Cortical Patterns Research Articles

Cortical Morphometric Similarity Remodeling in Traumatic Brain Injury Links Cognitive Impairments with Transcriptional Changes and Type-Specific Cells.

The heterogeneous injuries and resulting cognitive deficits pose significant challenges in the clinical management of mild traumatic brain injury (mTBI). However, the pathophysiological mechanisms related to heterogeneities of mTBI are still unclear. This study aims to explore the mechanisms underlying brain remodeling by examining the morphometric similarity (MS) alterations and corresponding transcriptomic signatures across adult and pediatric mTBI (adult mTBI: 112 acute patients, 47 follow-up chronic patients, 66 healthy controls [HCs]; pediatric mTBI: 30 acute patients, 31 HCs). A healthy adult cohort (N = 840) is included to derive the modularized brain MS networks representing interregional cortical connectivity. Subsequently, cortical MS remodeling patterns are identified involving mostly MS increases in the frontal modules with typical high MS and decreases in the occipital module with typical low MS, with more pronounced changes observed in the developing brain with mTBI. The abnormal MS changes are correlated with variable cognitive impairments. Moreover, cortical MS remodeling is also associated with the genes enriched in CA1 pyramidal cells and neuron-specific biological processes. The transcription-related cortical remodeling in mTBI might reveal the disruption of brain cellular architecture. Therapeutic modalities to intervene in specific cortex and tackle CA1 over-activation might better encircle the neurobiology of TBI.

Cortical structural degeneration and functional network connectivity changes in patients with subcortical vascular cognitive impairment.

To explore the structural basis of functional network connectivity (FNC) changes and early cortical degenerative patterns in subcortical vascular cognitive impairment (SVCI). We prospectively included SVCI cases and healthy controls (HCs). FNC alterations were evaluated using group-independent component analysis of resting-state functional MRI data. Cortical microstructural and macrostructural alterations were assessed using gray matter-based spatial statistics analysis with neurite orientation dispersion and density imaging and cortical thickness analysis with FreeSurfer software on T1-weighted images, respectively. Spearman correlation analyses were performed to assess relationships between FNC alterations and cortical microstructural/macrostructural alterations and between FNC, cortical thickness, or neurite density index (NDI)/orientation dispersion index (ODI) alterations and cognitive performance. Forty-six SVCI patients and 73 HCs were recruited. FNC analysis showed lower network connectivity between the visual network (VN) and sensorimotor network (SMN) in SVCI, positively correlated with information processing speed (p=0.008) and negatively with summary SVD score (p = 0.037). Cortical microstructural analyses exhibited a lower NDI, mainly in the VN and default mode network (DMN) areas (PFWE < 0.05, cluster > 100 voxels), and lower ODI, mainly in the SMN and DMN areas (PFWE < 0.05, cluster > 100 voxels) in SVCI, both of which were related to cognitive function (p < 0.05). However, cortical thickness did not differ between groups. Lower NDI in the lateral occipital cortex was linked to lower VN-SMN connectivity in SVCI (p = 0.002). Cortical microstructural alterations may serve as the basis for FNC changes in SVCI.

Probing Autism and ADHD subtypes using cortical signatures of the T1w/T2w-ratio and morphometry.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental conditions that share genetic etiology and frequently co-occur. Given this comorbidity and well-established clinical heterogeneity, identifying individuals with similar brain signatures may be valuable for predicting clinical outcomes and tailoring treatment strategies. Cortical myelination is a prominent developmental process, and its disruption is a candidate mechanism for both disorders. Yet, no studies have attempted to identify subtypes using T1w/T2w-ratio, a magnetic resonance imaging (MRI) based proxy for intracortical myelin. Moreover, cortical variability arises from numerous biological pathways, and multimodal approaches can integrate cortical metrics into a single network. We analyzed data from 310 individuals aged 2.6-23.6years, obtained from the Province of Ontario Neurodevelopmental (POND) Network consisting of individuals diagnosed with ASD (n=136), ADHD (n=100), and typically developing (TD) individuals (n=74). We first tested for differences in T1w/T2w-ratio between diagnostic categories and controls. We then performed unimodal (T1w/T2w-ratio) and multimodal (T1w/T2w-ratio, cortical thickness, and surface area) spectral clustering to identify diagnostic-blind subgroups. Linear models revealed no statistically significant case-control differences in T1w/T2w-ratio. Unimodal clustering mostly isolated single individual- or minority clusters, driven by image quality and intensity outliers. Multimodal clustering suggested three distinct subgroups, which transcended diagnostic boundaries, showing separate cortical patterns but similar clinical and cognitive profiles. T1w/T2w-ratio features were the most relevant for demarcation, followed by surface area. While our analysis revealed no significant case-control differences, multimodal clustering incorporating the T1w/T2w-ratio among cortical features holds promise for identifying biologically similar subsets of individuals with neurodevelopmental conditions.

Venlafaxine-induced serotonin syndrome causing bilateral cerebral strokes: a case report

A 21-year-old Caucasian woman was admitted to our neurologic intermediate care unit after attempting suicide by ingesting an estimated 15 g venlafaxine (Trevilor retard®), adding up to a serum concentration of approximately 17,943 μg/l. Brain magnetic resonance imaging (MRI) revealed bilateral cortical restricted-diffusion patterns, indicating ischemic lesions. We report a case of venlafaxine-induced serotonin syndrome most likely cumulating in diffuse artery vasospasm due to an autonomic effect mediated by the serotonergic and adrenergic systems, causing myocardial and cerebral injuries. The serotonin syndrome was treated symptomatically by administering fluids and benzodiazepines and managing the hyperthermia using paracetamol; also, medication with venlafaxine was stopped, and the hypoglycemia was treated. After 6 days, our patient was discharged to the psychiatric facility with no remaining neurologic deficit. The case report provides evidence of ischemic stroke as a rare adverse event of venlafaxine intoxication. Furthermore, we aim to increase awareness of hypoglycemia and epileptic seizures as complications of venlafaxine intoxication. In addition, we demonstrate important pitfalls in the diagnostic procedure and propose a treatment regimen for the underlying serotonin syndrome.

Dopamine D1 receptor activation in the striatum is sufficient to drive reinforcement of anteceding cortical patterns.

Timed dopamine signals underlie reinforcement learning, favoring neural activity patterns that drive behaviors with positive outcomes. In the striatum, dopamine activates five dopamine receptors (D1R-D5R), which are differentially expressed in striatal neurons. However, the role of specific dopamine receptors in reinforcement is poorly understood. Using our cell-specific D1R photo-agonist, we find that D1R activation in D1-expressing neurons in the dorsomedial striatum is sufficient to reinforce preceding neural firing patterns in defined ensembles of layer 5 cortico-striatal neurons of the mouse motor cortex. The reinforcement is cumulative and time dependent, with an optimal effect when D1R activation follows the selected neural pattern after a short interval. Our results show that D1R activation in striatal neurons can selectively reinforce cortical activity patterns, independent of a behavioral outcome or a reward, crucially contributing to the fundamental mechanisms that support cognitive functions like learning, memory, and decision-making.

Wearable non-invasive neuroprosthesis for targeted sensory restoration in neuropathy

Peripheral neuropathy (PN), the most common complication of diabetes, leads to sensory loss and associated health issues as pain and increased fall risk. However, present treatments do not counteract sensory loss, but only partially manage its consequences. Electrical neural stimulation holds promise to restore sensations, but its efficacy and benefits in PN damaged nerves are yet unknown. We designed a wearable sensory neuroprosthesis (NeuroStep) providing targeted neurostimulation of the undamaged nerve portion and assessed its functionality in 14 PN participants. Our system partially restored lost sensations in all participants through a purposely calibrated neurostimulation, despite PN nerves being less sensitive than healthy nerves (N = 22). Participants improved cadence and functional gait and reported a decrease of neuropathic pain after one day. Restored sensations activated cortical patterns resembling naturally located foot sensations. NeuroStep restores real-time intuitive sensations in PN participants, holding potential to enhance functional and health outcomes while advancing effective non-invasive neuromodulation.

Cortical Tau Aggregation Patterns Associated With Apraxia in Patients With Alzheimer Disease.

Apraxia is a frequently observed symptom in Alzheimer disease (AD), but the causal pathomechanism underlying this dysfunction is not well understood. Previous studies have demonstrated associations between various cognitive dysfunctions in AD and cortical tau deposition in specific brain areas, suggesting a causal relationship. Thus, we hypothesized that specific regional patterns of tau pathology in praxis-related brain regions may be associated with apraxic deficits in AD. For this purpose, we performed PET imaging with the second-generation tau-PET tracer [18F]PI-2620 in a well-defined group of patients with AD (N = 33) who had been systematically assessed for apraxia. Patients with a biomarker-confirmed diagnosis of AD were recruited in addition to a sample of cognitively unimpaired (CU1) control participants. Both groups underwent apraxia assessments with the Dementia Apraxia Screening Test. In addition, PET imaging with [18F]PI-2620 was performed to assess tau pathology in the patients with AD. To specifically investigate the association of apraxia severity with regional tau pathology, we compared the PET data from this group with an independent sample of amyloid-negative cognitively intact participants (CU2) by generation of z-score deviation maps and submitted these maps to a voxel-based multiple regression analysis. A total of 120 participants (39% female) with a mean age of 67.9 (9.2) years were included in the study (AD = 33; CU1; N = 33; CU2; N = 54). We identified a significant correlation between circumscribed clusters of tau aggregation in praxis-related brain regions (including parietal (angular gyrus), temporal, and occipital regions) and severity of apraxia in patients with AD. By contrast, no significant correlations between tau tracer uptake in primary motor cortex or subcortical brain regions and apraxia were observed. These results suggest that tau deposition in specific cortical praxis-related brain regions may induce local neuronal dysfunction leading to a dose-dependent functional decline in praxis performance in AD. The awareness of this relationship could further refine a differentiated individual diagnostic characterization and classification of patients with AD.

The 'Janus A' gene encodes a polo-kinase whose loss creates a dorsal/ventral intracellular homeosis in the ciliate, Tetrahymena.

Genetic studies on the protist, Tetrahymena thermophila provide a glimpse into the unexpectedly rich world of intracellular patterning that unfolds within the ciliate cell cortex. Ciliate pattern studies provide a useful counterpoint to animal models of pattern formation in that the unicellular model draws attention away from fields of cells (or nuclei) as the principal players in the metazoan pattern paradigm, focusing instead on fields of ciliated basal bodies serving as sources of positional information. In this study, we identify JANA, a Polo kinase of Tetrahymena, that serves as an important factor driving global, circumferential pattern. Loss of function of JanA results in global, mirror-duplication of ventral organelles on the dorsal surface: a kind of intracellular homeosis that has been named the 'janus' phenotype. Gain of function (over-expression) reduces or even eliminates cortical organelles within the ventral 'hemi-cell'. GFP-tagging reveals that JanA decorates basal bodies predominantly within the left-dorsal hemi-cell. These results led us to propose a model in which the default state of cortical patterning is a mirror-image assemblage of cortical organelles including oral apparatus, contractile vacuole pores and cytoproct. JanA normally suppresses organelle assembly in the dorsal hemi-cellular cortex, resulting in a simple, ventral assemblage of these organelles, a 'half-pattern' as it were. PLK inhibitors produce a janus phenocopy, but reveal other unanticipated roles for PLK activities involving more local patterning events that control organelle dimensions and organization. We discuss results in light of metazoan studies in which PLK activity links cell cycle control to intracellular symmetry breaking.

Comprehensive Analysis of Neurologic Complications Following Transradial Cerebral Angiography.

Transradial access (TRA) for cerebral angiography has become more popular due to fewer complications and greater patient comfort compared to transfemoral access. However, the frequency and nature of neurologic complications linked to TRA remain unclear. This study aimed to determine the incidence of symptomatic neurologic complications after transradial cerebral angiography, identify risk factors, and characterize clinical and imaging features of these complications. We retrospectively analyzed 1,679 consecutive cases of transradial cerebral angiography from a single institution between January 2018 and December 2020. Neurologic complications were defined as any symptomatic changes confirmed by diffusion-weighted imaging revealing ischemic lesions. A case-control matching method was used to enhance the reliability of the results. Clinical, procedural, and anatomical factors were examined for predictors of neurologic complications. Neurologic complications occurred in 1.0% (n=19) of cases, with 85% occurring within six hours post-procedure. No significant predictors of neurologic complications could be identified among the clinical, procedural, or anatomical factors assessed. Overall, 58% of patients experienced transient or reversible complications. Patients with permanent symptoms had mild to moderate disability (mRS scores of 1 or 2), with no severe disability (mRS score ≥3). Diffusion-weighted imaging commonly showed multifocal cortical or subcortical ischemic patterns, typically affecting the right middle cerebral artery territory or multiple territories, suggesting embolic mechanisms as a potential cause. Neurologic complications following transradial cerebral angiography were rare but occurred early in the post-procedural period. The observed ischemic patterns, particularly the right-sided predominance, suggest embolic mechanisms as a potential cause. However, further large-scale, multicenter prospective studies are essential to identify risk factors more clearly and enhance patient safety in this increasingly utilized transradial approach. ACA＝ anterior cerebral artery; ICAS＝ intracranial atherosclerotic stenosis; PCA＝ posterior cerebral artery; SCA＝ subclavian artery; TFA＝ transfemoral access; TRA＝ Transradial access; VAO＝ vertebral artery orifice; VBA＝ vertebrobasilar artery.

The Relationship Between Reduced Hand Dexterity and Brain Structure Abnormality in Older Adults.

Hand dexterity is affected by normal aging and neuroinflammatory processes in the brain. Understanding the relationship between hand dexterity and brain structure in neurotypical older adults may be informative about prodromal pathological processes, thus providing an opportunity for earlier diagnosis and intervention to improve functional outcomes. this study investigates the associations between hand dexterity and brain measures in neurotypical older adults (≥65 years) using the Nine-Hole Peg Test (9HPT) and magnetic resonance imaging (MRI). Elastic net regularized regression revealed that reduced hand dexterity in dominant and non-dominant hands was associated with an enlarged volume of the left choroid plexus, the region implicated in neuroinflammatory and altered myelination processes, and reduced myelin content in the left frontal operculum, the region implicated in motor imagery, action production, and higher-order motor functions. Distinct neural mechanisms underlying hand dexterity in dominant and non-dominant hands included the differences in caudate and thalamic volumes as well as altered cortical myelin patterns in frontal, temporal, parietal, and occipital regions supporting sensorimotor and visual processing and integration, attentional control, and eye movements. Although elastic net identified more predictive features for the dominant vs. non-dominant hand, the feature stability was higher for the latter, thus indicating higher generalizability for the non-dominant hand model. Our findings suggest that the 9HPT for hand dexterity might be a cost-effective screening tool for early detection of neuroinflammatory and neurodegenerative processes. Longitudinal studies are needed to validate our findings in a larger sample and explore the potential of hand dexterity as an early clinical marker.

Cuneus atrophy and Parkinsonian phenoconversion in cognitively unimpaired patients with isolated REM sleep behavior disorder.

Isolated rapid-eye-movement sleep behavior disorder (iRBD) is a strong predictor of Parkinson's disease and Dementia with Lewy bodies. Previous studies indicate that cortical atrophy in iRBD patients may be linked to cognitive impairment, but the pattern of atrophy is inconsistently reported. This study aimed to elucidate cortical atrophy patterns in a cognitively unimpaired iRBD cohort, focusing on regions associated with cognitive functions, particularly the cuneus/precuneus, and evaluated the predictive value for future phenoconversion. We conducted voxel-based morphometry and region of interest (ROI) analysis of structural MRI scans of 36 healthy controls and 19 iRBD patients, nine of whom also received a 3-year follow-up MRI scan. The iRBD patients were followed clinically for 8years, and time-to-event analyses, using Cox regression, were performed based on baseline ROI volumes. The iRBD patients had lower gray-matter volume in the cuneus/precuneus region as well as in subcortical structures (caudate nuclei and putamen) compared to controls. Eight iRBD patients developed either Parkinson's disease (N = 4) or Dementia with Lewy bodies (N = 4) during the follow-up period. Time-to-event analyses showed that lower right cuneus volume was associated with a higher risk of phenoconversion to alpha-synuclein-linked Parkinsonism in the iRBD patients (Hazard ratio = 13.0, CI: 1.53-110), and correlated with shorter time to conversion. In addition, lower volumes of the bilateral precuneus trended to indicate a higher risk of phenoconversion. These findings suggest a potential predictive value of cuneus and precuneus volumes in identifying iRBD patients at risk of disease progression, even before the onset of cognitive impairment.

Cortical hypometabolism in Parkinson's disease is linked to cholinergic basal forebrain atrophy.

Cortical hypometabolism on FDG-PET is a well-established neuroimaging biomarker of cognitive impairment in Parkinson's disease (PD), but its pathophysiologic origins are incompletely understood. Cholinergic basal forebrain (cBF) degeneration is a prominent pathological feature of PD-related cognitive impairment and may contribute to cortical hypometabolism through cholinergic denervation of cortical projection areas. Here, we investigated in-vivo associations between subregional cBF volumes on 3T-MRI, cortical hypometabolism on [18F]FDG-PET, and cognitive deficits in a cohort of 95 PD participants with varying degrees of cognitive impairment. We further assessed the spatial correspondence of the cortical pattern of cBF-associated hypometabolism with the pattern of cholinergic denervation in PD as assessed by [18F]FEOBV-PET imaging of presynaptic cholinergic terminal density in a second cohort. Lower volume of the cortically-projecting posterior cBF, but not of the anterior cBF, was significantly associated with extensive neocortical hypometabolism [p(FDR) < 0.05], which mediated the association between cBF atrophy and cognitive impairment (mediated proportion:43%, p < 0.001). In combined models, posterior cBF atrophy explained more variance in cortical hypometabolism (R2 = 0.26, p < 0.001) than local atrophy in the cortical areas themselves (R2 = 0.16, p = 0.01). Topographic correspondence analysis with the [18F]FEOBV-PET pattern revealed that cortical areas showing most pronounced cBF-associated hypometabolism correspond to those showing most severe cholinergic denervation in PD (Spearman's ρ = 0.57, p < 0.001). In conclusion, posterior cBF atrophy in PD is selectively associated with hypometabolism in denervated cortical target areas, which mediates the effect of cBF atrophy on cognitive impairment. These data provide first-time in-vivo evidence that cholinergic degeneration represents a principle pathological correlate of cortical hypometabolism underlying cognitive impairment in PD.

Link Prediction of Cortical Atrophy in Alzheimer’s Disease using Morphometric Correlation Networks

AbstractBackgroundPredictive biomarkers characterizing disease progression are called for in the context of emerging treatments for Alzheimer’s disease. We implemented a link prediction model on morphometric correlation networks(MCN) generated from structural MRI.MethodHigh‐resolution T1MPRAGE images were retrospectively collected at two timepoints (interval 2.6 ± 1.2 years) for each of the 32 AD patients (AD)(mean age 74.6 ± 6.8, 14F/18M) and age‐matched cognitively normal controls (CN)(n = 32, mean age 75.0 ± 6.3, 16F/16M) from Alzheimer’s Disease Neuroimaging Initiative database. Images were processed using Freesurfer(version7.2) cortical reconstruction pipeline followed by cortical volume quantification. Whole‐brain surface‐based analyses (set at p &lt; 0.05 and FDR &lt; 0.05) were performed to identify regions showing significant differences between CN and AD, and significant atrophy between two timepoints across AD followed by computation of interregional correlations of cortical volume changes. Topological robustness of the MCNs for both timepoints were quantified to assess the network robustness of AD in response to the removal of predominant nodes. The MCN was used to build a link prediction model. Graph embedding was implemented to learn and extract features of each node in the MCN, and the light gradient boosting machine algorithm was applied to classify the cortical changes as atrophy. The AUC(area under the receiver operating characteristic curve) was used to evaluate the model’s performance.ResultAD showed widespread cortical volume reduction. When examining the longitudinal cortical atrophy, the left superior temporal gyrus (STGl,p = 0.0108), precuneus (p = 0.0262), inferior(IPLl, p = 0.0019) and superior parietal lobule (SPLl,p = 0.0007), lingual gyrus(LGl,p = 0.0004); the right lateral occipital cortex (LOCr,p = 0.0168) and hippocampus(HCP r,p&lt;0.0001); and bilateral supramarginal gyri(SMGl,p = 0.0227; r,p = 0.0181) showed significant volume loss (Fig. 1) and were identified as predominant nodes in the MCN that led the co‐atrophy as AD progressed (Fig. 2). With AD progression, robustness was weaker and removal of predominant nodes significantly reduced network resilience. The link prediction model predicted the cortical atrophy pattern in AD with AUC of 0.97 (Fig. 3).ConclusionWe successfully implemented a model to predict progression of cortical atrophy and identified atrophy‐leading brain regions in AD. Future clinical translation of our approach can serve as an imaging biomarker.

Type 2 diabetes and Alzheimer's disease share common cortical neurodegenerative patterns

AbstractBackgroundType 2 diabetes (T2D) is a prevalent health condition associated with cognitive impairment and dementia. T2D induces adverse effects not only on the pancreas but also on the liver, kidneys, muscles, fat cells, and, notably, the brain. Both T2D and Alzheimer's disease (AD) exhibit associations with neurodegeneration, yet the extent of their shared patterns of brain atrophy remains poorly understood, potentially indicating common pathways. The primary objectives were to assess the similarity between neural degeneration patterns in T2D and AD and to identify commonalities between these two diseases.MethodWe employed linear models to compare neurodegeneration patterns linked to T2D and AD. A total of 43,172 participants from the United Kingdom Biobank (UKBB) (3,479 with T2D) and 8,378 from ADNI (871 with AD) were included in our study. We selected Free Surfer‐derived cortical thickness measures extracted from T1‐weighted MRI, age, sex, and blood biomarkers of T2D. The age range for UKBB was 40‐70 years, while for ADNI, it was 55‐97 years. We filtered data for individuals aged 55 and older, normalized features, and created age‐ and sex‐matched groups. We then created cortical atrophy maps using linear regression models for each group. Comparison of the AD and T2D maps was performed using permutation‐based tests accounting for spatial autocorrelation.ResultOur findings revealed similar patterns of neural degeneration in T2D and AD brain maps, particularly in the frontal, parietal, temporal, and occipital lobes, suggesting shared neuroanatomical alterations. Statistically significant overlap was observed in atrophy patterns between AD and T2D patients. T2D individuals exhibited greater atrophy in brain regions affected in AD, such as the hippocampus. Permutation analysis indicated no significant difference between the impact of T2D and AD on brain regions, supporting the notion that T2D is a substantial risk factor for AD.ConclusionThis study enhances our understanding of the similarities in how T2D and AD impact the brain, highlighting the potential connection between these conditions. Further research is warranted to explore underlying mechanisms and implications for clinical interventions.

Utility of CSF biomarkers in assessing neurodegeneration in Early‐Onset Alzheimer’s disease

AbstractBackgroundThere is a significant need for biomarkers of neurodegenerative burden in Early‐onset Alzheimer’s disease (EOAD). Evidence suggests that levels of specific CSF biomarkers (e.g., Neurofilament light (NfL), Synaptosomal‐Associated Protein (SNAP‐25), neurogranin, Visinin‐like protein 1 (VILIP‐1), Aß 42/40, phospho‐tau and total tau) index the extent of neurodegeneration in dementing illnesses. However, it remains unclear whether these biomarkers correlate to cortical atrophy patterns in EOAD. Based on prior work demonstrating correlations between NfL, SNAP‐25, neurogranin and Aß 42/40 CSF levels and cognitive impairment in EOAD (Dage et al. 2023), we hypothesized that these biomarkers (and not VILIP‐1, phospho‐tau or total tau) would variably predict cortical atrophy within our recently described EOAD signature (Touroutoglou et al. 2023).MethodWe recruited 92 EOAD patients. In each patient, atrophy within the EOAD cortical signature were calculated as W‐scores (i.e., Z‐scores adjusted for age and sex relative to a sample of healthy controls). We first ran a simple regression analysis of each of the 7 CSF biomarkers and W‐scores in the EOAD signature across EOAD patients. We then entered the biomarkers with significant correlations to the EOAD signature into a stepwise regression analysis with backward elimination to ascertain the most parsimonious model predicting atrophy in the EOAD signature. As a control region not expected to be related to these biomarkers, we assessed correlations to calcarine fissure cortical atrophy.ResultAs predicted, we observed a significant correlation between CSF levels of NfL, SNAP‐25, neurogranin and Aß 42/40 and atrophy within the EOAD signature. After entering these four biomarkers into the stepwise regression analysis, the most parsimonious model identified complementary contributions of NfL, SNAP‐25, and Aß 42/40, in predicting atrophy in the EOAD signature. There were no correlations between any biomarker and calcarine atrophy.ConclusionSelected CSF biomarkers in EOAD patients predict the degree of atrophy within the EOAD cortical signature. Ongoing work includes correlating these biomarkers with topographical atrophy patterns on the whole‐brain voxel‐wise level. Our results suggest that certain CSF biomarkers could assess neurodegenerative burden within EOAD individuals. This would provide valuable information regarding disease progression for clinical care and clinical trials involving disease‐modifying therapies.

Type 2 diabetes and Alzheimer's disease share common cortical neurodegenerative patterns

Type 2 diabetes and Alzheimer's disease share common cortical neurodegenerative patterns

Subsequent Memory Effects in Cortical Pattern Similarity Differ by Semantic Class.

Although living and nonliving stimuli are known to rely on distinct brain regions during perception, it is largely unknown if their episodic memory encoding mechanisms differ as well. To investigate this issue, we asked participants to encode object pictures (e.g., a picture of a tiger) and to retrieve them later in response to their names (e.g., word "tiger"). For each of four semantic classes (living-animate, living-inanimate, nonliving-large, and nonliving-small), we examined differences in the similarity in activation patterns (neural pattern similarity [NPS]) for subsequently remembered versus forgotten items. Higher NPS for remembered items suggests an advantage of within-class item similarity, whereas lower NPS for remembered items indicates an advantage for item distinctiveness. We expect NPS within class-specific regions to be higher for remembered than for forgotten items. For example, the parahippocampal cortex has a well-known role in scene processing [Aminoff, E. M., Kveraga, K., & Bar, M. The role of the parahippocampal cortex in cognition. Trends in Cognitive Sciences, 17, 379-390, 2013], and the anterior temporal and inferior frontal gyrus have well-known roles in object processing [Clarke, A., & Tyler, L. K. Object-specific semantic coding in human perirhinal cortex. Journal of Neuroscience, 34, 4766-4775, 2014]. As such, we expect to see higher NPS for remembered items in these regions pertaining to scenes and objects, respectively. Consistent with this hypothesis, in fusiform, parahippocampal, and retrosplenial regions, higher NPS predicted memory for subclasses of nonliving objects, whereas in the left inferior frontal and left retrosplenial regions, lower NPS predicted memory for subclasses of living objects. Taken together, the results support the idea that subsequent memory depends on a balance of similarity and distinctiveness and demonstrate that the neural mechanisms of episodic encoding differ across semantic categories.

Functional anatomy of the subthalamic nucleus and the pathophysiology of cardinal features of Parkinson's disease unraveled by focused ultrasound ablation.

The subthalamic nucleus (STN) modulates basal ganglia output and plays a fundamental role in the pathophysiology of Parkinson's disease (PD). Blockade/ablation of the STN improves motor signs in PD. We assessed the topography of focused ultrasound subthalamotomy (n = 39) by voxel-based lesion-symptom mapping to identify statistically validated brain voxels with the optimal effect against each cardinal feature and their respective cortical connectivity patterns by diffusion-weighted tractography. Bradykinesia and rigidity amelioration were associated with ablation of the rostral motor STN subregion connected to the supplementary motor and premotor cortices, whereas antitremor effect was explained by lesioning the posterolateral STN projection to the primary motor cortex. These findings were corroborated prospectively in another PD cohort (n = 12). This work concurs with recent deep brain stimulation findings that suggest different corticosubthalamic circuits underlying each PD cardinal feature. Our results provide sound evidence in humans of segregated anatomy of subthalamic-cortical connections and their distinct role in PD pathophysiology and normal motor control.

Patterns of tau, amyloid and synuclein pathology in ageing, Alzheimer's disease and synucleinopathies.

Alzheimer's disease (AD) is neuropathologically defined by deposits of misfolded hyperphosphorylated tau (HP-tau) and β-amyloid. Lewy body (LB) dementia, which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is characterised pathologically by α-synuclein aggregates. HP-tau and β-amyloid can also occur as copathologies in LB dementia, and a diagnosis mixedAD/DLB can be made if present in sufficient quantities. We hypothesised the spread of these abnormal proteins selectively affects vulnerable areas, resulting in pathologic regional covariance that differentially associates with pre-mortem clinical characteristics. Our aims were to map regional quantitative pathology (HP-tau, β-amyloid, α-synuclein) and investigate the spatial distributions from tissue microarray (TMA) post-mortem samples across healthy aging, AD and LB dementia. The study involved 159 clinico-pathologically diagnosed human post-mortem brains (48 controls, 47 AD, 25 DLB, 20 mixedAD/DLB, 19 PDD). The burden of HP-tau, β-amyloid and α-synuclein was quantitatively assessed in cortical and subcortical areas. Principal components (PC) analysis was applied across all cases to determine the pattern nature of HP-tau, β-amyloid and α-synuclein. Further analyses explored the relationships of these pathological patterns with cognitive and symptom variables. Cortical (tauPC1) and temporolimbic (tauPC2) patterns were observed for HP-tau. For β-amyloid, a cortical-subcortical pattern (amylPC1) was identified. For α-synuclein, four patterns emerged: 'posterior temporal - occipital (synPC1)', 'anterior temporal-frontal (synPC2)', 'parieto-cingulate-insula (synPC3)', and 'frontostriatal-amygdala (synPC4)'. Distinct synPC scores were apparent among DLB, mixedAD/DLB and PDD, and may relate to different spreading patterns of α-synuclein pathology. In dementia, cognitive measures correlated with tauPC1, tauPC2 and amylPC1 pattern scores (P≤0.02), whereas such variables did not relate to α-synuclein parameters in these or combined LB dementia cases. Mediation analysis then revealed that in the presence of amylPC1, tauPC1 had a direct effect on global cognition in dementia (n=65, P=0.04), while tauPC1 mediated the relationship between amylPC1 and cognition through the indirect pathway (amylPC1→ tauPC1 → global cognition) (P<0.05). Lastly, in synucleinopathies, synPC1 and synPC4 pattern scores were associated with visual hallucinations and motor impairment, respectively (P=0.02). In conclusion, distinct patterns of α-synuclein pathology were apparent in LB dementia, which could explain some of the disease heterogeneity and differing spreading patterns among these conditions. Visual hallucinations and motor severity were associated with specific α-synuclein topographies in LB dementia that may be important to the clinical phenotype, and could, after necessary testing/validation, be integrated into semi-quantitative routine pathological assessment.

Effects of parental socioeconomic status on offspring's fetal neurodevelopment.

Emerging evidence underscores the prenatal period's critical role in shaping later cognition and health, influenced by an intricate interplay of parental genetic and environmental factors. Birth weight is commonly used as a retrospective indicator of fetal development, but recent focus has shifted to more specific proxies of neurodevelopment, like cortical sulcal patterns, which are established in utero and remain stable after birth. This study aimed to elucidate the interrelated effects of parental socioeconomic status, brain volume, birth weight, and sulcal patterns in the anterior cingulate cortex. Utilizing structural Magnetic Resonance Imaging (MRI), parental educational attainment, and related polygenic risk scores, the study analyzed 203 healthy right-handed participants aged 9 to 18. Structural equation modeling demonstrated that the anterior cingulate cortex sulcal pattern is influenced by parental socioeconomic status and global brain volume, with socioeconomic status correlating with a polygenic risk score. These findings suggest that prenatal neurodevelopmental processes may mediate the intergenerational transmission of inequalities.