels and cortical thickness in patients with MDD, focusing on the corticolimbic circuit, to elucidate the influence of neuroinflammation on structural brain changes and contribute to a deeper understanding of the pathophysiology of MDD. METHOD: A total of 114 patients with MDD and 101 healthy controls (HC) matched for age, sex, and body mass index (BMI) were recruited. All participants were assessed for depression severity using the Hamilton Depression Rating Scale (HDRS), and 3.0 T T1 weighted brain MRI data were acquired. Additionally, cytokine levels were measured using a highly sensitive bead-based multiplex immunosorbent assay. RESULTS: Patients diagnosed with MDD exhibited notably elevated levels of interleukin-6 (p = 0.005) and interleukin-8 (p = 0.005), alongside significant cortical thinning in the left anterior cingulate gyrus and left superior frontal gyrus, with these findings maintaining significance even after applying Bonferroni correction. Furthermore, increased interleukin-6 and interleukin-8 levels in patients with MDD are associated with alterations in the left frontomarginal gyrus and right anterior cingulate cortex (ACC). CONCLUSIONS: This suggests a potential influence of neuroinflammation on right ACC function in MDD patients, warranting longitudinal research to explore interleukin-6 and interleukin-8 mediated neurotoxicity in MDD vulnerability and brain morphology changes.

Toll-Like Receptor mRNA Levels in Schizophrenia: Association With Complement Factors and Cingulate Gyrus Cortical Thinning.

BACKGROUND AND HYPOTHESES: Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. STUDY DESIGN: Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. STUDY RESULTS: We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. CONCLUSIONS: The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.