Gray Matter Research Articles

Functional network modules overlap and are linked to interindividual connectome differences during human brain development.

The modular structure of functional connectomes in the human brain undergoes substantial reorganization during development. However, previous studies have implicitly assumed that each region participates in one single module, ignoring the potential spatial overlap between modules. How the overlapping functional modules develop and whether this development is related to gray and white matter features remain unknown. Using longitudinal multimodal structural, functional, and diffusion MRI data from 305 children (aged 6 to 14 years), we investigated the maturation of overlapping modules of functional networks and further revealed their structural associations. An edge-centric network model was used to identify the overlapping modules, and the nodal overlap in module affiliations was quantified using the entropy measure. We showed a regionally heterogeneous spatial topography of the overlapping extent of brain nodes in module affiliations in children, with higher entropy (i.e., more module involvement) in the ventral attention, somatomotor, and subcortical regions and lower entropy (i.e., less module involvement) in the visual and default-mode regions. The overlapping modules developed in a linear, spatially dissociable manner, with decreased entropy (i.e., decreased module involvement) in the dorsomedial prefrontal cortex, ventral prefrontal cortex, and putamen and increased entropy (i.e., increased module involvement) in the parietal lobules and lateral prefrontal cortex. The overlapping modular patterns captured individual brain maturity as characterized by chronological age and were predicted by integrating gray matter morphology and white matter microstructural properties. Our findings highlight the maturation of overlapping functional modules and their structural substrates, thereby advancing our understanding of the principles of connectome development.

Clinical and Radiological Profile of Nine Patients with Metachromatic Leukodystrophy

Introduction: Metachromatic leukodystrophy (MLD) is a rare, demyelinating, autosomal recessive lysosomal storage disease caused by a deficiency in the arylsulfatase A enzyme (ASA), which is encoded by ARSA gene. A lack of ASA activity results in an accumulation of sulfatides in the myelin sheaths of both the central and peripheral nervous systems, leading to developmental and neurocognitive progressive deterioration that can be observed in all age groups. Methods: We present a total of 9 patients with MLD with an average age of 61 months, whose clinical, laboratory and cranial magnetic resonance imaging findings were evaluated, and who underwent an ARSA gene molecular analysis. Results: Of the 9 patients, 7 had the late infantile form of the condition, 2 had the juvenile form, and 3 were identified through family screening. The median age at diagnosis was 30 months (min 3–max 73 months), the mean ASA activity value was 2 nmol/h/mgprt and the median cranial MR imaging severity score was 10 (min 5–max 18). The grey and white matter volumes of all patients, evaluated using volBrain software, were within the normal range. At an average age of 48 months, the late-infantile MLD patients were unable to control any body part. Conclusions: Hematopoietic stem cell transplantation (HSCT), a treatment option for both the juvenile and adult forms of MLD in asymptomatic or early symptomatic patients, was performed on two of the asymptomatic and early symptomatic patients, and post-HSCT ASA activity settled within the normal range and their developmental milestones stabilized. It is important to diagnose MLD in the asymptomatic period and newborn screening can support early diagnosis.

Circadian Rhythms Tied to Changes in Brain Morphology in a Densely Sampled Male.

Circadian, infradian, and seasonal changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species. However, the relationship between circadian changes in steroid hormone production and rhythmic changes in brain morphology in humans is largely unknown. Here, we examined the relationship between diurnal fluctuations in steroid hormones and multiscale brain morphology in a precision imaging study of a male who completed 40 MRI and serological assessments at 7 A.M. and 8 P.M. over the course of a month, targeting hormone concentrations at their peak and nadir. Diurnal fluctuations in steroid hormones were tied to pronounced changes in global and regional brain morphology. From morning to evening, total brain volume, gray matter volume, and cortical thickness decreased, coincident with decreases in steroid hormone concentrations (testosterone, estradiol, and cortisol). In parallel, cerebrospinal fluid and ventricle size increased from A.M. to P.M. Global changes were driven by decreases within the occipital and parietal cortices. These findings highlight natural rhythms in brain morphology that keep time with the diurnal ebb and flow of steroid hormones.

Neurotropic Murine β-Coronavirus Infection Causes Differential Expression of Connexin 47 in Oligodendrocyte Subpopulations Associated with Demyelination.

Gap junctions (GJs) play a crucial role in the survival of oligodendrocytes and myelination of the central nervous system (CNS). In this study, we investigated the spatiotemporal changes in the expression of oligodendroglial GJ protein connexin 47 (Cx47), its primary astroglial coupling partner, Cx43, and their association with demyelination following intracerebral infection with mouse hepatitis virus (MHV). Neurotropic strains of MHV, a β-coronavirus, induce an acute encephalomyelitis followed by a chronic demyelinating disease that shares similarities with the human disease multiple sclerosis (MS). Our results reveal that Cx47 GJs are persistently lost in mature oligodendrocytes, not only in demyelinating lesions but also in surrounding normal appearing white and gray matter areas, following an initial loss of astroglial Cx43 GJs during acute infection. At later stages after viral clearance, astroglial Cx43 GJs re-emerge but mature oligodendrocytes fail to fully re-establish GJs with astrocytes due to lack of Cx47 GJ expression. In contrast, at this later demyelinating stage, the increased oligodendrocyte precursor cells appear to exhibit Cx47 GJs. Our findings further highlight varying degrees of demyelination in distinct spinal cord regions, with the thoracic cord showing the most pronounced demyelination. The regional difference in demyelination correlates well with dynamic changes in the proportion of different oligodendrocyte lineage cells exhibiting differential Cx47 GJ expression, suggesting an important mechanism of progressive demyelination even after viral clearance.

Association between Neural Plasticity and Pain-Related Fear in Chronic Ankle Instability: A Structural Neuroimaging Study.

Pain-related movement fear is a contributing factor to residual pain and functional deficits in chronic ankle instability (CAI), but its underlying neural mechanisms remain unclear. We aimed to (1) delineate whether participants with CAI exhibit discernible differences in specific emotion and pain-related brain regions, compared to a healthy control (HC) cohort and (2) explore potential neural mechanisms underlying pain and fear in participants with CAI, with an emphasis on investigating possible associations with pain-related neural plasticity. Cross-sectional study. University research laboratory. 28 participants with CAI (17males and 11 females; age: 31.28±6.31 years) and 28 HCs (16 males and 12 females; age: 30.18±7.59 years). We analyzed T1 structural imaging data from participants and assessed their fear of movement and pain intensity using the Tampa Scale for Kinesiophobia (TSK) and the Visual Analog Scale (VAS) for pain, respectively. We compared the mean gray matter (GM) density of pain-related area between the two groups and their correlations with the TSK and VAS scores. In comparison with the HC group, participants with CAI showed a significant decrease in the mean GM density in the prefrontal cortex (Cohen's d = -0.808) and periaqueductal gray (Cohen's d = -0.934). In participants with CAI, the mean GM density of the prefrontal cortex (PFC) was negatively correlated with the TSK scores (r = -0.531). During intense exercise, the mean GM density of the periaqueductal gray (PAG) was negatively correlated with the VAS scores (r = -0.484). Additionally, TSK scores were positively correlated with VAS scores (r = 0.455). Our exploratory findings suggest that, in participants with CAI, the atrophy of the PFC and PAG may be associated with pain-related fear. Future clinical diagnosis and treatment for CAI should consider the impact of psychological barriers on functional recovery.

How to detect affect recognition alterations in amyotrophic lateral sclerosis.

To define the clinical usability of an affect recognition (AR) battery-the Comprehensive Affect Testing System (CATS)-in an Italian sample of patients with amyotrophic lateral sclerosis (ALS). 96 ALS patients and 116 healthy controls underwent a neuropsychological assessment including the AR subtests of the abbreviated version of the CATS (CATS-A). CATS-A AR subtests and their global score (CATS-A AR Quotient, ARQ) were assessed for their factorial, convergent, and divergent validity. The diagnostic accuracy of each CATS-A AR measure in discriminating ALS patients with cognitive impairment from cognitively normal controls and patients was tested via receiver-operating characteristics analyses. Optimal cut-offs were identified for CATS-A AR measures yielding an acceptable AUC value (≥ .70). The ability of CATS-A ARQ to discriminate between different ALS cognitive phenotypes was also tested. Gray-matter (GM) volumes of controls, ALS with normal (ALS-nARQ), and impaired ARQ score (ALS-iARQ) were compared using ANCOVA models. CATS-A AR subtests and ARQ proved to have moderate-to-strong convergent and divergent validity. Almost all considered CATS-A measures reached acceptable accuracy and diagnostic power (AUC range = .79-.83). ARQ showed to be the best diagnostic measure (sensitivity = .80; specificity = .75) and discriminated between different ALS cognitive phenotypes. Compared to ALS-nARQ, ALS-iARQ patients showed reduced GM volumes in the right anterior cingulate, right middle frontal, left inferior temporal, and superior occipital regions. The AR subtests of the CATS-A, and in particular the CATS-A ARQ, are sound measures of AR in ALS. AR deficits may be a valid marker of frontotemporal involvement in these patients.

Neural network architecture of a mammalian brain

Connectomics research is making rapid advances, although models revealing general principles of connectional architecture are far from complete. Our analysis of 106 published connection reports indicates that the adult rat brain interregional connectome has about 76,940 of a possible 623,310 axonal connections between its 790 gray matter regions mapped in a reference atlas, equating to a network density of 12.3%. We examined the sexually dimorphic network using multiresolution consensus clustering that generated a nested hierarchy of interconnected modules/subsystems with three first-order modules and 157 terminal modules in females. Top-down hierarchy analysis suggests a mirror-image primary module pair in the central nervous system's rostral sector (forebrain-midbrain) associated with behavior control, and a single primary module in the intermediate sector (rhombicbrain) associated with behavior execution; the implications of these results are considered in relation to brain development and evolution. Bottom-up hierarchy analysis reveals known and unfamiliar modules suggesting strong experimentally testable hypotheses. Global network analyses indicate that all hubs are in the rostral module pair, a rich club extends through all three primary modules, and the network exhibits small-world attributes. Simulated lesions of all regions individually enabled ranking their impact on global network organization, and the visual path from the retina was used as a specific example, including the effects of cyclic connection weight changes from the endogenous circadian rhythm generator, suprachiasmatic nucleus. This study elucidates principles of interregional neuronal network architecture for a mammalian brain and suggests a strategy for modeling dynamic structural connectivity.

Association of MicroRNA Expression and Serum Neurofilament Light Chain Levels with Clinical and Radiological Findings in Multiple Sclerosis

microRNAs (miRNAs) are promising biomarkers for many diseases, including multiple sclerosis (MS). The neurofilament light chain (NfL) is a biomarker that can detect axonal damage in different neurological diseases. The objective of this study was to evaluate the association of the expression profile of pre-selected miRNAs and NfL levels with clinical and radiological variables in MS patients. We conducted a 1-year longitudinal prospective study in MS patients with different clinical forms. We measured clinical disability using the expanded disability status scale (EDSS), the magnetic resonance imaging (MRI) volumetry baseline, and cognitive functioning using the processing speed test (PST) at baseline and 1 year later. Selected serum miRNAs and serum NfL (sNfL) levels were quantified. Seventy-three patients were recruited. MiR-126.3p correlated with EDSS and cognitive status at baseline and miR-126.3p and miR-9p correlated with cognitive deterioration at 1 year. Correlations with regional brain volumes were observed between miR-126.3p and the cortical gray matter, cerebellum, putamen, and pallidum; miR-146a.5p with the cerebellum and pallidum; miR-29b.3p with white matter and the pallidum; miR-138.5p with the pallidum; and miR-9.5p with the thalamus. sNfL was correlated with miR-9.5p. miR-146a.5p was also associated with the MS phenotype. These data justify future studies to further explore the utility of miRNAs (mirR-126.3p, miR-146.5p, and miR.9-5p) and sNfL levels as biomarkers of MS.

Dimethyl Fumarate Strongly Ameliorates Gray and White Matter Brain Injury and Modulates Glial Activation after Severe Hypoxia–Ischemia in Neonatal Rats

Neonatal hypoxia–ischemia is a major cause of infant death and disability. The only clinically accepted treatment is therapeutic hypothermia; however, cooling is less effective in the most severely encephalopathic infants. Here, we wanted to test the neuroprotective effect of the antioxidant dimethyl fumarate after severe hypoxia–ischemia in neonatal rats. We used a modified Rice–Vannucci model to generate severe hypoxic–ischemic brain damage in day 7 postnatal rats, which were randomized into four experimental groups: Sham, Sham + DMF, non-treated HI, and HI + DMF. We analyzed brain tissue loss, global and regional (cortex and hippocampus) neuropathological scores, white matter injury, and microglial and astroglial reactivity. Compared to non-treated HI animals, HI + DMF pups showed a reduced brain area loss (p = 0.0031), an improved neuropathological score (p = 0.0016), reduced white matter injuries by preserving myelin tracts (p < 0.001), and diminished astroglial (p < 0.001) and microglial (p < 0.01) activation. After severe hypoxia–ischemia in neonatal rats, DMF induced a strong neuroprotective response, reducing cerebral infarction, gray and white matter damage, and astroglial and microglial activation. Although further molecular studies are needed and its translation to human babies would need to evaluate the molecule in piglets or lambs, DMF may be a potential treatment against neonatal encephalopathy.

Morphometry of medial temporal lobe subregions using high-resolution T2-weighted MRI in ADNI3: Why, how, and what's next?

This paper for the 20th anniversary of the Alzheimer's Disease Neuroimaging Initiative (ADNI) provides an overview of magnetic resonance imaging (MRI) of medial temporal lobe (MTL) subregions in ADNI using a dedicated high-resolution T2-weighted sequence. A review of the work that supported the inclusion of this imaging modality into ADNI Phase 3 is followed by a brief description of the ADNI MTL imaging and analysis protocols and a summary of studies that have used these data. This review is supplemented by a new study that uses novel surface-based tools to characterize MTL neurodegeneration across biomarker-defined AD stages. This analysis reveals a pattern of spreading cortical thinning associated with increasing levels of tau pathology in the presence of elevated amyloid beta, with apparent epicenters in the transentorhinal region and inferior hippocampal subfields. The paper concludes with an outlook for high-resolution imaging of the MTL in ADNI Phase 4. HIGHLIGHTS: As of Phase 3, the Alzheimer's Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) protocol includes a high-resolution T2-weighted MRI scan optimized for imaging hippocampal subfields and medial temporal lobe (MTL) subregions. These scans are processed by the ADNI core to obtain automatic segmentations of MTL subregions and to derive morphologic measurements. More detailed granular examination of MTL neurodegeneration in response to disease progression is achieved by applying surface-based modeling techniques. Surface-based analysis of gray matter loss in MTL subregions reveals increasing and spatially expanding patterns of neurodegeneration with advancing stages of Alzheimer's disease (AD), as defined based on amyloid and tau positron emission tomography biomarkers in accordance with recently proposed criteria. These patterns closely align with post mortem literature on spread of pathological tau in AD, supporting the role of tau pathology in the presence of elevated levels of amyloid beta as the driver of neurodegeneration.

Neuroanatomical changes observed over the course of a human pregnancy.

Pregnancy is a period of profound hormonal and physiological changes experienced by millions of women annually, yet the neural changes unfolding in the maternal brain throughout gestation are not well studied in humans. Leveraging precision imaging, we mapped neuroanatomical changes in an individual from preconception through 2 years postpartum. Pronounced decreases in gray matter volume and cortical thickness were evident across the brain, standing in contrast to increases in white matter microstructural integrity, ventricle volume and cerebrospinal fluid, with few regions untouched by the transition to motherhood. This dataset serves as a comprehensive map of the human brain across gestation, providing an open-access resource for the brain imaging community to further explore and understand the maternal brain.

Alterations in cortical and subcortical neuroanatomy and associations with behavior in females with fragile X syndrome.

To address substantial gaps in the literature on neuroanatomical variations in females with fragile X syndrome (FXS). Surface-based modeling techniques were applied to the magnetic resonance imaging of 45 females with FXS (mean age = 10 years 9 months, range 6 years-16 years 4 months, SD = 2 years 9 months) and 33 age-matched and developmentally matched females without FXS to elucidate differences in cortical gray matter volume, surface area, and thickness. Gray matter volumes in subcortical regions were examined to ascertain differences in subcortical volume. In females with FXS, cortical volume was greater bilaterally in the occipital pole and smaller in the right postcentral gyrus. Seven regions demonstrated lower surface area in participants with FXS, while cortical thickness was significantly greater over the posterior and medial surfaces in the group with FXS. Subcortical region of interest analyses demonstrated greater volume in the caudate nucleus, globus pallidus, and nucleus accumbens in the group with FXS. Global gray matter volume, pial thickness, and surface area were associated with behavioral outcomes in the group with FXS but not in the comparison group. Females with FXS demonstrated unique cortical and subcortical gray matter anatomy relative to a matched comparison group. These findings may be relevant to the pathogenesis of the FXS behavioral phenotype and provide insights into behavioral interventions targeted to this population.

The effect of alemtuzumab on neurodegeneration in relapsing-remitting multiple sclerosis: A five-year prospective mono-center study

BackgroundRelapsing-remitting multiple sclerosis (RRMS) is an inflammatory and neurodegenerative disease. After two or more short courses of alemtuzumab (ALZ), an immune reconstitution is achieved, which long-term results in reduced disease activity. We aimed to investigate the effect of ALZ on measures of neurodegeneration (i.e., brain atrophy, and retinal layer thinning). MethodsWe designed an observational prospective mono-center study in RRMS patients initiating ALZ treatment. Patients were assessed at baseline (month 0) and thereafter annually for five years with clinical measures, synthetic magnetic resonance imaging (SyMRI) and optical coherence tomography (OCT), with a re-baseline SyMRI scan and an OCT exam 24 months after initiating ALZ. Persons with neurological symptoms but without evidence of neurological disease served as symptomatic controls (SCs, n = 27). ResultsForty-nine RRMS patients were included. Baseline median expanded disability status scale [2.0 (IQR 1.5)] was unchanged during follow-up, 71 % were progression-free, 33 % achieved no evidence of disease activity-3 (NEDA-3). Between baseline and month 60, SyMRI showed a reduction of brain parenchymal fraction (BPF) and grey matter (GM) volume in patients. The BPF reduction was greater in RRMS patients than in SCs (p < 0.05), and more pronounced in patients with high pre-baseline disease activity than in those without (p < 0.01). OCT showed significant thinning of macular ganglion cell and inner plexiform layers (mGCIPL) and in peripapillary retinal nerve fiber layer (pRNFL) in patients. In contrast, absolute values of white matter (WM) volume and myelin content (MyC) quantified by SyMRI, were stable or increased after re-baseline (month 24) and up to month 60, and this increase appeared limited to patients without high pre-baseline disease activity and to patients with NEDA-3 or disability worsening during follow-up. A strong positive correlation between WM volume and GM volume at baseline was lost after ALZ intervention for their delta values, i.e., change from re-baseline (month 24) to month 60. While the positive baseline correlation between WM volume and MyC increased for their delta values, the positive baseline correlation between GM volume and MyC changed to negative for their delta values. ConclusionWe showed that neurodegeneration continued in RRMS patients under ALZ treatment, but it appeared to be limited to BPF and GM, and more pronounced in patients with disease activity. Our data suggest that patients who respond to ALZ treatment show signs of remyelination. OCT and SyMRI have potential to quantify measures of neurodegeneration that is affected by treatment intervention in RRMS.

Molecular and micro-architectural mapping of gray matter alterations in psychosis.

The psychosis spectrum encompasses a heterogeneous range of clinical conditions associated with abnormal brain development. Detecting patterns of atypical neuroanatomical maturation across psychiatric disorders requires an interpretable metric standardized by age-, sex- and site-effect. The molecular and micro-architectural attributes that account for these deviations in brain structure from typical neurodevelopment are still unknown. Here, we aggregate structural magnetic resonance imaging data from 38,696 healthy controls (HC) and 1256 psychosis-related conditions, including first-degree relatives of schizophrenia (SCZ) and schizoaffective disorder (SAD) patients (n = 160), individuals who had psychotic experiences (n = 157), patients who experienced a first episode of psychosis (FEP, n = 352), and individuals with chronic SCZ or SAD (n = 587). Using a normative modeling approach, we generated centile scores for cortical gray matter (GM) phenotypes, identifying deviations in regional volumes below the expected trajectory for all conditions, with a greater impact on the clinically diagnosed ones, FEP and chronic. Additionally, we mapped 46 neurobiological features from healthy individuals (including neurotransmitters, cell types, layer thickness, microstructure, cortical expansion, and metabolism) to these abnormal centiles using a multivariate approach. Results revealed that neurobiological features were highly co-localized with centile deviations, where metabolism (e.g., cerebral metabolic rate of oxygen (CMRGlu) and cerebral blood flow (CBF)) and neurotransmitter concentrations (e.g., serotonin (5-HT) and acetylcholine (α4β2) receptors) showed the most consistent spatial overlap with abnormal GM trajectories. Taken together these findings shed light on the vulnerability factors that may underlie atypical brain maturation during different stages of psychosis.

Artificial Gravity: An Effective Countermeasure for Microgravity-Induced Headward Fluid Shift?

Long-duration spaceflight is associated with pathophysiological changes in the intracranial compartment hypothetically linked to microgravity-induced headward fluid shift. This study aimed to determine if daily artificial gravity (AG) sessions can mitigate these effects, supporting its application as a countermeasure to spaceflight. Twenty-four healthy adult volunteers (16 men) were exposed to 60 days of six-degree head-down tilt bed rest (HDTBR) as a ground-based analog of chronic headward fluid shift. Subjects were divided equally into three groups: No AG (control), daily 30-minute intermittent AG (iAG), and daily 30-minute continuous (cAG). Internal carotid artery (ICA) stroke volume (ICASV), ICA resistive index (ICARI), ICA flow rate (ICAFR), aqueductal cerebral spinal fluid flow velocity (CSFV), and intracranial volumetrics were quantified at 3T. MRI was performed at baseline, 14 and 52 days into HDTBR, and three days after HDTBR(recovery). A mixed model approach was used with intervention and time as the fixed effect factors and the subject as the random effect factor. Compared to baseline, HDTBR was characterized by expansion of lateral ventricular, white matter, gray matter, and brain + total intracranial cerebral spinal fluid volumes, increased CSFv, decreased ICASV, and decreased ICAFR by 52 days into HBTBR (All Ps <0.05). ICARI was only increased 14 days into HDTBR (P <0.05). Neither iAG nor cAG significantly affected measurements compared to HDTBR alone, indicating that thirty minutes of daily exposure was insufficient to mitigate the intracranial effects of headward fluid shift. Greater AG session exposure time, gravitational force or both are suggested for future countermeasure research.

Neural basis of false recognition in Alzheimer's disease and dementia with lewy bodies.

In Alzheimer's disease (AD), reports on the association between false recognition and brain structure have been inconsistent. In dementia with Lewy bodies (DLB), no such association has been reported. This study aimed to identify brain regions associated with false recognition in AD and DLB by analyzing regional gray matter volume (rGMV). We included 184 patients with AD and 60 patients with DLB. The number of false recognitions was assessed using the Alzheimer's Disease Assessment Scale' word recognition task. Brain regions associated with the number of false recognitions were examined by voxel-based morphometry analysis. The number of false recognitions significantly negatively correlated with rGMV in the bilateral hippocampus, left parahippocampal gyrus, bilateral amygdala, and bilateral entorhinal cortex in patients with AD (p < 0.05, family-wise error [FEW] corrected) and in the bilateral hippocampus, left parahippocampal gyrus, right inferior frontal gyrus, right middle frontal gyrus, right basal forebrain, right insula, left medial and lateral orbital gyri, and left fusiform in those with DLB (p < 0.05, FWE corrected). Bilateral hippocampus and left parahippocampal gyrus were associated with false recognition in both diseases. However, we found there were regions where the association between false recognition and rGMV differed from disease to disease.

A - 1 Informant Report of Practical Judgment Is Associated with Mild Cognitive Impairment and Measures of Brain Structure in a Nondemented Sample of Older Adults

Abstract Objective Given the potential risks associated with compromised judgment in older adulthood, we examined whether informant-reported practical judgment abilities were associated with cognitive impairment and measures of brain structure. Method 97 community-dwelling older adults with informants (Mage = 74.64 ± 7.42, Medu = 15.76 ± 2.42, 74%female, 92%white) underwent neuropsychological evaluation, including the Test of Practical Judgment-Informant (TOP-J-INF), a 15-item informant-reported scale of judgment ability. Participants were diagnosed with mild cognitive impairment (MCI; n = 33) or as neuropsychologically unimpaired (n = 64). Participants completed an MRI study including T1-weighted image processed with FreeSurfer software (v 6.0.0) to obtain estimates of gray matter volume and cortical thickness (parcellated with the Desikan-Killiany atlas). Logistic and linear models analyzed the association of TOP-J-INF with MCI diagnosis and brain volume/thickness (in separate models). To better support the exploratory nature of this analysis of associations with structural brain variables, we did not apply correction for multiple comparisons. Results Each additional point on the TOP-J-INF increased the odds of MCI diagnosis by 16.8% (OR = 1.168, p = 0.004). Worse judgment was associated with reduced brain volume in the right parahippocampal gyrus (β = −11.688, p = 0.032), superior temporal gyrus (β = −51.330, p = 0.040), rostral anterior cingulate cortex (β = −25.704, p = 0.004); and reduced thickness of the left transverse temporal gyrus (β = −0.010, p = 0.041). Conclusions To our knowledge, this is the first study to investigate the relationship between informant report of judgment and measures of brain structure, providing support that informant concerns about a loved one’s compromised judgment is associated with volume/thickness reduction in key brain regions. Assessing practical judgment abilities via informants could provide critical clinical information when working with vulnerable older individuals.

Association between blood-based protein biomarkers and brain MRI in the Alzheimer's disease continuum: a systematic review.

Blood-based biomarkers (BBM) are becoming easily detectable tools to reveal pathological changes in Alzheimer's disease (AD). A comprehensive and up-to-date overview of the association between BBM and brain MRI parameters is not available. This systematic review aimed to summarize the literature on the associations between the main BBM and MRI markers across the clinical AD continuum. A systematic literature search was carried out on PubMed and Web of Science and a total of 33 articles were included. Hippocampal volume was positively correlated with Aβ42 and Aβ42/Aβ40 and negatively with Aβ40 plasma levels. P-tau181 and p-tau217 concentrations were negatively correlated with temporal grey matter volume and cortical thickness. NfL levels were negatively correlated with white matter microstructural integrity, whereas GFAP levels were positively correlated with myo-inositol values in the posterior cingulate cortex/precuneus. These findings highlight consistent associations between various BBM and brain MRI markers even in the pre-clinical and prodromal stages of AD. This suggests a possible advantage in combining multiple AD-related markers to improve accuracy of early diagnosis, prognosis, progression monitoring and treatment response.

Functional conductivity imaging: quantitative mapping of brain activity.

Theory and modelling suggest that detection of neuronal activity may be feasible using phase sensitive MRI methods. Successful detection of neuronal activity both in vitro and in vivo has been described while others have reported negative results. Magnetic resonance electrical properties tomography may be a route by which signal changes can be identified. Here, we report successful and repeatable detection at 3 Tesla of human brain activation in response to visual and somatosensory stimuli using a functional version of tissue conductivity imaging (funCI). This detects activation in both white and grey matter with apparent tissue conductivity changes of 0.1 S/m (17-20%, depending on the tissue baseline conductivity measure) allowing visualization of complete system circuitry. The degree of activation scales with the degree of the stimulus (duration or contrast). The conductivity response functions show a distinct timecourse from that of traditional fMRI haemodynamic (BOLD or Blood Oxygenation Level Dependent) response functions, peaking within milliseconds of stimulus cessation and returning to baseline within 3-4s. We demonstrate the utility of the funCI approach by showing robust activation of the lateral somatosensory circuitry on stimulation of an index finger, on stimulation of a big toe or of noxious (heat) stimulation of the face as well as activation of visual circuitry on visual stimulation in up to five different individuals. The sensitivity and repeatability of this approach provides further evidence that magnetic resonance imaging approaches can detect brain activation beyond changes in blood supply.

Acute exercise alters brain glucose metabolism in aging and Alzheimer's disease.

There is evidence that aerobic exercise improves brain health. Benefits may be modulated by acute physiological responses to exercise, but this has not been well characterized in older or cognitively impaired adults. The randomized controlled trial 'AEROBIC' (NCT04299308) enrolled 60 older adults who were cognitively healthy (n=30) or cognitively impaired (n=30) to characterize the acute brain responses to moderate [45-55% heart rate reserve (HRR)] and higher (65-75% HRR) intensity acute exercise. Each participant received two fluorodeoxyglucose positron emission tomography (FDG-PET) scans, one at rest and one following acute exercise. Change in cerebral glucose metabolism from rest to exercise was the primary outcome. Blood biomarker responses were also characterized as secondary outcomes. Whole grey matter FDG-PET standardized uptake value ratio (SUVR) differed between exercise (1.045±0.082) and rest (0.985±0.077) across subjects [Diff=-0.060, t(58)=13.8, P<0.001] regardless of diagnosis. Exercise increased lactate area under the curve (AUC) [F(1,56)=161.99, P<0.001] more in the higher intensity group [mean difference (MD)=97.0±50.8] than the moderate intensity group (MD=40.3±27.5; t=-5.252, P<0.001). Change in lactate AUC and FDG-PET SUVR correlated significantly (R2=0.179, P<0.001). Acute exercise decreased whole grey matter cerebral glucose metabolism. This effect tracked with the systemic lactate response, suggesting that lactate may serve as a key brain fuel during exercise. Direct measurements of brain lactate metabolism in response to exercise are warranted. KEY POINTS: Acute exercise is associated with a drop in global brain glucose metabolism in both cognitively healthy older adults and those with Alzheimer's disease. Blood lactate levels increase following acute exercise. Change in brain metabolism tracks with blood lactate, suggesting it may be an important brain fuel. Acute exercise stimulates changes in brain-derived neurotrophic factor and other blood biomarkers.