Subclinical atherosclerosis and brain health in midlife: Rationale and design of the PESA-Brain study.

RATIONALE: Cognitive decline and dementia have been reportedly linked to atherosclerosis, the main cause of cardiovascular disease. Cohort studies identifying early brain alterations associated with subclinical atherosclerosis are warranted to understand the potential of prevention strategies before cerebral damage becomes symptomatic and irreversible. METHODS & DESIGN: The Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal observational cohort study that recruited 4,184 asymptomatic middle-aged individuals (40-54 years) in 2010 in Madrid (Spain) to thoroughly characterize subclinical atherosclerosis development over time. In this framework, the PESA-Brain study has been designed to identify early structural, functional and vascular brain changes associated with midlife atherosclerosis and cardiovascular risk factors. The PESA-Brain study targets 1,000 participants at the 10-year follow-up PESA visit and consists of thorough neuropsychological testing, advanced multimodal neuroimaging, and quantification of blood-based neuropathological biomarkers. PRIMARY HYPOTHESIS: We hypothesize that, in middle-age, the presence of cardiovascular risk factors and a high burden of subclinical atherosclerosis will be associated with structural, functional and vascular brain alterations, greater amyloid burden and subtle cognitive impairment. We further hypothesize that the link between subclinical atherosclerosis and poor brain health in midlife will be mediated by cerebrovascular pathology and intracranial atherosclerosis. ENROLLMENT DATES: The PESA-Brain study started in October 2020 and is estimated to be completed by December 2024. CONCLUSION: This study is in a unique position to unveil novel relationships between cardiovascular and brain alterations in the health-to-disease transition, which may have important implications for interventional and therapeutic approaches. CLINICALTRIALS: gov identifier: NCT01410318.

Previous pregnancies might mitigate cortical brain differences associated with surgical menopause.

Surgical menopause causes a sharp drop in estrogen levels in middle-aged women, thus preventing the gradual physiological adaptation that is characteristic of the perimenopause. Previous studies suggest that surgical menopause might increase the risk of dementia later in life. In addition, the transition to motherhood entails long-lasting endocrine and neuronal adaptations. We compared differences in whole-brain cortical volume between women who reached menopause by surgery and a group of women who reached spontaneous non-surgical menopause and determined whether these cortical differences were influenced by previous childbearing. Using surface-based neuroimaging techniques, we investigated cortical volume differences in 201 middle-aged women (134 women who experienced non-surgical menopause, 78 of whom were parous women; and 67 women who experienced surgical menopause, 39 of whom were parous women). We found significant atrophy in the frontal and temporal regions in women who experienced surgical menopause. Nulliparous women with surgical menopause showed significant lower cortical volume in the left temporal gyrus extending to the medial temporal lobe cortex, as well as in the precuneus bilaterally compared to parous women with surgical menopause; whereas our results revealed no significant differences between parous women with surgical menopause and both parous and nulliparous women who reached a non-surgical menopause. Furthermore, in the surgical menopause group, we found a negative correlation between cortical volume and age at first pregnancy in the temporal lobe. Our study suggests that the long-term brain remodeling of parity may mitigate the neural impact of the sudden drop in estrogen levels that characterizes surgical menopause.

ABLE: Automated Brain Lines Extraction Based on Laplacian Surface Collapse.

The archetypical folded shape of the human cortex has been a long-standing topic for neuroscientific research. Nevertheless, the accurate neuroanatomical segmentation of sulci remains a challenge. Part of the problem is the uncertainty of where a sulcus transitions into a gyrus and vice versa. This problem can be avoided by focusing on sulcal fundi and gyral crowns, which represent the topological opposites of cortical folding. We present Automated Brain Lines Extraction (ABLE), a method based on Laplacian surface collapse to reliably segment sulcal fundi and gyral crown lines. ABLE is built to work on standard FreeSurfer outputs and eludes the delineation of anastomotic sulci while maintaining sulcal fundi lines that traverse the regions with the highest depth and curvature. First, it segments the cortex into gyral and sulcal surfaces; then, each surface is spatially filtered. A Laplacian-collapse-based algorithm is applied to obtain a thinned representation of the surfaces. This surface is then used for careful detection of the endpoints of the lines. Finally, sulcal fundi and gyral crown lines are obtained by eroding the surfaces while preserving the connectivity between the endpoints. The method is validated by comparing ABLE with three other sulcal extraction methods using the Human Connectome Project (HCP) test-retest database to assess the reproducibility of the different tools. The results confirm ABLE as a reliable method for obtaining sulcal lines with an accurate representation of the sulcal topology while ignoring anastomotic branches and the overestimation of the sulcal fundi lines. ABLE is publicly available via https://github.com/HGGM-LIM/ABLE .

Longitudinal Allometry of Sulcal Morphology in Health and Schizophrenia.

Scaling between subcomponents of folding and total brain volume (TBV) in healthy individuals (HIs) is allometric. It is unclear whether this is true in schizophrenia (SZ) or first-episode psychosis (FEP). This study confirmed normative allometric scaling norms in HIs using discovery and replication samples. Cross-sectional and longitudinal diagnostic differences in folding subcomponents were then assessed using an allometric framework. Structural imaging from a longitudinal (Sample 1: HI and SZ, nHI Baseline = 298, nSZ Baseline = 169, nHI Follow-up = 293, nSZ Follow-up = 168, totaling 1087 images, all individuals ≥ 2 images, age 16-69 years) and a cross-sectional sample (Sample 2: nHI = 61 and nFEP = 89, age 10-30 years), all human males and females, is leveraged to calculate global folding and its nested subcomponents: sulcation index (SI, total sulcal/cortical hull area) and determinants of sulcal area: sulcal length and sulcal depth. Scaling of SI, sulcal area, and sulcal length with TBV in SZ and FEP was allometric and did not differ from HIs. Longitudinal age trajectories demonstrated steeper loss of SI and sulcal area through adulthood in SZ. Longitudinal allometric analysis revealed that both annual change in SI and sulcal area was significantly stronger related to change in TBV in SZ compared with HIs. Our results detail the first evidence of the disproportionate contribution of changes in SI and sulcal area to TBV changes in SZ. Longitudinal allometric analysis of sulcal morphology provides deeper insight into lifespan trajectories of cortical folding in SZ.SIGNIFICANCE STATEMENT Psychotic disorders are associated with deficits in cortical folding and brain size, but we lack knowledge of how these two morphometric features are related. We leverage cross-sectional and longitudinal samples in which we decompose folding into a set of nested subcomponents: sulcal and hull area, and sulcal depth and length. We reveal that, in both schizophrenia and first-episode psychosis, (1) scaling of subcomponents with brain size is different from expected scaling laws and (2) caution is warranted when interpreting results from traditional methods for brain size correction. Longitudinal allometric scaling points to loss of sulcal area as a principal contributor to loss of brain size in schizophrenia. These findings advance the understanding of cortical folding atypicalities in psychotic disorders.

Tract-specific damage at spinal cord level in pure hereditary spastic paraplegia type 4: a diffusion tensor imaging study.

BACKGROUND: SPG4 is a subtype of hereditary spastic paraplegia (HSP), an upper motor neuron disorder characterized by axonal degeneration of the corticospinal tracts and the fasciculus gracilis. The few neuroimaging studies that have focused on the spinal cord in HSP are based mainly on the analysis of structural characteristics. METHODS: We assessed diffusion-related characteristics of the spinal cord using diffusion tensor imaging (DTI), as well as structural and shape-related properties in 12 SPG4 patients and 14 controls. We used linear mixed effects models up to T3 in order to analyze the global effects of 'group' and 'clinical data' on structural and diffusion data. For DTI, we carried out a region of interest (ROI) analysis in native space for the whole spinal cord, the anterior and lateral funiculi, and the dorsal columns. We also performed a voxelwise analysis of the spinal cord to study local diffusion-related changes. RESULTS: A reduced cross-sectional area was observed in the cervical region of SPG4 patients, with significant anteroposterior flattening. DTI analyses revealed significantly decreased fractional anisotropy (FA) and increased radial diffusivity at all the cervical and thoracic levels, particularly in the lateral funiculi and dorsal columns. The FA changes in SPG4 patients were significantly related to disease severity, measured as the Spastic Paraplegia Rating Scale score. CONCLUSIONS: Our results in SPG4 indicate tract-specific axonal damage at the level of the cervical and thoracic spinal cord. This finding is correlated with the degree of motor disability.

Corticospinal tract and motor cortex degeneration in pure hereditary spastic paraparesis type 4 (SPG4).

Objective: SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. HSP is considered an upper motor neuron disorder characterized by progressive retrograde degeneration, or "dying-back" phenomenon, of the corticospinal tract's longest axons. Neuroimaging studies mainly focus on white matter changes and, although previous studies reported cortical thinning in complicated HSP forms, cortical changes remain unclear in SPG4 patients. This work aimed to compare changes in white matter microstructure and cortical thickness between 12 SPG4 patients and 22 healthy age-matched controls. We also explore whether white matter alterations are related to cortical thickness and their correlation with clinical symptoms. Methods: we used fixel-based analysis, an advanced diffusion-weighted imaging technique, and probabilistic tractography of the corticospinal tracts. We also analyzed cortical morphometry using whole-brain surface-based and atlas-based methods in sensorimotor areas. Results: SPG4 patients showed bilateral involvement in the corticospinal tracts; this was more intense in the distal portion than in the upper segments and was associated with the degree of clinical impairment. We found a significant correlation between disease severity and fiber density and cross-section of the corticospinal tracts. Furthermore, corticospinal tract changes were significantly correlated with bilateral cortical thinning in the precentral gyrus in SPG4 patients. Conclusions: Our data point to axonal damage of the corticospinal motor neurons in SPG4 patients might be related to cortical thinning in motor regions.

Sex Differences in Lifespan Trajectories and Variability of Human Sulcal and Gyral Morphology.

Sex differences in the development and aging of human sulcal morphology have been understudied. We charted sex differences in trajectories and inter-individual variability of global sulcal depth, width, and length, pial surface area, exposed (hull) gyral surface area, unexposed sulcal surface area, cortical thickness, gyral span, and cortex volume across the lifespan in a longitudinal sample (700 scans, 194 participants 2 scans, 104 three scans, age range: 16-70 years) of neurotypical males and females. After adjusting for brain volume, females had thicker cortex and steeper thickness decline until age 40 years; trajectories converged thereafter. Across sexes, sulcal shortening was faster before age 40, while sulcal shallowing and widening were faster thereafter. Although hull area remained stable, sulcal surface area declined and was more strongly associated with sulcal shortening than with sulcal shallowing and widening. Males showed greater variability for cortex volume and lower variability for sulcal width. Our findings highlight the association between loss of sulcal area, notably through sulcal shortening, with cortex volume loss. Studying sex differences in lifespan trajectories may improve knowledge of individual differences in brain development and the pathophysiology of neuropsychiatric conditions.

Intradialytic hypotension and relationship with cognitive function and brain morphometry.

BACKGROUND: The haemodynamic stress brought about by dialysis could justify the loss of structural and functional integrity of the central nervous system (CNS). The main objective of this study was to analyse the relationship between intradialytic hypotension (IDH) and cognitive function and brain morphometry. METHODS: The cross-sectional KIDBRAIN study (Cohort Study of Morphological Changes of the Brain by MRI in Chronic Kidney Disease Patients) included 68 prevalent patients with no history of neurological disorders (cerebrovascular disease and cognitive impairment) undergoing haemodialysis (HD). We analysed 18 non-consecutive dialysis sessions (first three of each month over a 6-month period) and various definitions of IDH were recorded. Global cognitive function (GCF) was assessed using the Mini-Mental State Examination (MMSE) and parameters of structural integrity of the CNS were obtained using volume morphometry magnetic resonance imaging analysis [grey matter (GM), white matter (WM) and hippocampus). RESULTS: A greater number of sessions with IDH were associated with less volume of WM (r = -0.359,P = 0.003) and hippocampus (r = -0.395, P = 0.001) independent of cardiovascular risk factors according to multivariable linear regression models (ß = -0.198, P = 0.046 for WM; ß = -0.253, P = 0.017 for hippocampus). The GCF by the MMSE was 27.3 ± 7.3.1 and was associated with WM volume (ß = 0.403, P = 0.001) independent of GM and hippocampus volume. Symptomatic IDH was associated with GCF (r = -0.420, P < 0.001) in adjusted analysis (ß = -0.339, P = 0.008). CONCLUSIONS: Even when asymptomatic, IDH is associated with a lower WM and hippocampus volume and reduced GCF in patients undergoing HD, thus suggesting greater vulnerability of the brain to the haemodynamic stress that may be generated by a dialysis session.

Do Pregnancy-Induced Brain Changes Reverse? The Brain of a Mother Six Years after Parturition.

Neuroimaging researchers commonly assume that the brain of a mother is comparable to that of a nulliparous woman. However, pregnancy leads to pronounced gray matter volume reductions in the mother's brain, which have been associated with maternal attachment towards the baby. Beyond two years postpartum, no study has explored whether these brain changes are maintained or instead return to pre-pregnancy levels. The present study tested whether gray matter volume reductions detected in primiparous women are still present six years after parturition. Using data from a unique, prospective neuroimaging study, we compared the gray matter volume of 25 primiparous and 22 nulliparous women across three sessions: before conception (n = 25/22), during the first months of postpartum (n = 25/21), and at six years after parturition (n = 7/5). We found that most of the pregnancy-induced gray matter volume reductions persist six years after parturition (classifying women as having been pregnant or not with 91.67% of total accuracy). We also found that brain changes at six years postpartum are associated with measures of mother-to-infant attachment. These findings open the possibility that pregnancy-induced brain changes are permanent and encourage neuroimaging studies to routinely include pregnancy-related information as a relevant demographic variable.

Thalamic atrophy in patients with pure hereditary spastic paraplegia type 4.

SPG4 is an autosomal dominant pure form of hereditary spastic paraplegia (HSP) caused by mutations in the SPAST gene. HSP is considered an upper motor neuron disorder characterized by progressive spasticity and weakness of the lower limbs caused by degeneration of the corticospinal tract. In other neurodegenerative motor disorders, the thalamus and basal ganglia are affected, with a considerable impact on disease progression. However, only a few works have studied these brain structures in HSP, mainly in complex forms of this disease. Our research aims to detect potential alterations in the volume and shape of the thalamus and various basal ganglia structures by comparing 12 patients with pure HSP and 18 healthy controls. We used two neuroimaging procedures: automated segmentation of the subcortical structures (thalamus, hippocampus, caudate nucleus, globus pallidus, and putamen) in native space and shape analysis of the structures. We found a significant reduction in thalamic volume bilaterally, as well as an inward deformation, mainly in the sensory-motor thalamic regions in patients with pure HSP and a mutation in SPG4. We also observed a significant negative correlation between the shape of the thalamus and clinical scores (the Spastic Paraplegia Rating Scale score and disease duration). Moreover, we found a 'Group × Age' interaction that was closely related to the severity of the disease. No differences in volume or in shape were found in the remaining subcortical structures studied. Our results suggest that changes in structure of the thalamus could be an imaging biomarker of disease progression in pHSP.