Lifetime Stressful Events Associated with Alzheimer's Pathologies, Neuroinflammation and Brain Structure in a Risk Enriched Cohort.

OBJECTIVE: Along with the known effects of stress on brain structure and inflammatory processes, increasing evidence suggest a role of chronic stress in the pathogenesis of Alzheimer's disease (AD). We investigated the association of accumulated stressful life events (SLEs) with AD pathologies, neuroinflammation, and gray matter (GM) volume among cognitively unimpaired (CU) individuals at heightened risk of AD. METHODS: This cross-sectional cohort study included 1,290 CU participants (aged 48-77) from the ALFA cohort with SLE, lumbar puncture (n = 393), and/or structural magnetic resonance imaging (n = 1,234) assessments. Using multiple regression analyses, we examined the associations of total SLEs with cerebrospinal fluid (1) phosphorylated (p)-tau181 and Aß1-42/1-40 ratio, (2) interleukin 6 (IL-6), and (3) GM volumes voxel-wise. Further, we performed stratified and interaction analyses with sex, history of psychiatric disease, and evaluated SLEs during specific life periods. RESULTS: Within the whole sample, only childhood and midlife SLEs, but not total SLEs, were associated with AD pathophysiology and neuroinflammation. Among those with a history of psychiatric disease SLEs were associated with higher p-tau181 and IL-6. Participants with history of psychiatric disease and men, showed lower Aß1-42/1-40 with higher SLEs. Participants with history of psychiatric disease and women showed reduced GM volumes in somatic regions and prefrontal and limbic regions, respectively. INTERPRETATION: We did not find evidence supporting the association of total SLEs with AD, neuroinflammation, and atrophy pathways. Instead, the associations appear to be contingent on events occurring during early and midlife, sex and history of psychiatric disease. ANN NEUROL 2024;95:1058-1068.

Functional structure of local connections and differentiation of cerebral cortex areas in the neonate.

Neuroimaging research on functional connectivity can provide valuable information on the developmental differentiation of the infant cerebral cortex into its functional areas. We examined healthy neonates to comprehensively map brain functional connectivity using a combination of local measures that uniquely capture the rich spatial structure of cerebral cortex functional connections. Optimal functional MRI scans were obtained in 61 neonates. Local functional connectivity maps were based on Iso-Distance Average Correlation (IDAC) measures. Single distance maps and maps combining three distinct IDAC measures were used to assess different levels of cortical area functional differentiation. A set of brain areas showed higher connectivity than the rest of the brain parenchyma in each local distance map. These areas were consistent with those supporting basic aspects of the neonatal repertoire of adaptive behaviors and included the sensorimotor, auditory and visual cortices, the frontal operculum/anterior insula (relevant for sucking, swallowing and the sense of taste), paracentral lobule (processing anal and urethral sphincter activity), default mode network (relevant for self-awareness), and limbic-emotional structures such as the anterior cingulate cortex, amygdala and hippocampus. However, the results also indicate that brain areas presumed to be actively developing may not necessarily be mature. In fact, combined distance, second-level maps confirmed that the functional differentiation of the cerebral cortex into functional areas in neonates is far from complete. Our results provide a more comprehensive understanding of the developing brain systems, while also highlighting the substantial developmental journey that the neonatal brain must undergo to reach adulthood.

Texture-based morphometry in relation to apolipoprotein ε4 genotype, ageing and sex in a midlife population.

Brain atrophy and cortical thinning are typically observed in people with Alzheimer's disease (AD) and, to a lesser extent, in those with mild cognitive impairment. In asymptomatic middle-aged apolipoprotein ε4 (ΑPOE4) carriers, who are at higher risk of future AD, study reports are discordant with limited evidence of brain structural differences between carriers and non-carriers of the ε4 allele. Alternative imaging markers with higher sensitivity at the presymptomatic stage, ideally quantified using typically acquired structural MRI scans, would thus be of great benefit for the detection of early disease, disease monitoring and subject stratification. In the present cross-sectional study, we investigated textural properties of T1-weighted 3T MRI scans in relation to APOE4 genotype, age and sex. We pooled together data from the PREVENT-Dementia and ALFA studies focused on midlife healthy populations with dementia risk factors (analysable cohort: 1585 participants; mean age 56.2 ± 7.4 years). Voxel-based and texture (examined features: contrast, entropy, energy, homogeneity) based morphometry was used to identify areas of volumetric and textural differences between APOE4 carriers and non-carriers. Textural maps were generated and were subsequently harmonised using voxel-wise COMBAT. For all analyses, APOE4, sex, age and years of education were used as model predictors. Interactions between APOE4 and age were further examined. There were no group differences in regional brain volume or texture based on APOE4 carriership or when age × APOE4 interactions were examined. Older people tended to have a less homogeneous textural profile in grey and white matter and a more homogeneous profile in the ventricles. A more heterogeneous textural profile was observed for females in areas such as the ventricles, frontal and parietal lobes and for males in the brainstem, cerebellum, precuneus and cingulate. Overall, we have shown the absence of volumetric and textural differences between APOE4 carriers and non-carriers at midlife and have established associations of textural features with ageing and sex.

Time-encoded ASL reveals lower cerebral blood flow in the early AD continuum.

INTRODUCTION: Cerebral blood flow (CBF) is reduced in cognitively impaired (CI) Alzheimer's disease (AD) patients. We checked the sensitivity of time-encoded arterial spin labeling (te-ASL) in measuring CBF alterations in individuals with positive AD biomarkers and associations with relevant biomarkers in cognitively unimpaired (CU) individuals. METHODS: We compared te-ASL with single-postlabel delay (PLD) ASL in measuring CBF in 59 adults across the AD continuum, classified as CU amyloid beta (Aß) negative (-), CU Aß positive (+), and CI Aß+. We sought associations of CBF with biomarkers of AD, cerebrovascular disease, synaptic dysfunction, neurodegeneration, and cognition in CU participants. RESULTS: te-ASL was more sensitive at detecting CBF reduction in the CU Aß+ and CI Aß+ groups. In CU participants, lower CBF was associated with altered biomarkers of Aß, tau, synaptic dysfunction, and neurodegeneration. DISCUSSION: CBF reduction occurs early in the AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF changes in AD. HIGHLIGHTS: Lower CBF can be detected in CU subjects in the early AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF alterations in AD. CBF is linked to biomarkers of AD, synaptic dysfunction, and neurodegeneration.

Neuroimaging Methods for MRI Analysis in CSF Biomarkers Studies.

Among others, the existence of pathophysiological biomarkers such as cerebrospinal fluid (CSF) Aß-42, t-tau, and p-tau preceding the onset of Alzheimer's disease (AD) symptomatology has shifted the conceptualization of AD as a continuum. In addition, magnetic resonance imaging (MRI) enables the study of structural and functional cross-sectional correlates and longitudinal changes in vivo, and therefore, the combination of CSF data and imaging analyses emerges as a synergistic approach to understand the structural correlates related with specific AD-related biomarkers. In this chapter, we describe the methods used in neuroimaging that will allow researchers to combine data on CSF metabolites with imaging analyses.

Omega-3 blood biomarkers relate to brain glucose uptake in individuals at risk of Alzheimer's disease dementia.

INTRODUCTION: Brain glucose hypometabolism is a preclinical feature of Alzheimer's disease (AD). Dietary omega-3 fatty acids promote brain glucose metabolism, but clinical research is incipient. Circulating omega-3s objectively reflect their dietary intake. METHODS: This was a cross-sectional study in 320 cognitively unimpaired participants at increased risk of AD dementia. Using lipidomics, we determined blood docosahexaenoic (DHA) and alpha-linolenic (ALA) acid levels (omega-3s from marine and plant origin, respectively). We assessed brain glucose metabolism using [18-F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). RESULTS: Blood ALA directly related to FDG uptake in brain areas known to be affected in AD. Stronger associations were observed in apolipoprotein E ε4 carriers and homozygotes. For DHA, significant direct associations were restricted to amyloid beta-positive tau-positive participants. DISCUSSION: Blood omega-3 directly relate to preserved glucose metabolism in AD-vulnerable brain regions in individuals at increased risk of AD dementia. This adds to the benefits of omega-3 supplementation in the preclinical stage of AD dementia. Highlights: Blood omega-3s were related to brain glucose uptake in participants at risk of Alzheimer's disease (AD) dementia.Complementary associations were observed for omega-3 from marine and plant sources.Foods rich in omega-3 might be useful in early features of AD.

Structural brain differences in the Alzheimer's disease continuum: Insights into the heterogeneity from a large multi-site neuroimaging consortium.

INTRODUCTION: Neurodegenerative diseases require collaborative, multi-site research to comprehensively grasp their complex and diverse pathological progression, yet there is caution in aggregating global data due to data heterogeneity. The current study investigates brain structure across stages of Alzheimer's disease (AD), and how relationships vary across sources of heterogeneity. METHODS: Using 6 international datasets(n>27,000), associations of structural neuroimaging markers were investigated in relation to the AD continuum via meta-analysis. We investigated whether associations varied across elements of MRI acquisition, study design and populations. RESULTS: Modest differences in associations were found dependent on how data were acquired, however patterns were similar. Preliminary results suggest neuroimaging marker-AD relationships differ across ethnic groups. DISCUSSION: Diversity in data offers unique insights into the neural substrate of AD, however harmonised processing and transparency of data collection is needed. Global collaborations should embrace inherent heterogeneity that exists within the data and quantify its contribution to research findings at the meta-analytical stage.

The mediating role of neuroimaging-derived biological brain age in the association between risk factors for dementia and cognitive decline in middle-aged and older individuals without cognitive impairment: a cohort study.

BACKGROUND: Neuroimaging-based brain-age delta has been shown to be a mediator linking cardiovascular risk factors to cognitive function. We aimed to assess the mediating role of brain-age delta in the association between modifiable risk factors of dementia and longitudinal cognitive decline in middle-aged and older individuals who are asymptomatic, stratified by Alzheimer's disease pathology. We also explored whether the mediation effect is specific to cognitive domain. METHODS: In this cohort study, we included participants from the ALFA+ cohort aged between 45 years and 65 years who were cognitively unimpaired and who had available structural MRI, cerebrospinal fluid ß-amyloid (Aß)42 and Aß40 measurements obtained within 1 year of each other, modifiable risk factors assessment, and cognitive evaluation over 3 years. Participants were recruited from the Barcelonaßeta Brain Research Center (Barcelona, Spain). Included individuals underwent a first assessment between Oct 25, 2016, and Jan 28, 2020, and a follow-up cognitive assessment 3·28 (SD 0·27) years later. We computed brain-age delta and composites of different cognitive function domains (preclinical Alzheimer's cognitive composite [PACC], attention, executive function, episodic memory, visual processing, and language). We used partial least squares path modelling to explore mediation effects in the associations between modifiable risk factors (including cardiovascular, mental health, mood, metabolic or endocrine history, and alcohol use) and changes in cognitive composites. To assess the role of Alzheimer's disease pathology, we computed separate models for Aß-negative and Aß-positive individuals. FINDINGS: Of the 419 participants enrolled in ALFA+, 302 met our inclusion criteria, of which 108 participants were classified as Aß-positive and 194 as Aß-negative. In Aß-positive individuals, brain-age delta partially mediated (percent mediation proportion 15·73% [95% CI 14·22-16·66]) the association between modifiable risk factors and decline in overall cognition (across cognitive domains). Brain-age delta fully mediated (mediation proportion 28·03% [26·25-29·21]) the effect of modifiable risk factors on the PACC, wherein increased values for risk factors correlated with an older brain-age delta, and, consequently, an older brain-age delta was linked to greater PACC decline. This effect appears to be primarily driven by memory decline. Mediation was not significant in Aß-negative individuals (3·52% [0·072-4·17]) on PACC, although path coefficients were not significantly different from those in the Aß-positive group. INTERPRETATION: Our findings suggest that brain-age delta captures the association between modifiable risk factors and longitudinal cognitive decline in middle-aged and older people. In asymptomatic middle-aged and older individuals who are Aß-positive, the pathology might be the strongest driver of cognitive decline, whereas the effect of risk factors is smaller. Our results highlight the potential of brain-age delta as an objective outcome measure for preventive lifestyle interventions targeting cognitive decline. FUNDING: La Caixa Foundation, the TriBEKa Imaging Platform, and the Universities and Research Secretariat of the Catalan Government. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

APOE ɛ4 exacerbates age-dependent deficits in cortical microstructure.

The apolipoprotein E ɛ4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease. However, the mechanisms by which apolipoprotein E ɛ4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein ɛ4 and its interactions with age and education on cortical microstructure in cognitively normal individuals. Data from 1954 participants were included from the PREVENT-Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non-carriers and 757 apolipoprotein E ɛ4 carriers). Structural MRI datasets were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index maps from diffusion MRI datasets. Primary analyses were focused on (i) the main effects of apolipoprotein E ɛ4, and (ii) the interactions of apolipoprotein E ɛ4 with age and education on lobar and vertex-wise Orientation Dispersion Index and implemented using Permutation Analysis of Linear Models. There were apolipoprotein E ɛ4 × age interactions in the temporo-parietal and frontal lobes, indicating steeper age-dependent Orientation Dispersion Index changes in apolipoprotein E ɛ4 carriers. Steeper age-related Orientation Dispersion Index declines were observed among apolipoprotein E ɛ4 carriers with lower years of education. We demonstrated that apolipoprotein E ɛ4 worsened age-related Orientation Dispersion Index decreases in brain regions typically associated with atrophy patterns of Alzheimer's disease. This finding also suggests that apolipoprotein E ɛ4 may hasten the onset age of dementia by accelerating age-dependent reductions in cortical Orientation Dispersion Index.

Bases cerebrales de la atención sostenida y la memoria de trabajo: un estudio de resonancia magnética funcional basado en el Continuous Performance Test / Cerebral networks of sustained attention and working memory: a functional magnetic resonance imaging study based on the Continuous Performance Test

Introducción. Uno de los paradigmas más utilizados en el estudio de la atención es el Continuous Performance Test (CPT). La versión de pares idénticos (CPT-IP) se ha utilizado ampliamente para evaluar los déficits de atención en los trastornos del neurodesarrollo, neurológicos y psiquiátricos. Sin embargo, la localización de la activación cerebral de las redes atencionales varía significativamente según el diseño de resonancia magnética funcional (RMf) usado. Objetivo. Diseñar una tarea para evaluar la atención sostenida y la memoria de trabajo mediante RMf para proporcionar datos de investigación relacionados con la localización y el papel de estas funciones. Sujetos y métodos. El estudio contó con la participación de 40 estudiantes, todos ellos diestros (50%, mujeres; rango: 18-25 años). La tarea de CPT-IP se diseñó como una tarea de bloques, en la que se combinaban los períodos CPT-IP con los de reposo. Resultados. La tarea de CPT-IP utilizada activa una red formada por regiones frontales, parietales y occipitales, y éstas se relacionan con funciones ejecutivas y atencionales. Conclusiones. La tarea de CPT-IP utilizada en nuestro trabajo proporciona datos normativos en adultos sanos para el estudio del sustrato neural de la atención sostenida y la memoria de trabajo. Estos datos podrían ser útiles para evaluar trastornos que cursan con déficits en memoria de trabajo y en atención sostenida (AU)

Introduction. One of the most used paradigms in the study of attention is the Continuous Performance Test (CPT). The identical pairs version (CPT-IP) has been widely used to evaluate attention deficits in developmental, neurological and psychiatric disorders. However, the specific locations and the relative distribution of brain activation in networks identified with functional imaging, varies significantly with differences in task design. AIM. To design a task to evaluate sustained attention using functional magnetic resonance imaging (fMRI), and thus to provide data for research concerned with the role of these functions. SUBJECTS AND METHODS. Forty right-handed, healthy students (50% women; age range: 18-25 years) were recruited. A CPT-IP implemented as a block design was used to assess sustained attention during the fMRI session. RESULTS. The behavioural results from the CPT-IP task showed a good performance in all subjects, higher than 80% of hits. fMRI results showed that the used CPT-IP task activates a network of frontal, parietal and occipital areas, and that these are related to executive and attentional functions. CONCLUSIONS. In relation to the use of the CPT to study of attention and working memory, this task provides normative data in healthy adults, and it could be useful to evaluate disorders which have attentional and working memory déficits (AU)

Cambios en resonancia magnética funcional de la corteza sensitivomotora en pacientes con traumatismo craneoencefálico tras un programa intensivo de rehabilitación / Changes in the functional magnetic resonance imaging of the sensorimotor cortex in traumatic brain injury after intensive rehabilitation

Objetivo. Evaluar el potencial de reorganización de la corteza sensitivomotora en pacientes con traumatismo craneoencefálico (TCE) después de un programa intensivo de rehabilitación. Pacientes y métodos. Se valoraron los cambios en la resonancia magnética funcional (RMf) motora en un paciente de 17 años afecto de TCE grave antes y después de un programa de rehabilitación motora. Las tareas realizadas durante el análisis con RMf fueron: oposición sucesiva del pulgar a los demás dedos de la mano (RMf motora de la mano) y flexión plantar del tobillo y de los dedos (RMf motora del pie), en ambos casos bilateral con períodos de reposo intercalados. Resultados. Previamente al tratamiento, las áreas cerebrales activadas durante la RMf motora de la mano derecha fueron el área motora primaria (M1), el área motora suplementaria (AMS), el área parietal superior y la región poscentral. Para la mano izquierda, las áreas de mayor actividad fueron M1 y cerebelo. Posteriormente al tratamiento, las áreas activadas fueron la región pre y poscentral para la mano derecha y la región precentral para la mano izquierda. Para la función motora del pie, las áreas activadas antes del tratamiento fueron el área paracentral para el pie derecho, y el AMS y el área poscentral para el pie izquierdo. Después del tratamiento, la activación para el pie derecho se vio en el área paracentral, y la activación para el pie izquierdo en el área paracentral y en el AMS. Conclusiones. La disminución de la actividad cortical posterior al tratamiento puede explicarse como una reorganización cortical, que en el presente estudio se correlaciona con los automatismos y habilidades motoras adquiridas por el paciente durante el proceso de rehabilitación (AU)

Aim. To evaluate the potential reorganization of the sensorimotor cortex in a patient with traumatic brain injury after an intensive motor rehabilitation. Patients and methods. A 17-year-old male with severe traumatic brain injury was submitted to functional magnetic resonance imaging (fMRI) analyses of motor control before and after motor rehabilitation. The motor tasks performed during fMRI were finger tapping, ankle plantar flexion, and toe flexion. Results. Prior to treatment, the cerebrally activated areas for the right hand during finger tapping were the primary motor (M1), supplementary motor area (SMA), superior parietal and postcentral areas. For the left hand, the areas were the M1 and the cerebellum. After treatment, the activated areas were the pre and postcentral areas for the right hand and the precentral area for the left hand. For the foot motor-task, the activated areas prior to treatment were the paracentral area for the right foot, and the SMA, paracentral and poscentral areas for the left. After treatment, activation for the right foot was seen in the paracentral area, and activation for the left foot was seen in the paracentral area and SMA. Conclusions. The decrease in the post-treatment activation pattern could be explained as a cortical reorganization, which in the current study was related to motor skill and motor automatism acquired by the patient (AU)

Resultados en el estudio del córtex auditivo mediante resonancia magnética funcional (I): características generales y resultados individuales / Results of a functional magnetic resonance study of the primary auditory cortex (I): general characteristics and individual outcomes

Objetivo: Investigar y demostrar los modelos de activación en el córtex auditivo primario mediante la resonancia magnética funcional (RMf). Material y métodos: Se estimuló la audición, a 32 voluntarios normo oyentes (intervalo de edad, 18-49 años), con tonos de 750 y 2.000 Hz en ciclos de 20 s de estimulación, seguidos por 20 s de reposo. Se empleó un escáner de RM de 1,5 T y la herramienta estadística SPM2. Resultados: Para ambas frecuencias (750 y 2.000 Hz) en 29 de 32 sujetos (90,62 %) se registró una activación cortical auditiva en la circunvolución de Heschl de ambos hemisferios con una p < 0,001. Ante la estimulación auditiva monoaural se ha registrado una activación cortical auditiva bilateral que, generalmente, fue mayor en el hemisferio contralateral al oído estimulado. Conclusiones: Estos resultados demuestran que la RMf es una técnica de imagen útil para la investigación del córtex auditivo. La estimulación monoaural con tonos puros activa, predominantemente, el córtex auditivo contralateral (AU)

Objective: To demonstrate and investigate the activation patterns of the primary auditory cortex (Heschl’s gyrus) using functional magnetic resonance imaging (fMRI). Material and methods: Pure tone stimuli at 750 Hz and 2000 Hz were delivered to the right and left ear of 32 normal-hearing volunteers (18-49 years old) in 20-second on-off cycles. The fMRI data were obtained using a 1.5 Tesla scanner and processed with SPM2. Results: For both tone frequencies, bilateral hemispheric activation was identified in the transverse temporal gyrus (Heschl’s gyrus) in 29 subjects (90.62 %) in response to pure tonestimuli with a probability level of p < 0.001. For monaural stimulation, bilateral hemispheric activation was observed with generally greater extent of activation in the Heschl’s gyrus (HG) contralateral to the stimulated ear. Conclusions: These results demonstrate that fMRI is a useful imaging technique to investigate the auditory cortex. The contralateral auditory cortex is more responsive than the ipsilateral cortex to tones presented monaurally (AU)