Hemispheric asymmetry in cortical thinning reflects intrinsic organization of the neurotransmitter systems and homotopic functional connectivity.

Hemispheric lateralization and its origins have been of great interest in neuroscience for over a century. The left-right asymmetry in cortical thickness may stem from differential maturation of the cerebral cortex in the two hemispheres. Here, we investigated the spatial pattern of hemispheric differences in cortical thinning during adolescence, and its relationship with the density of neurotransmitter receptors and homotopic functional connectivity. Using longitudinal data from IMAGEN study (N = 532), we found that many cortical regions in the frontal and temporal lobes thinned more in the right hemisphere than in the left. Conversely, several regions in the occipital and parietal lobes thinned less in the right (vs. left) hemisphere. We then revealed that regions thinning more in the right (vs. left) hemispheres had higher density of neurotransmitter receptors and transporters in the right (vs. left) side. Moreover, the hemispheric differences in cortical thinning were predicted by homotopic functional connectivity. Specifically, regions with stronger homotopic functional connectivity showed a more symmetrical rate of cortical thinning between the left and right hemispheres, compared with regions with weaker homotopic functional connectivity. Based on these findings, we suggest that the typical patterns of hemispheric differences in cortical thinning may reflect the intrinsic organization of the neurotransmitter systems and related patterns of homotopic functional connectivity.

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.

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.

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.

Accelerated cortical thinning precedes and predicts conversion to psychosis: The NAPLS3 longitudinal study of youth at clinical high-risk.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis.

Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-ß-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stßinteraction = -0.062, P = 0.032), higher education level (Stßinteraction = -0.072, P = 0.011) and higher intracranial volume (Stßinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.

Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.

Regional cortical thinning, demyelination and iron loss in cerebral small vessel disease.

The link between white matter hyperintensities (WMH) and cortical thinning is thought to be an important pathway by which WMH contributes to cognitive deficits in cerebral small vessel disease (SVD). However, the mechanism behind this association and the underlying tissue composition abnormalities are unclear. The objective of this study is to determine the association between WMH and cortical thickness, and the in vivo tissue composition abnormalities in the WMH-connected cortical regions. In this cross-sectional study, we included 213 participants with SVD who underwent standardized protocol including multimodal neuroimaging scans and cognitive assessment (i.e. processing speed, executive function and memory). We identified the cortex connected to WMH using probabilistic tractography starting from the WMH and defined the WMH-connected regions at three connectivity levels (low, medium and high connectivity level). We calculated the cortical thickness, myelin and iron of the cortex based on T1-weighted, quantitative R1, R2* and susceptibility maps. We used diffusion-weighted imaging to estimate the mean diffusivity of the connecting white matter tracts. We found that cortical thickness, R1, R2* and susceptibility values in the WMH-connected regions were significantly lower than in the WMH-unconnected regions (all Pcorrected < 0.001). Linear regression analyses showed that higher mean diffusivity of the connecting white matter tracts were related to lower thickness (ß = -0.30, Pcorrected < 0.001), lower R1 (ß = -0.26, Pcorrected = 0.001), lower R2* (ß = -0.32, Pcorrected < 0.001) and lower susceptibility values (ß = -0.39, Pcorrected < 0.001) of WMH-connected cortical regions at high connectivity level. In addition, lower scores on processing speed were significantly related to lower cortical thickness (ß = 0.20, Pcorrected = 0.030), lower R1 values (ß = 0.20, Pcorrected = 0.006), lower R2* values (ß = 0.29, Pcorrected = 0.006) and lower susceptibility values (ß = 0.19, Pcorrected = 0.024) of the WMH-connected regions at high connectivity level, independent of WMH volumes and the cortical measures of WMH-unconnected regions. Together, our study demonstrated that the microstructural integrity of white matter tracts passing through WMH is related to the regional cortical abnormalities as measured by thickness, R1, R2* and susceptibility values in the connected cortical regions. These findings are indicative of cortical thinning, demyelination and iron loss in the cortex, which is most likely through the disruption of the connecting white matter tracts and may contribute to processing speed impairment in SVD, a key clinical feature of SVD. These findings may have implications for finding intervention targets for the treatment of cognitive impairment in SVD by preventing secondary 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.

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).

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.

Multimodal and multiscale evidence for network-based cortical thinning in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is associated with widespread, irregular cortical thickness (CT) reductions across the brain. However, little is known regarding mechanisms that govern spatial distribution of the reductions. METHODS: We combined multimodal MRI and genetic, cytoarchitectonic and chemoarchitectonic data to examine structural covariance, functional synchronization, gene co-expression, cytoarchitectonic similarity and chemoarchitectonic covariance between regions atrophied in MDD. RESULTS: Regions atrophied in MDD were associated with significantly higher structural covariance, functional synchronization, gene co-expression and chemoarchitectonic covariance. These results were robust against methodological variations in brain parcellation and null model, reproducible in patients and controls, and independent of age at onset of MDD. Despite no significant differences in the cytoarchitectonic similarity, MDD-related CT reductions were susceptible to specific cytoarchitectonic class of association cortex. Further, we found that nodal shortest path lengths to disease epicenters derived from structural (right supramarginal gyrus) and chemoarchitectonic covariance (right sulcus intermedius primus) networks of healthy brains were correlated with the extent to which a region was atrophied in MDD, supporting the transneuronal spread hypothesis that regions closer to the epicenters are more susceptible to MDD. Finally, we showed that structural covariance and functional synchronization among regions atrophied in MDD were mainly related to genes enriched in metabolic and membrane-related processes, driven by genes in excitatory neurons, and associated with specific neurotransmitter transporters and receptors. CONCLUSIONS: Altogether, our findings provide empirical evidence for and genetic and molecular insights into connectivity-constrained CT thinning in MDD.

Baseline long-term potentiation-like cortical plasticity is associated with longitudinal cortical thinning in healthy adults and in adults with bipolar disorder type II.

The precise neurobiological processes underlying cerebral cortical thinning in aging and psychiatric illnesses remain undetermined, yet aging- and synaptic dysfunction-related loss of synapses are potentially important mechanisms. We used long-term potentiation-like plasticity of the visual evoked potential as an index of synaptic function in the cortex and hypothesized that plasticity at baseline would be negatively associated with future cortical thinning in healthy adults and in adults with bipolar disorder type II. Thirty-two healthy adults and 15 adults with bipolar disorder type II underwent electroencephalography-based measurement of visual evoked potential plasticity and 3T magnetic resonance imaging of the brain at baseline and a follow-up brain scan on average 2.3 years later. The relationships between visual evoked potential plasticity at baseline and longitudinal cortical thickness changes were examined using Freesurfer and the Permutation Analysis of Linear Models tool. The analyses showed a negative association between the plasticity of the N1 visual evoked potential amplitude at baseline and thinning rate in the medial and lateral parietal and medial occipital cortices in healthy adults and in the right medial occipital cortex in the total sample of healthy adults and adults with bipolar disorder type II, indicating greater thinning over time in subjects with less N1 plasticity (pFWER < .05). Although preliminary, the results indicate an association between visual evoked potential plasticity and the future rate of cortical thinning in healthy adults and in bipolar disorder type II, supporting the hypothesis that cortical thinning might be related to synaptic dysfunction.

Gene transcriptional expression of cortical thinning during childhood and adolescence.

The cognitive and behavioral development of children and adolescents is closely related to the maturation of brain morphology. Although the trajectory of brain development has been depicted in detail, the underlying biological mechanism of normal cortical morphological development in childhood and adolescence remains unclear. By combining the Allen Human Brain Atlas dataset with two single-site magnetic resonance imaging data including 427 and 733 subjects from China and the United States, respectively, we performed partial least squares regression and enrichment analysis to explore the relationship between the gene transcriptional expression and the development of cortical thickness in childhood and adolescence. We found that the spatial model of normal cortical thinning during childhood and adolescence is associated with genes expressed predominantly in astrocytes, microglia, excitatory and inhibitory neurons. Top cortical development-related genes are enriched for energy-related and DNA-related terms and are associated with psychological and cognitive disorders. Interestingly, there is a great deal of similarity between the findings derived from the two single-site datasets. This fills the gap between early cortical development and transcriptomes, which promotes an integrative understanding of the potential biological neural mechanisms.

Turning and multitask gait unmask gait disturbance in mild-to-moderate multiple sclerosis: Underlying specific cortical thinning and connecting fibers damage.

Multiple sclerosis (MS) causes gait and cognitive impairments that are partially normalized by compensatory mechanisms. We aimed to identify the gait tasks that unmask gait disturbance and the underlying neural correlates in MS. We included 25 patients with MS (Expanded Disability Status Scale score: median 2.0, interquartile range 1.0-2.5) and 19 healthy controls. Fast-paced gait examinations with inertial measurement units were conducted, including straight or circular walking with or without cognitive/motor tasks, and the timed up and go test (TUG). Receiver operating characteristic curve analysis was performed to distinguish both groups by the gait parameters. The correlation between gait parameters and cortical thickness or fractional anisotropy values was examined by using three-dimensional T1-weighted imaging and diffusion tensor imaging, respectively (corrected p < .05). Total TUG duration (>6.0 s, sensitivity 88.0%, specificity 84.2%) and stride velocity during cognitive dual-task circular walking (<1.12 m/s, 84.0%, 84.2%) had the highest discriminative power of the two groups. Deterioration of these gait parameters was correlated with thinner cortical thickness in regional areas, including the left precuneus and left temporoparietal junction, overlapped with parts of the default mode network, ventral attention network, and frontoparietal network. Total TUG duration was negatively correlated with fractional anisotropy values in the deep cerebral white matter areas. Turning and multitask gait may be optimal to unveil partially compensated gait disturbance in patients with mild-to-moderate MS through dynamic balance control and multitask processing, based on the structural damage in functional networks.

Tau pathology as determinant of changes in atrophy and cerebral blood flow: a multi-modal longitudinal imaging study.

PURPOSE: Tau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF. METHODS: We included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 ± 7.5 years, 44% female, 57% amyloid-ß positive [Aß +], 26 cognitively impaired [CI]) who underwent dynamic [18F]flortaucipir PET and structural MRI at baseline and 25 ± 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [18F]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [18F]flortaucipir PET binding potential (BPND) and R1 values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BPND in Braak I, III/IV, and V/VI regions and cortical thickness or R1 in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BPND in case of analyses with annual change as determinant. All analyses were performed in Aß- cognitively normal (CN) individuals and Aß+ (CN and CI) individuals separately. RESULTS: In Aß+ individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either Aß+ or Aß- individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in Aß + individuals. CONCLUSION: We showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal.

Basal Forebrain Atrophy, Cortical Thinning, and Amyloid-ß Status in Parkinson's disease-Related Cognitive Decline.

BACKGROUND: Degeneration of the cortically-projecting cholinergic basal forebrain (cBF) is a well-established pathologic correlate of cognitive decline in Parkinson's disease (PD). In Alzheimer's disease (AD) the effect of cBF degeneration on cognitive decline was found to be mediated by parallel atrophy of denervated cortical areas. OBJECTIVES: To examine whether the association between cBF degeneration and cognitive decline in PD is mediated by parallel atrophy of cortical areas and whether these associations depend on the presence of comorbid AD pathology. METHODS: We studied 162 de novo PD patients who underwent serial 3 T magnetic resonance imaging scanning (follow-up: 2.33 ± 1.46 years) within the Parkinson's Progression Markers Initiative. cBF volume and regional cortical thickness were automatically calculated using established procedures. Individual slopes of structural brain changes and cognitive decline were estimated using linear-mixed models. Associations between longitudinal cBF degeneration, regional cortical thinning, and cognitive decline were assessed using regression analyses and mediation effects were assessed using nonparametric bootstrap. Complementary analyses assessed the effect of amyloid-ß biomarker positivity on these associations. RESULTS: After controlling for global brain atrophy, longitudinal cBF degeneration was highly correlated with faster cortical thinning (PFDR < 0.05), and thinning in cBF-associated cortical areas mediated the association between cBF degeneration and cognitive decline (rcBF-MoCA = 0.30, P < 0.001). Interestingly, both longitudinal cBF degeneration and its association with cortical thinning were largely independent of amyloid-ß status. CONCLUSIONS: cBF degeneration in PD is linked to parallel thinning of cortical target areas, which mediate the effect on cognitive decline. These associations are independent of amyloid-ß status, indicating that they reflect proper features of PD pathophysiology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Serum neurofilament light concentrations are associated with cortical thinning in anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is characterized by severe emaciation and drastic reductions of brain mass, but the underlying mechanisms remain unclear. The present study investigated the putative association between the serum-based protein markers of brain damage neurofilament light (NF-L), tau protein, and glial fibrillary acidic protein (GFAP) and cortical thinning in acute AN. METHODS: Blood samples and magnetic resonance imaging scans were obtained from 52 predominantly adolescent, female patients with AN before and after partial weight restoration (increase in body mass index >14%). The effect of marker levels before weight gain and change in marker levels on cortical thickness (CT) was modeled at each vertex of the cortical surface using linear mixed-effect models. To test whether the observed effects were specific to AN, follow-up analyses exploring a potential general association of marker levels with CT were conducted in a female healthy control (HC) sample (n = 147). RESULTS: In AN, higher baseline levels of NF-L, an established marker of axonal damage, were associated with lower CT in several regions, with the most prominent clusters located in bilateral temporal lobes. Tau protein and GFAP were not associated with CT. In HC, no associations between damage marker levels and CT were detected. CONCLUSIONS: A speculative interpretation would be that cortical thinning in acute AN might be at least partially a result of axonal damage processes. Further studies should thus test the potential of serum NF-L to become a reliable, low-cost and minimally invasive marker of structural brain alterations in AN.

Reduced cerebral cortex thickness is related to overexpression of exosomal miR-146a-5p in medication-free patients with major depressive disorder.

BACKGROUND: Previous studies have confirmed that miR-146a-5p overexpression suppresses neurogenesis, thereby enhancing depression-like behaviors. However, it remains unclear how miR-146a-5p dysregulation produces in vivo brain structural abnormalities in patients with major depressive disorder (MDD). METHODS: In this case-control study, we combined cortical morphology analysis of magnetic resonance imaging (MRI) and miR-146a-5p quantification to investigate the neuropathological effect of miR-146a-5p on cortical thickness in MDD patients. Serum-derived exosomes that were considered to readily cross the blood-brain barrier and contain miR-146a-5p were isolated for miRNA quantification. Moreover, follow-up MRI scans were performed in the MDD patients after 6 weeks of antidepressant treatment to further validate the clinical relevance of the relationship between miR-146a-5p and brain structural abnormalities. RESULTS: In total, 113 medication-free MDD patients and 107 matched healthy controls were included. Vertex-vise general linear model revealed miR-146a-5p-dependent cortical thinning in MDD patients compared with healthy individuals, i.e., overexpression of miR-146a-5p was associated with reduced cortical thickness in the left orbitofrontal cortex (OFC), anterior cingulate cortex, bilateral lateral occipital cortices (LOCs), etc. Moreover, this relationship between baseline miR-146a-5p and cortical thinning was nonsignificant for all regions in the patients who had received antidepressant treatment, and higher baseline miR-146a-5p expression was found to be related to greater longitudinal cortical thickening in the left OFC and right LOC. CONCLUSIONS: The findings of this study reveal a relationship between miR-146a-5p overexpression and cortical atrophy and thus may help specify the in vivo mediating effect of miR-146a-5p dysregulation on brain structural abnormalities in patients with MDD.

Cortical thickness is related to cognitive-motor automaticity and attention allocation in individuals with Alzheimer's disease: a regions of interest study.

Alzheimer's disease (AD) is characterized by a distinct pattern of cortical thinning and resultant changes in cognition and function. These result in prominent deficits in cognitive-motor automaticity. The relationship between AD-related cortical thinning and decreased automaticity is not well-understood. We aimed to investigate the relationship between cortical thickness regions-of-interest (ROI) and automaticity and attention allocation in AD using hypothesis-driven and exploratory approaches. We performed an ROI analysis of 46 patients with AD. Data regarding MR images, demographic characteristics, cognitive-motor dual task performance, and cognition were extracted from medical records. Cortical thickness was calculated from MR T1 images using FreeSurfer. Data from the dual task assessment was used to calculate the combined dual task effect (cDTE), a measure of cognitive-motor automaticity, and the modified attention allocation index (mAAI). Four hierarchical multiple linear regression models were conducted regressing cDTE and mAAI separately on (1) hypothesis-generated ROIs and (2) exploratory ROIs. For cDTE, cortical thicknesses explained 20.5% (p = 0.014) and 25.9% (p = 0.002) variability in automaticity in the hypothesized ROI and exploratory models, respectively. The dorsal lateral prefrontal cortex (DLPFC) (ß = - 0.479, p = 0.018) and superior parietal cortex (SPC) (ß = 0.467, p = 0.003), and were predictors of automaticity. For mAAI, cortical thicknesses explained 20.7% (p = 0.025) and 28.3% (p = 0.003) variability in attention allocation in the hypothesized ROI and exploratory models, respectively. Thinning of SPC and fusiform gyrus were associated with motor prioritization (ß = - 0.405, p = 0.013 and ß = - 0.632, p = 0.004, respectively), whereas thinning of the DLPFC was associated with cognitive prioritization (ß = 0.523, p = 0.022). Cortical thinning in AD was related to cognitive-motor automaticity and task prioritization, particularly in the DLPFC and SPC. This suggests that these regions may play a primary role in automaticity and attentional strategy during dual-tasking.