Brain Volume Changes Research Articles

Brain Volume Changes Over 1 Year in Ozanimod-treated Patients with Early-relapsing Multiple Sclerosis: An Interim Analysis of the ENLIGHTEN Study (P11-6.017)

Brain Volume Changes Over 1 Year in Ozanimod-treated Patients with Early-relapsing Multiple Sclerosis: An Interim Analysis of the ENLIGHTEN Study (P11-6.017)

Glymphatic inhibition exacerbates tau propagation in an Alzheimer’s disease model

BackgroundThe aggregation and spread of misfolded amyloid structured proteins, such as tau and α-synuclein, are key pathological features associated with neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. These proteins possess a prion-like property, enabling their transmission from cell to cell leading to propagation throughout the central and peripheral nervous systems. While the mechanisms underlying their intracellular spread are still being elucidated, targeting the extracellular space has emerged as a potential therapeutic approach. The glymphatic system, a brain-wide pathway responsible for clearing extracellular metabolic waste from the central nervous system, has gained attention as a promising target for removing these toxic proteins.MethodsIn this study, we investigated the impact of long-term modulation of glymphatic function on tau aggregation and spread by chronically treating a mouse model of tau propagation with a pharmacological inhibitor of AQP4, TGN-020. Thy1-hTau.P301S mice were intracerebrally inoculated with tau into the hippocampus and overlying cortex, and subsequently treated with TGN-020 (3 doses/week, 50 mg/kg TGN-020, i.p.) for 10-weeks. During this time, animal memory was studied using cognitive behavioural tasks, and structural MR images were acquired of the brain in vivo prior to brain extraction for immunohistochemical characterisation.ResultsOur findings demonstrate increased tau aggregation in the brain and transhemispheric propagation in the hippocampus following the inhibition of glymphatic clearance. Moreover, disruption of the glymphatic system aggravated recognition memory in tau inoculated mice and exacerbated regional changes in brain volume detected in the model. When initiation of drug treatment was delayed for several weeks post-inoculation, the alterations were attenuated.ConclusionsThese results indicate that by modulating AQP4 function and, consequently, glymphatic clearance, it is possible to modify the propagation and pathological impact of tau in the brain, particularly during the initial stages of the disease. These findings highlight the critical role of the glymphatic system in preserving healthy brain homeostasis and offer valuable insights into the therapeutic implications of targeting this system for managing neurodegenerative diseases characterized by protein aggregation and spread.

Pseudo-time Series Structural MRI Revealing Progressive Gray Matter Changes with Elevated Intraocular Pressure in Primary Open-Angle Glaucoma: A Preliminary Study

Rationale and ObjectivesPrimary open-angle glaucoma (POAG) is accompanied with gray matter changes across the brain. However, causal relationships of the gray matter changes have not been fully understood. Our aim was to investigate the causality of gray matter progressive changes in POAG using Granger causality (GC) analysis and structural MRI. Materials and MethodsStructural MRI from 20 healthy controls and 30 POAG patients with elevated intraocular pressure (IOP) were collected. We performed voxel-wise gray matter volume comparisons between control and POAG groups, and between control and 4 POAG subgroups (categorized by IOP). Then, we sequenced the structural MRI data of all POAG patients and conducted both voxel-wise and region of interest (ROI)-wise GC analysis to investigate the causality of gray matter volume changes in POAG brain. ResultsCompared with healthy controls, reduced gray matter volumes across the brain were found, gray matter volume enlargements in the thalamus, caudate nucleus and cuneus were also observed in POAG brain (false discovery rate (FDR) corrected at q<0.05). As IOP elevated, the reductions of gray matter volume were more severe in the cerebellum and frontal lobe. GC analysis revealed that the bilateral cerebellum, visual cortices, and the frontal regions served independently as primary hubs of the directional causal network, and projected causal effects to the parietal and temporal regions of the brain (FDR corrected at q<0.05). ConclusionPOAG exhibits progressive gray matter alterations across the brain, with oculomotor regions and visual cortices as independent primary hubs. The current results may deepen our understanding of neuropathology of POAG.

Altered brain morphology and functional connectivity in postmenopausal women: automatic segmentation of whole-brain and thalamic subnuclei and resting-state fMRI.

The transition to menopause is associated with various physiological changes, including alterations in brain structure and function. However, menopause-related structural and functional changes are poorly understood. The purpose of this study was not only to compare the brain volume changes between premenopausal and postmenopausal women, but also to evaluate the functional connectivity between the targeted brain regions associated with structural atrophy in postmenopausal women. Each 21 premenopausal and postmenopausal women underwent magnetic resonance imaging (MRI). T1-weighted MRI and resting-state functional MRI data were used to compare the brain volume and seed-based functional connectivity, respectively. In statistical analysis, multivariate analysis of variance, with age and whole brain volume as covariates, was used to evaluate surface areas and subcortical volumes between the two groups. Postmenopausal women showed significantly smaller cortical surface, especially in the left medial orbitofrontal cortex (mOFC), right superior temporal cortex, and right lateral orbitofrontal cortex, compared to premenopausal women (p < 0.05, Bonferroni-corrected) as well as significantly decreased functional connectivity between the left mOFC and the right thalamus was observed (p < 0.005, Monte-Carlo corrected). Although postmenopausal women did not show volume atrophy in the right thalamus, the volume of the right pulvinar anterior, which is one of the distinguished thalamic subnuclei, was significantly decreased (p < 0.05, Bonferroni-corrected). Taken together, our findings suggest that diminished brain volume and functional connectivity may be linked to menopause-related symptoms caused by the lower sex hormone levels.

Associations of dietary patterns and longitudinal brain-volume change in Japanese community-dwelling adults: results from the national institute for longevity sciences-longitudinal study of aging

BackgroundThe association of dietary patterns and longitudinal changes in brain volume has rarely been investigated in Japanese individuals. We prospectively investigated this association in middle-aged and older Japanese community-dwelling adults.MethodsData with a 2-year follow-up from the sixth wave (July 2008 to July 2010; baseline) to the seventh (July 2010 to July 2012; follow-up) of the National Institute for Longevity Sciences-Longitudinal Study of Aging project were analyzed. Dietary intake was assessed using a 3-day dietary record, and longitudinal volume changes (%) in the total gray matter (TGM), total white matter, and frontal, parietal, occipital, temporal, and insular lobes were assessed using 3-dimensional T1 magnetic resonance imaging scans. Multiple factor analysis and hierarchical clustering revealed sex-specific dietary patterns. Associations between dietary patterns and annual brain-volume changes (%) were evaluated using general linear models adjusted for age, apoprotein E genotype, body mass index, medical history, lifestyle behaviors, socioeconomic factors, and energy intake.ResultsAmong the 1636 participants (age: 40.3–89.2 years), three dietary patterns were determined for men (n = 815; Western; Vegetable-Fruit-Dairy; and Traditional Japanese diets) and women (n = 821; Western; Grain-Vegetable-Fruit; and Traditional Japanese diets). Compared to women following the Western diet, those on the Traditional Japanese diet had less TGM atrophy. Multivariable-adjusted β (95% confidence interval) of the annual change (%) of TGM was − 0.145 (-0.287 to -0.002; P = 0.047), which correlated with reduced parietal lobe atrophy. No association between dietary pattern and brain atrophy was observed in men.ConclusionsAdherence to healthy dietary patterns, with higher consumption of whole grains, seafood, vegetables, fruits, mushrooms, soybean products, and green tea, potentially confers a protective effect against brain atrophy in middle-aged and older Japanese women but not in men. Further research to confirm these results and ascertain the underlying mechanisms is required. This study highlights the importance of sex-specific effects on the relationship between dietary patterns and brain health in diverse populations.

CD4+ CD11b+ T cells infiltrate and aggravate the traumatic brain injury depending on brain-to-cervical lymph node signaling.

We aim to identify the specific CD4+ T-cell subtype influenced by brain-to-CLN signaling and explore their role during the acute phase of traumatic brain injury (TBI). Cervical lymphadenectomy or cervical afferent lymphatic ligation was performed before TBI. Cytokine array and western blot were used to detect cytokines, while the motor function was assessed using mNss and rotarod test. CD4+ T-cell subtypes in blood, brain, and CLNs were analyzed with Cytometry by time-of-flight analysis (CyTOF) or fluorescence-activated cell sorting (FACS). Brain edema and volume changes were measured by 9.4T MRI. Neuronal apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Cervical lymphadenectomy and ligation of cervical lymphatic vessels resulted in a decreased infiltration of CD4+ T cells, specifically CD11b-positive CD4+ T cells, within the affected region. The population of CD4+ CD11b+ T cells increased in ligated CLNs, accompanied by a decrease in the average fluorescence intensity of sphingosine-1-phosphate receptor-1 (S1PR1) on these cells. Administration of CD4+ CD11b+ T cells sorted from CLNs into the lateral ventricle reversed the attenuated neurologic deficits, brain edema, and lesion volume following cervical lymphadenectomy. The infiltration of CD4+ CD11b+ T cells exacerbates secondary brain damage in TBI, and this process is modulated by brain-to-CLN signaling.

Childhood engagement in cognitively stimulating activities moderates relationships between brain structure and cognitive function in adulthood

Greater engagement in cognitively stimulating activities (CSA) during adulthood has been shown to protect against neurocognitive decline, but no studies have investigated whether CSA during childhood protects against effects of brain changes on cognition later in life. The current study tested the moderating role of childhood CSA in the relationships between brain structure and cognitive performance during adulthood. At baseline (N=250) and 5-year follow-up (N=204) healthy adults aged 20–80 underwent MRI to assess four structural brain measures and completed neuropsychological tests to measure three cognitive domains. Participants were categorized into low and high childhood CSA based on self-report questionnaires. Results of multivariable linear regressions analyzing interactions between CSA, brain structure, and cognition showed that higher childhood CSA was associated with a weaker relationship between cortical thickness and memory at baseline, and attenuated the effects of change in cortical thickness and brain volume on decline in processing speed over time. These findings suggest higher CSA during childhood may mitigate the effects of brain structure changes on cognitive function later in life.

White and Gray Matter Changes are Associated With Neurocognitive Decline in HIV Infection.

To investigate the relationship between neurocognitive deficits and structural changes on brain magnetic resonance imaging in people living with HIV (PLWH) with good virological control on combination antiretroviral therapy, compared with socioeconomically matched control participants recruited from the same communities. Brain magnetic resonance imaging scans, and clinical and neuropsychological data were obtained from virologically controlled PLWH (viral load of <50 c/mL and at least 1 year of combination antiretroviral therapy) and socioeconomically matched control participants. Magnetic resonance imaging was carried out on 3 T scanner with 8-channel head coils and segmented using Classification using Derivative-based Features. Multiple regression analysis was performed to examine the association between brain volume and various clinical and neuropsychiatric parameters adjusting for age, race, and sex. To evaluate longitudinal changes in brain volumes, a random coefficient model was used to evaluate the changes over time (age) adjusting for sex and race. The cross-sectional study included 164 PLWH and 51 controls, and the longitudinal study included 68 PLWH and 20 controls with 2 or more visits (mean 2.2 years, range 0.8-5.1 years). Gray matter (GM) atrophy rate was significantly higher in PLWH compared with control participants, and importantly, the GM and global atrophy was associated with the various neuropsychological domain scores. Higher volume of white matter hyperintensities were associated with increased atherosclerotic cardiovascular disease risk score, and decreased executive functioning and memory domain scores in PLWH. These findings suggest ongoing neurological damage even in virologically controlled participants, with significant implications for clinical management of PLWH. ANN NEUROL 2024;95:941-950.

Classification of patients with migraine and healthy subjects using gross brain volume changes

AbstractBackground and PurposeDespite reports of changes in gray matter and white matter in individuals with migraines, research on detecting whole‐brain gross volume changes in migraines is very rare. Therefore, we aimed to investigate gross volume changes associated with migraine and test its potential in developing a neuroimaging biomarker for objective diagnosis of migraine.MethodologyIn this study, 45 patients with migraine and 46 healthy controls were scanned using a 3T MRI scanner, and 3D, T1‐weighted brain MR images were obtained. First, Tensor‐based morphometry and Voxel‐based morphometry were performed using Computational Anatomy Toolbox (CAT 12) to compute gross volumes, gray matter volumes, white matter volumes, and cerebrospinal fluid volumes. Univariate analyses were performed using two‐sample t‐test and the results were corrected for multiple comparisons. Second, multivariate pattern analyses (MVPA) were conducted to classify the patients with migraine and healthy controls.ResultsReduced gross volumes in patients were detected in middle frontal gyrus, superior frontal gyrus, inferior temporal gyrus and middle temporal gyrus of right cerebrum, middle temporal gyrus and angular gyrus of the left cerebrum, cuneus, and left cerebellum. Reduced gray matter volumes were detected in superior frontal, right middle frontal, right inferior temporal, and right middle temporal. The results of MVPA indicated that gross volume changes can improve the classification accuracy (73.63%) than other structural metrics such as gray matter (70%), white matter (66.3%), and cerebrospinal fluid volumes (58.69%).ConclusionWe conclude that the gross volumetric alterations can serve as a better neuroimaging marker for the objective diagnosis of migraine.

Automated magnetic resonance imaging quantification of cerebral parenchymal and ventricular volume following subarachnoid hemorrhage: associations with cognition

This study aims to investigate cerebral parenchymal and ventricular volume changes after subarachnoid hemorrhage (SAH) and their potential association with cognitive impairment. 17 patients with aneurysmal SAH (aSAH) and 21 patients with angiographically negative SAH (anSAH) without visually apparent parenchymal loss on conventional magnetic resonance imaging (MRI) were included, along with 76 healthy controls. Volumetric analyses were performed using an automated clinical segmentation and quantification tool. Measurements were compared to on-board normative reference database (n = 1923) adjusted for age, sex, and intracranial volume. Cognition was assessed with tests for psychomotor speed, attentional control, (working) memory, executive functioning, and social cognition. All measurements took place 5 months after SAH. Lower cerebral parenchymal volumes were most pronounced in the frontal lobe (aSAH: n = 6 [35%], anSAH n = 7 [33%]), while higher volumes were most substantial in the lateral ventricle (aSAH: n = 5 [29%], anSAH n = 9 [43%]). No significant differences in regional brain volumes were observed between both SAH groups. Patients with lower frontal lobe volume exhibited significantly lower scores in psychomotor speed (U = 81, p = 0.02) and attentional control (t = 2.86, p = 0.004). Additionally, higher lateral ventricle volume was associated with poorer memory (t = 3.06, p = 0.002). Regional brain volume changes in patients with SAH without visible parenchymal abnormalities on MRI can still be quantified using a fully automatic clinical-grade tool, exposing changes which may contribute to cognitive impairment. Therefore, it is important to provide neuropsychological assessment for both SAH groups, also including those with clinically mild symptoms.

Neurogenesis-independent mechanisms of MRI-detectable hippocampal volume increase following electroconvulsive stimulation

Electroconvulsive therapy (ECT) is one of the most effective psychiatric treatments but the underlying mechanisms are still unclear. In vivo human magnetic resonance imaging (MRI) studies have consistently reported ECT-induced transient hippocampal volume increases, and an animal model of ECT (electroconvulsive stimulation: ECS) was shown to increase neurogenesis. However, a causal relationship between neurogenesis and MRI-detectable hippocampal volume increases following ECT has not been verified. In this study, mice were randomly allocated into four groups, each undergoing a different number of ECS sessions (e.g., 0, 3, 6, 9). T2-weighted images were acquired using 11.7-tesla MRI. A whole brain voxel-based morphometry analysis was conducted to identify any ECS-induced brain volume changes. Additionally, a histological examination with super-resolution microscopy was conducted to investigate microstructural changes in the brain regions that showed volume changes following ECS. Furthermore, parallel experiments were performed on X-ray-irradiated mice to investigate the causal relationship between neurogenesis and ECS-related volume changes. As a result, we revealed for the first time that ECS induced MRI-detectable, dose-dependent hippocampal volume increase in mice. Furthermore, increased hippocampal volumes following ECS were seen even in mice lacking neurogenesis, suggesting that neurogenesis is not required for the increase. The comprehensive histological analyses identified an increase in excitatory synaptic density in the ventral CA1 as the major contributor to the observed hippocampal volume increase following ECS. Our findings demonstrate that modification of synaptic structures rather than neurogenesis may be the underlying biological mechanism of ECT/ECS-induced hippocampal volume increase.

Effect of Xiaoyaosan on brain volume and microstructure diffusion changes to exert antidepressant-like effects in mice with chronic social defeat stress.

Depression is a prevalent mental disorder characterized by persistent negative mood and loss of pleasure. Although there are various treatment modalities available for depression, the rates of response and remission remain low. Xiaoyaosan (XYS), a traditional Chinese herbal formula with a long history of use in treating depression, has shown promising effects. However, the underlying mechanism of its therapeutic action remains elusive. The aim of this study is to investigate the neuroimaging changes in the brain associated with the antidepressant-like effects of XYS. Here, we combined voxel-based morphometry of T2-weighted images and voxel-based analysis on diffusion tensor images to evaluate alterations in brain morphometry and microstructure between chronic social defeat stress (CSDS) model mice and control mice. Additionally, we examined the effect of XYS treatment on structural disruptions in the brains of XYS-treated mice. Furthermore, we explored the therapeutic effect of 18β-glycyrrhetinic acid (18β-GA), which was identified as the primary compound present in the brain following administration of XYS. Significant differences in brain structure were utilized as classification features for distinguishing mice with depression model form the controls using a machine learning method. Significant changes in brain volume and diffusion metrics were observed in the CSDS model mice, primarily concentrated in the nucleus accumbens (ACB), primary somatosensory area (SSP), thalamus (TH), hypothalamus (HY), basomedical amygdala nucleus (BMA), caudoputamen (CP), and retrosplenial area (RSP). However, both XYS and 18β-GA treatment prevented disruptions in brain volume and diffusion metrics in certain regions, including bilateral HY, right SSP, right ACB, bilateral CP, and left TH. The classification models based on each type of neuroimaging feature achieved high accuracy levels (gray matter volume: 76.39%, AUC=0.83; white matter volume: 76.39%, AUC=0.92; fractional anisotropy: 82.64%, AUC=0.9; radial diffusivity: 76.39%, AUC=0.82). Among these machine learning analyses, the right ACB, right HY, and right CP were identified as the most important brain regions for classification purposes. These findings suggested that XYS can prevent abnormal changes in brain volume and microstructure within TH, SSP, ACB, and CP to exert prophylactic antidepressant-like effects in CSDS model mice. The neuroimaging features within these regions demonstrate excellent performance for classifying CSDS model mice from controls while providing valuable insights into the antidepressant effects of XYS.

Generative artificial intelligence model for simulating structural brain changes in schizophrenia.

Recent advancements in generative artificial intelligence (AI) for image generation have presented significant opportunities for medical imaging, offering a promising way to generate realistic virtual medical images while ensuring patient privacy. The generation of a large number of virtual medical images through AI has the potential to augment training datasets for discriminative AI models, particularly in fields with limited data availability, such as neuroimaging. Current studies on generative AI in neuroimaging have mainly focused on disease discrimination; however, its potential for simulating complex phenomena in psychiatric disorders remains unknown. In this study, as examples of a simulation, we aimed to present a novel generative AI model that transforms magnetic resonance imaging (MRI) images of healthy individuals into images that resemble those of patients with schizophrenia (SZ) and explore its application. We used anonymized public datasets from the Center for Biomedical Research Excellence (SZ, 71 patients; healthy subjects [HSs], 71 patients) and the Autism Brain Imaging Data Exchange (autism spectrum disorder [ASD], 79 subjects; HSs, 105 subjects). We developed a model to transform MRI images of HSs into MRI images of SZ using cycle generative adversarial networks. The efficacy of the transformation was evaluated using voxel-based morphometry to assess the differences in brain region volumes and the accuracy of age prediction pre- and post-transformation. In addition, the model was examined for its applicability in simulating disease comorbidities and disease progression. The model successfully transformed HS images into SZ images and identified brain volume changes consistent with existing case-control studies. We also applied this model to ASD MRI images, where simulations comparing SZ with and without ASD backgrounds highlighted the differences in brain structures due to comorbidities. Furthermore, simulating disease progression while preserving individual characteristics showcased the model's ability to reflect realistic disease trajectories. The results suggest that our generative AI model can capture subtle changes in brain structures associated with SZ, providing a novel tool for visualizing brain changes in different diseases. The potential of this model extends beyond clinical diagnosis to advances in the simulation of disease mechanisms, which may ultimately contribute to the refinement of therapeutic strategies.

Automatic estimation of brain parenchymal fraction in patients with multple sclerosis: a comparison between synthetic MRI and an established automated brain segmentation software based on FSL

PurposeWe aimed to validate the estimation of the brain parenchymal fraction (BPF) in patients with multiple sclerosis (MS) using synthetic magnetic resonance imaging (SyMRI) by comparison with software tools of the FMRIB Software Library (FSL). In addition to a cross-sectional method comparison, longitudinal volume changes were assessed to further elucidate the suitability of SyMRI for quantification of disease-specific changes.MethodsMRI data from 216 patients with MS and 28 control participants were included for volume estimation by SyMRI and FSL-SIENAX. Moreover, longitudinal data from 35 patients with MS were used to compare registration-based percentage brain volume changes estimated using FSL-SIENA to difference-based calculations of volume changes using SyMRI.ResultsWe observed strong correlations of estimated brain volumes between the two methods. While SyMRI overestimated grey matter and BPF compared to FSL-SIENAX, indicating a systematic bias, there was excellent agreement according to intra-class correlation coefficients for grey matter and good agreement for BPF and white matter. Bland–Altman plots suggested that the inter-method differences in BPF were smaller in patients with brain atrophy compared to those without atrophy. Longitudinal analyses revealed a tendency for higher atrophy rates for SyMRI than for SIENA, but SyMRI had a robust correlation and a good agreement with SIENA.ConclusionIn summary, BPF based on data from SyMRI and FSL-SIENAX is not directly transferable because an overestimation and higher variability of SyMRI values were observed. However, the consistency and correlations between the two methods were satisfactory, and SyMRI was suitable to quantify disease-specific atrophy in MS.

Volumetric changes in brain MRI of infants with hypoxic-ischemic encephalopathy and abnormal neurodevelopment who underwent therapeutic hypothermia

BackgroundHypoxic-ischemic encephalopathy (HIE) is a severe neonatal complication that can result in 40–60 % of long-term morbidity. Magnetic Resonance Imaging (MRI) is a noninvasive method which is usually performed before discharge to visually assess acquired cerebral lesions associated with HIE and severity of lesions possibly providing a guide for detecting adverse outcomes. This study aims to evaluate the impact of HIE on brain volume changes observed in MRI scans performed at a mean 10 days of life, which can serve as a prognostic indicator for abnormal neurodevelopmental (ND) outcomes at 18–24 months among HIE infants. MethodsWe retrospectively identified a cohort of HIE patients between June 2013 and March 2017. The inclusion criteria for therapeutic hypothermia (TH) were a gestational age ≥35 weeks, a birth weight ≥1800 g, and the presence of ≥ moderate HIE. Brain MRI was performed at a mean 10 days of life and brain volumes (total brain volume, cerebral volume, cerebellar volume, brain stem volume, and ventricle volume) were measured for quantitative assessment. At 18–24 months, the infants returned for follow-up evaluations, during which their cognitive, language, and motor skills were assessed using the Bayley Scales of Infant and Toddler Development III. ResultsThe study recruited a total of 240 infants between 2013 and 2017 for volumetric brain MRI evaluation. Among these, 83 were normal control infants, 107 were TH-treated HIE infants and 37 were HIE infants who did not receive TH due to contraindications. Clinical evaluation was further proceeded. We compared the brain volumes between the normal control infants (n = 83) with normal ND but TH-treated HIE infants (n = 76), abnormal ND TH-treated HIE infants (n = 31), and the severe HIE MRI group with no TH (n = 37). The abnormal ND TH-treated HIE infants demonstrated a significant decrease in brainstem volume and an increase in ventricle size (p < 0.001) (Table 4). Lastly, the severe brain MRI group who did not receive TH showed significantly smaller brain stem (p = 0.006), cerebellar (p = 0.006) and cerebrum volumes (p = 0.027), accompanied by larger ventricular size (p = 0.013) compared to the normal control group (Table 5). ConclusionIn addition to assessing the location of brain injuries in MRI scans, the reduction in brain stem volume coupled with an increase in ventricular volume in HIE infants may serve as a biomarker indicating severe HIE and adverse long-term ND outcomes among HIE infants who either received therapeutic hypothermia (TH) treatment or not.

Association of plasma Alzheimer’s and neurodegenerative disease biomarkers with brain volume loss and cognitive decline

AbstractBackgroundAlthough plasma Alzheimer’s disease (AD) and neurodegenerative disease biomarkers have been associated with reduced cognition and lower brain volume, few studies have examined whether plasma biomarkers measured in predominately cognitively unimpaired adults are associated with longitudinal brain volume loss and cognitive decline. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of AD pathology (Aß42/40, phosphorylated tau [pTau‐181]), reactive astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline.MethodPlasma biomarkers (Aß42/40, pTau‐181, GFAP, NfL) were measured using Quanterix SIMOA assays. Baseline visits were considered the earliest visits that had concurrent 3T MRI scans and plasma biomarker measurements, and the earliest visits that had concurrent cognitive assessments and plasma biomarker measurements. Composite Z scores were computed to reflect 5 cognitive domains (Figure 1). Linear mixed effects models adjusted for baseline age, sex, race, education, estimated glomerular filtration rate, and total intracranial volume (brain volume analyses), were used to examine the association of plasma biomarkers with baseline and longitudinal brain volume and cognition. False Discovery Rate correction was used to adjust for multiple comparisons.ResultBrain volume analyses included 628 participants (mean age±SD: 71.0±10.2; Table 1) with an average of 3.3 MRI scans over 4.7 years. Cognition analyses included 686 participants (mean age±SD: 71.4±10.1) with an average of 3.9 cognitive assessments over 5.7 years. Although Aß42/40 was unrelated to brain volume changes, higher pTau‐181 was associated with longitudinal declines in total gray matter volume and regional declines in medial temporal regions. Higher GFAP was associated with longitudinal increases in ventricular volume, whereas NfL was not associated with brain volume change (Table 2). Both lower Aß42/40 and higher pTau‐181 were associated with a decline in verbal memory. Additionally, lower Aß42/40 was associated with a decline in visuospatial performance. Further, higher GFAP was associated with a decline in verbal fluency (Figure 1).ConclusionPlasma biomarkers of AD pathology and astrogliosis may serve as markers of future brain atrophy and cognitive decline.

Brain volume changes caused by anti‐amyloid beta drugs and association with ARIA

AbstractBackgroundThe potential benefit of anti‐Aβ drugs to cognition in Alzheimer’s disease (AD) remains under active debate. Anti‐Aβ drugs also frequently cause accelerated changes to brain volume. This is concerning because loss of brain tissue is the proximate cause of cognitive dysfunction in AD and volume changes are supportive and objective evidence of disease progression.MethodPubMed, Embase and Clinicaltrial.gov databases were searched to evaluate brain volume changes caused by different sub‐classes of anti‐amyloid beta (Aβ) drugs trialed in patients with Alzheimer’s disease. The inclusion criteria for this systematic review and meta‐analysis were: (1) randomized controlled trials of patients treated with anti‐Aβ drugs that have demonstrated to favorably change at least one biomarker of pathological Aβ; and (2) detailed MRI data sufficient to assess the volumetric changes in at least one brain region. Amyloid‐Related Imaging Abnormalities (ARIA) were investigated when reported in clinical trials. Of the 145 trials reviewed, 31 were included in the final analyses (n = 8062 to 10279).ResultA meta‐analysis on the highest dose of each trial on hippocampus, ventricle, and whole brain revealed drug‐induced acceleration of volume changes that varied by anti‐Aβ drug class. Secretase inhibitors accelerated atrophy to the hippocampus (mean difference: ‐37.1 µL [‐19.6% relative to change in placebo]; 95% confidence interval: ‐47.0 to ‐27.1) and whole brain (‐3.3mL [‐21.8% relative to change in placebo]; 95% confidence interval: ‐4.1 to 2.5). Conversely, ARIA‐inducing monoclonal antibodies accelerated ventricular enlargement (mean difference: +2.1mL [+38.7% relative to change in placebo]; 95% confidence interval: 1.5 to 2.8) where a striking correlation between ventricular volume and ARIA frequency was observed (r = 0.86, p = 6.22×10−7).ConclusionThese findings reveal the potential for anti‐Aβ therapies to compromise long‐term brain health by accelerating brain atrophy and provide new insight into the adverse impact of ARIA. Six recommendations emerge from these findings.

The Effects of Moderate and High Intensity Aerobic Exercise on Lipid and Lipoprotein Metabolism and Brain Volume in Cognitively Normal Older Australians: Data from the IPAC Study

AbstractBackgroundA common misconception about ageing is that a decline in brain health is solely observed in those who have dementia. In fact, decreases in cognitive function and reductions in brain volume are commonly observed in adults over the age of 65. Brain changes in older adulthood have been shown to be decreased in individuals who are more physically active, with alterations in lipid and lipoprotein metabolism emerging as a potential mechanism, however this is still not well understood. In light of this, our study aims to investigate the effects of moderate and high intensity aerobic exercise on lipid and lipoprotein metabolism to assess the efficacy of exercise in reducing brain atrophy in cognitively normal older adults.MethodSamples were collected from the Intense Physical Activity and Cognition (IPAC) study, during which a six‐month randomised controlled trial was performed to observe the impact of aerobic exercise on brain volume measurements in cognitively normal older adults (n = 99, aged 60‐80). Blood samples and neuroimaging measures were collected at baseline and following the completion of the intervention (6 months). Baseline and post‐intervention plasma samples were collected and analysed using 1H‐NMR spectroscopy to quantify 112 lipoproteins, followed by a comprehensive in‐house mass spectrometry (MS) lipids screen targeting &gt;1200 individual lipid species.ResultPreliminary analyses suggest that lipid and lipoprotein metabolism is altered by aerobic exercise and that these alterations are associated with changes in brain volume. Further analyses will increase the sample size, and also evaluate other factors (i.e. sex, APOE status) as potential moderators of the link between aerobic exercise and the metabolism of lipids and lipoproteins.ConclusionTo our knowledge, this study is the first to establish the relationship between exercise and lipids and lipoprotein metabolism, and their association to brain volume in cognitively normal older adults. The significance of our findings will be evaluated further using an external validation cohort. The discovery of novel lipids or metabolic pathways will create avenues for future research into new therapeutic targets for future healthy ageing interventions.

Stress system dysfunction and changes in brain volume and functional connectivity in older adults with subclinical depressive symptoms

AbstractBackgroundSubclinical depressive symptoms are associated with increased risk of Alzheimer’s disease (AD). This link could be related to stress system dysfunction, known to occur in both depression and AD, and to depend notably on the hippocampus which is particularly sensitive to AD. We aimed at investigating the links between levels of blood stress markers and changes in brain regions involved in the stress response in older adults with subclinical depressive symptoms.MethodCognitively unimpaired older adults with (DepS; n = 73) or without (NoDepS; n = 58) subclinical depressive symptoms (defined using the 15‐item version of the Geriatric Depression Scale), from the baseline data of the Age‐Well trial (NCT02977819) were included. For each participant, levels of cortisol, epinephrine and norepinephrine were obtained from blood sampling. Moreover, the functional connectivity (FC) between, and the gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields were extracted from resting‐state functional, and structural T1‐weighted, MRI. Levels of blood stress markers and neuroimaging measures were compared between groups. Regression analyses were then conducted between levels of blood markers and brain measures. Analyses were corrected for age, sex, education and anxiety symptoms with statistical significance set to p&lt;0.05.ResultHigher blood epinephrine level (p&lt;0.024), and FC between the hypothalamus and the CA1 hippocampal subfield (p&lt;0.040), was found in DepS compared to NoDepS (Fig.1). This higher epinephrine level was associated with greater FC between the hypothalamus and the CA1 (p&lt;0.007) and Subiculum (p&lt;0.013) subfields (Fig.2). Lower GM volume in the CA1 (p&lt;0.008) and DG/CA2‐3‐4 (p&lt;0.013) subfields was also found in the DepS group (Fig.3), but was not associated with epinephrine level. No significant between‐group difference in blood cortisol and norepinephrine levels was observed.ConclusionSubclinical depressive symptoms in aging are associated with higher blood epinephrine level related to greater FC between the hypothalamus and hippocampal subfields (CA1 and Subiculum) – suggesting an increased sympathetic nervous system activity. They are also associated with GM atrophy in specific hippocampal subfields, including the CA1 that is sensitive to AD. These two distinct mechanisms at this preclinical stage of depression may at least partly explain that depression is a risk factor for AD.

Proteomics identifies immunological drivers of post‐infection brain atrophy and cognitive decline

AbstractBackgroundPrior infections can modify the risk for dementia and neurodegenerative disease, yet the mechanisms by which infections contribute to neurodegeneration remain unclear.MethodWe examined how infection diagnoses documented in the Baltimore Longitudinal Study of Aging (BLSA) are associated with rates of change in brain volumes over time, and how these same infections relate to dementia risk using hospital records from UK Biobank and a Finnish multicohort sample (the Finnish Public Sector study, the Health and Social Support study, and the Still Working study). After determining how infections differentially relate to an immunological plasma proteome (942 proteins) in BLSA participants, we then identified a subset of infection‐related proteins that also predict changes in brain regions vulnerable to infection‐specific atrophy (candidate proteins). In addition to evaluating their associations with longitudinal cognitive performance as well as Alzheimer’s disease and related dementias (ADRD) plasma biomarkers (Aβ42/40, GFAP, NfL, pTau‐181), we also investigated the causal link between candidate proteins and longitudinal brain volume loss using Mendelian randomization. Study design is illustrated in Figure 1.ResultA total of 982 cognitively normal participants (age: 65.4 [SD 14.9]); 55.2% female; 66.9% white) were included in the primary MRI analysis. Of the 15 infections examined, we identified six diagnoses related to accelerated brain volume loss, including influenza, viral, respiratory, and skin/subcutaneous infections, with atrophy commonly observed in the temporal lobe. Each infection linked to brain volume loss in the BLSA was associated with increased risk of dementia in the UK Biobank (n = 495,896), with many also associated with increased risk in the Finnish multicohort sample (n = 273,132). From a set of 260 infection‐related proteins, we identified 35 candidate proteins that also predicted changes in brain regions vulnerable to infection‐specific atrophy (Figure 2A‐F). Many candidate proteins were related to cognitive decline, plasma ADRD biomarkers or mechanistically implicated in longitudinal brain volume loss in Mendelian randomization analyses (Figure 2G‐H; Figure 3A).ConclusionWe demonstrate that infections are linked to accelerated regional brain atrophy and dementia risk. Additionally, we identify molecular mediators by which infections may contribute to neurodegeneration (Figure 3B).