Glutamate chemical exchange saturation transfer (GluCEST) MRI to evaluate the relationship between demyelination and glutamate content in depressed mice.

Glutamatergic alteration is one of the potential mechanisms of depression. However, there is no consensus on whether glutamate metabolism changes affect the myelin structure of depression in mouse models. Glutamate chemical exchange saturation transfer (GluCEST) is a novel and powerful molecular imaging technique that can visualize glutamate distribution. In this study, we used the GluCEST imaging technique to look at glutamate levels in mice under chronic unpredictable mild stress (CUMS) and how they relate to demyelination. The CUMS mice were exposed to different stress factors for 6 weeks. Evaluated of depression in CUMS mice by behavioral tests. MRI scans were then performed, including T2-mapping, GluCEST, and diffusion tensor imaging (DTI) sequences. Brain tissues were collected for Luxol Fast Blue staining and immunofluorescence staining to analyze the changes in the myelin sheath. Artificially sketched regions of interest (ROI) (corpus callosum, hippocampus, and thalamus) were used to calculate the GluCEST value, fractional anisotropy (FA), and T2 value. Compared with the control group, the GluCEST value in the ROIs of CUMS mice significantly decreased. Similarly, the FA value in ROIs was lower in the CUMS group than in the CTRL group, but the T2 value did not differ significantly between the two groups. The histological results showed that ROIs in the CUMS group had demyelination compared with the CTRL group, indicating that DTI was more sensitive than T2 mapping in detecting myelin abnormalities. Furthermore, the GluCEST value in the ROIs correlates positively with the FA value. These findings suggest that altered glutamate metabolism may be one of the important factors leading to demyelination in depression, and GluCEST is expected to serve as an imaging biological marker for the diagnosis of demyelination in depression.

Hippocampal recording with a soft microelectrode array in a cranial window imaging scheme: a validation study.

The hippocampus has a crucial role in the formation, consolidation and recall of memories as well as in navigation related processes. These functions are in the focus of neuroscience and different disciplines have contributed to this research field for decades. Two-photon imaging in awake animals is a valuable new aspect for these observations, especially when it is supported by electrophysiology. In this study, we applied high speed two-photon hippocampal imaging through a chronically implanted, soft, transparent microelectrode (STM) device incorporated into a cranial window chamber in awake mice. We monitored the impedance of the recording sites over the course of the experiments to observe long-term changes in recording quality. The large-scale ipsilateral local field potential (LFP) recordings from the dorsal hippocampus provided reliable sharp wave-ripples (SPW-Rs), multi-unit activity (MUA) and single-unit activity (SUA) for up to two months. Calcium imaging of GCaMP6f. labeled cells from the CA1 pyramidal layer under the transparent device was possible even after six months in thy1-GCaMP6f. transgenic mice. We investigated the immune response with GFAP staining after the end of the long-term experiments. Based on our results, this dedicated transparent electrode device proved to be suitable for simultaneous two-photon imaging and large-scale electrophysiological measurements in chronic experiments in mice.

Parietal memory network and memory encoding versus retrieval impairments in PD-MCI patients: A hippocampal volume and cortical thickness study.

OBJECTIVE: The pathophysiology behind memory impairment in Parkinson's Disease Mild Cognitive Impairment (PD-MCI) is unclear. This study aims to investigate the hippocampal and cortical atrophy patterns in PD-MCI patients with different types of memory impairments, categorized as Retrieval Failure (RF) and Encoding Failure (EF). METHODS: The study included 16 healthy controls (HC) and 34 PD-MCI patients, divided into RF (N = 18) and EF (N = 16) groups based on their Verbal Memory Processes Test (VMPT) scores, including spontaneous recall, recognition, and Index of Sensitivity to Cueing (ISC). Hippocampal subfields and cortical thicknesses were measured using the FreeSurfer software for automatic segmentation. RESULTS: Compared to the HC group, the EF group exhibited significant atrophy in the left lateral occipital region and the right caudal middle frontal, superior temporal, and inferior temporal regions (p⟨0.05). The RF group displayed significant atrophy in the left lateral occipital, middle temporal, and precentral regions, as well as the right pars orbitalis and superior frontal regions (p⟨0.05). Hippocampal subfield analysis revealed distinct volume differences between HC-EF and RF-EF groups, with significant reductions in the CA1, CA3, and CA4 subregions in the EF group, but no differences between HC and RF groups (p > 0.05). CONCLUSION: Gray matter atrophy patterns differ in PD-MCI patients with encoding and retrieval memory impairments. The significant hippocampal atrophy in the EF group, particularly in the CA subregions, highlights its potential role in disease progression and memory decline. Additionally, the convergence of atrophy in the lateral occipital cortex across both RF and EF groups suggests the involvement of the Parietal Memory Network (PMN) in PD-related memory impairment.

Memory-related brain potentials for visual objects in early AD show impairment and compensatory mechanisms.

Impaired episodic memory is the primary feature of early Alzheimer's disease (AD), but not all memories are equally affected. Patients with AD and amnestic Mild Cognitive Impairment (aMCI) remember pictures better than words, to a greater extent than healthy elderly. We investigated neural mechanisms for visual object recognition in 30 patients (14 AD, 16 aMCI) and 36 cognitively unimpaired healthy (19 in the "preclinical" stage of AD). Event-related brain potentials (ERPs) were recorded while participants performed a visual object recognition task. Hippocampal occupancy (integrity), amyloid (florbetapir) PET, and neuropsychological measures of verbal & visual memory, executive function were also collected. A right-frontal ERP recognition effect (500-700 ms post-stimulus) was seen in cognitively unimpaired participants only, and significantly correlated with memory and executive function abilities. A later right-posterior negative ERP effect (700-900 ms) correlated with visual memory abilities across participants with low verbal memory ability, and may reflect a compensatory mechanism. A correlation of this retrieval-related negativity with right hippocampal occupancy (r = 0.55), implicates the hippocampus in the engagement of compensatory perceptual retrieval mechanisms. Our results suggest that early AD patients are impaired in goal-directed retrieval processing, but may engage compensatory perceptual mechanisms which rely on hippocampal function.

Endocannabinoid concentrations in major depression: effects of childhood maltreatment and relation to hippocampal volume.

Evidence from preclinical animal models suggests that the stress-buffering function of the endocannabinoid (eCB) system may help protect against stress-related reductions in hippocampal volume, as is documented in major depressive disorder (MDD). However, stress exposure may also lead to dysregulation of this system. Thus, pathways from marked stress histories, such as childhood maltreatment (CM), to smaller hippocampal volumes and MDD in humans may depend on dysregulated versus intact eCB functioning. We examined whether the relation between MDD and peripheral eCB concentrations would vary as a function of CM history. Further, we examined whether eCBs moderate the relation of CM/MDD and hippocampal volume. Ninety-one adults with MDD and 62 healthy comparison participants (HCs) were recruited for a study from the Canadian Biomarker Integration Network in Depression program (CAN-BIND-04). The eCBs, anandamide (AEA) and 2-arachidonylglycerol (2-AG), were assessed from blood plasma. Severe CM history was assessed retrospectively via contextual interview. MDD was associated with eCBs, though not all associations were moderated by CM or in the direction expected. Specifically, MDD was associated with higher AEA compared to HCs regardless of CM history, a difference that could be attributed to psychotropic medications. MDD was also associated with higher 2-AG, but only for participants with CM. Consistent with hypotheses, we found lower left hippocampal volume in participants with versus without CM, but only for those with lower AEA, and not moderate or high AEA. Our study presents the first evidence in humans implicating eCBs in stress-related mechanisms involving reduced hippocampal volume in MDD.

Identification of tauopathy-associated lipid signatures in Alzheimer's disease mouse brain using label-free chemical imaging.

There is cumulative evidence that lipid metabolism plays a key role in the pathogenesis of various neurodegenerative disorders including Alzheimer's disease (AD). Visualising lipid content in a non-destructive label-free manner can aid in elucidating the AD phenotypes towards a better understanding of the disease. In this study, we combined multiple optical molecular-specific methods, Fourier transform infrared (FTIR) spectroscopic imaging, synchrotron radiation-infrared (SR-IR) microscopy, Raman and stimulated Raman scattering (SRS) microscopy, and optical-photothermal infrared (O-PTIR) microscopy with multivariate data analysis, to investigate the biochemistry of brain hippocampus in situ using a mouse model of tauopathy (rTg4510). We observed a significant difference in the morphology and lipid content between transgenic (TG) and wild type (WT) samples. Immunohistochemical staining revealed some degree of microglia co-localisation with elevated lipids in the brain. These results provide new evidence of tauopathy-related dysfunction in a preclinical study at a subcellular level.

The brain hierarchically represents the past and future during multistep anticipation.

Memory for temporal structure enables both planning of future events and retrospection of past events. We investigated how the brain flexibly represents extended temporal sequences into the past and future during anticipation. Participants learned sequences of environments in immersive virtual reality. Pairs of sequences had the same environments in a different order, enabling context-specific learning. During fMRI, participants anticipated upcoming environments multiple steps into the future in a given sequence. Temporal structure was represented in the hippocampus and across higher-order visual regions (1) bidirectionally, with graded representations into the past and future and (2) hierarchically, with further events into the past and future represented in successively more anterior brain regions. In hippocampus, these bidirectional representations were context-specific, and suppression of far-away environments predicted response time costs in anticipation. Together, this work sheds light on how we flexibly represent sequential structure to enable planning over multiple timescales.

Performance of Plasma Biomarkers Combined with Structural MRI to Identify Candidate Participants for Alzheimer's Disease-Modifying Therapy.

BACKGROUND: Recently, two monoclonal antibodies that lower amyloid plaques have shown promising results for the treatment of Mild Cognitive Impairment (MCI) and mild dementia due to Alzheimer's disease (AD). These treatments require the identification of cognitively impaired older adults with biomarker evidence of AD pathology using CSF biomarkers or amyloid-PET. Previous studies showed plasma biomarkers (plasma Aß42/Aß40 and p-tau181) and hippocampal volume from structural MRI correlated with brain amyloid pathology. We hypothesized plasma biomarkers with hippocampal volume would identify patients who are suitable candidates for disease-modifying therapy. OBJECTIVES: To evaluate the performance of plasma AD biomarkers and hippocampal atrophy to detect MCI or AD with amyloid pathology confirmed by amyloid-PET or CSF biomarkers in ADNI. DESIGN: A cross-sectional and longitudinal study. SETTING AND PARTICIPANTS: Data were from the Alzheimer's Disease Neuroimaging Initiative. Participants were aged 55-90 years old with plasma biomarker and structural MRI brain data. MEASUREMENTS: The optimum cut-off point for plasma Aß42/Aß40, p-tau181, and NFL and the performance of combined biomarkers and hippocampal atrophy for detecting cognitive impairment with brain amyloid pathology were evaluated. The association between baseline plasma biomarkers and clinical progression, defined by CDR-Sum of Boxes (CDR-SB) and diagnostic conversion over two years, was evaluated using a Weibull time-to-event analysis. RESULTS: A total of 428 participants were included; 167 had normal cognition, 245 had MCI, and 16 had mild AD. Among MCI and AD, 140 participants had elevated amyloid levels by PET or CSF. Plasma Aß42/Aß40 provided the best accuracy (sensitivity 79%, specificity 66%, AUC 0.73, 95% CI 0.68-0.77) to detect drug candidate participants at baseline. Combined plasma Aß42/40, p-tau181, and hippocampal atrophy increased the specificity for diagnosis (96%), but had lower sensitivity (34%), and AUC (0.65). Hippocampal atrophy combined with the abnormal plasma p-tau181 or hippocampal atrophy alone showed high sensitivity to detect clinical progression (by CDR-SB worsening) of the drug-candidate participants within the next 2 years (sensitivity 93% and 89%, respectively). CONCLUSION: Plasma biomarkers and structural MRI can help identify patients who are currently eligible for anti-amyloid treatment and are likely to progress clinically, in cases where amyloid-PET or CSF biomarkers are not available.

Longitudinal hippocampal axis in large-scale cortical systems underlying development and episodic memory.

The hippocampus is functionally specialized along its longitudinal axis with intricate interactions with cortical systems, which is crucial for understanding development and cognition. Using a well-established connectopic mapping technique on two large resting-state functional MRI datasets, we systematically quantified topographic organization of the hippocampal functional connectivity (hippocampal gradient) and its cortical interaction in developing brains. We revealed hippocampal functional hierarchy within the large-scale cortical brain systems, with the anterior hippocampus preferentially connected to an anterior temporal (AT) pathway and the posterior hippocampus embedded in a posterior medial (PM) pathway. We examined the developmental effects of the primary gradient and its whole-brain functional interaction. We observed increased functional specialization along the hippocampal long axis and found a general whole-brain connectivity shift from the posterior to the anterior hippocampus during development. Using phenotypic predictive modeling, we further delineated how the hippocampus is differentially integrated into the whole-brain cortical hierarchy underlying episodic memory and identified several key nodes within PM/AT systems. Our results highlight the importance of hippocampal gradient and its cortical interaction in development and for supporting episodic memory.

Morphological correlates of anxiety-related experiences during a ketamine infusion.

OBJECTIVES: Ketamine exerts rapid antidepressant effects by enhancing neuroplasticity, particularly in the amygdala and hippocampus-regions involved in fear processing and learning. While the role of ketamine's dissociative effects in its antidepressant response is debated, anxiety experienced during infusion has been negatively correlated with treatment outcomes. METHODS: In this single-blind, placebo-controlled study, a subset of 17 healthy volunteers (6 males, 23.12 ± 1.9 years) received intravenously a placebo in the first and 0.5 mg/kg racemic ketamine in the second session. Anxiety-related experiences were assessed by the 5D-ASC score obtained post-infusion, structural magnetic resonance imaging scans were acquired 4 h post-infusion. An anxiety-score was obtained from the 5D-ASC. Relation between post-placebo amygdala volume, hippocampal volume, and its subfields with the anxiety-score were assessed using linear regression models. RESULTS: Results showed a statistically significant negative relation between hippocampal head volume and the anxiety score (ß = -0.733, p = 0.006), with trending negative association for each subfield's head and the score. CONCLUSION: These findings suggest that anxiety-related experiences during ketamine infusion may be mediated by the hippocampus, with smaller hippocampal volumes leading to more anxiety-related experiences. Thus, hippocampal subfield volumes may be used as a predictor for anxiety-related events during ketamine use and might predict treatment outcome in future approaches.

Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline.

White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05-0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorß and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE.

PET imaging identifies anti-inflammatory effects of fluoxetine and a correlation of glucose metabolism during epileptogenesis with chronic seizure frequency.

The serotonergic system has shown to be altered during epileptogenesis and in chronic epilepsy, making selective serotonin reuptake inhibitors interesting candidates for antiepileptogenic therapy. In this study, we aimed to evaluate disease-modifying effects of fluoxetine during experimental epileptogenesis. Status epilepticus (SE) was induced by lithium-pilocarpine, and female rats were treated either with vehicle or fluoxetine over 15 days. Animals were subjected to 18F-FDG (7 days post-SE), 18F-GE180 (15 days post-SE) and 18F-flumazenil positron emission tomography (PET, 21 days post-SE). Uptake (18F-FDG), volume of distribution (18F-GE180) and binding potential (18F-flumazenil) were calculated. In addition, hyperexcitability testing and video-EEG monitoring were performed. Fluoxetine treatment did not alter brain glucose metabolism. 18F-GE180 PET indicated lower neuroinflammation in the hippocampus of treated animals (-22.6%, p = 0.042), but no differences were found in GABAA receptor density. Video-EEG monitoring did not reveal a treatment effect on seizure frequency. However, independently of the treatment, hippocampal FDG uptake 7 days after SE correlated with seizure frequency during the chronic phase (r = -0.58; p = 0.015). Fluoxetine treatment exerted anti-inflammatory effects in rats during epileptogenesis. However, this effect did not alter disease outcome. Importantly, FDG-PET in early epileptogenesis showed biomarker potential as higher glucose metabolism correlated to lower seizure frequency in the chronic phase.

Functional activity and connectivity signatures of ketamine and lamotrigine during negative emotional processing: a double-blind randomized controlled fMRI study.

Ketamine is a highly effective antidepressant (AD) that targets the glutamatergic system and exerts profound effects on brain circuits during negative emotional processing. Interestingly, the effects of ketamine on brain measures are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Examining the antagonistic effects of ketamine and lamotrigine on glutamate transmission holds promise to identify effects of ketamine that are mediated through changes in the glutamatergic system. Investigating this modulation in relation to both the acute and sustained effects of ketamine on functional activity and connectivity during negative emotional processing should therefore provide novel insights. 75 healthy subjects were investigated in a double-blind, single-dose, randomized, placebo-controlled, parallel-group study with three treatment conditions (ketamine, lamotrigine pre-treatment, placebo). Participants completed an emotional face viewing task during ketamine infusion and 24 h later. Acute ketamine administration decreased hippocampal and Default Mode Network (DMN) activity and increased fronto-limbic coupling during negative emotional processing. Furthermore, while lamotrigine abolished the ketamine-induced increase in functional connectivity, it had no acute effect on activity. Sustained (24 h later) effects of ketamine were only found for functional activity, with a significant reduction in the posterior DMN. This effect was blocked by pretreatment with lamotrigine. Our results suggest that both the acute increases in fronto-limbic coupling and the delayed decrease in posterior DMN activity, but not the attenuated limbic and DMN recruitment after ketamine, are mediated by altered glutamatergic transmission.

Associations between parental rearing style and amygdala and hippocampal subfield abnormalities in drug-naive females with anorexia nervosa.

BACKGROUND: Altered volumes in the hippocampus and amygdala have been linked to anorexia nervosa (AN). This study aimed to investigate amygdala and hippocampal subfields volume abnormalities in AN patients, and their associations with parental rearing practices and clinical psychological characteristics. METHODS: This study included twenty-nine drug-naive females with AN from West China Hospital of Sichuan University, China, and fifty-nine age- and gender-matched healthy controls (HCs) recruited through advertisement. All participants underwent T1-weighted imaging. Amygdala and hippocampal subfields volume was calculated using FreeSurfer 7.0. The Core Self-Evaluation Scale (CSES) and Rosenberg Self-Esteem Scale (RSES) were used to assess the psychological characteristics of AN patients. The Egna Minnen av Barndoms Uppfostran (EMBU) was employed to evaluate parental rearing practices. Group differences in brain volumes were analyzed with covariates like age and total intracranial volume (TIV). Partial correlation analysis explored the correlations between brain region volumes and clinical psychological characteristics. RESULTS: AN patients exhibited lower RSES and CSES scores, and more adverse parental rearing style than healthy norms. After adjusting for covariates, AN patients showed decreased gray matter volume (GMV) in the left medial (Me) and cortical (Co) nucleus, as well as in the right hippocampal-amygdala transition area (HATA). GMV in the left Me was correlated with years of education among HCs but not among AN patients. GMV in the right HATA was positively correlated with paternal penalty and severity, as well as maternal overinterference. CONCLUSION: This study supports structure abnormalities in amygdala and hippocampus in AN patients and suggests that parental rearing practices may be associated with hippocampal abnormalities, potentially contributing to the pathophysiology of AN. Addressing appropriate parental rearing styles may offer a positive impact on AN.

Borderline personality disorder and post-traumatic stress disorder in adolescents: protocol for a comparative study of borderline personality disorder with and without comorbid post-traumatic stress disorder (BORDERSTRESS-ADO).

BACKGROUND: Borderline Personality Disorder (BPD) is a prevalent and debilitating psychiatric condition often accompanied by Post-Traumatic Stress Disorder (PTSD), with a substantial prevalence of trauma history among affected individuals. The clinical, cognitive, and cerebral parallels shared with PTSD suggest a trauma-related etiology for BPD. Studies consistently demonstrate a reduction in hippocampal volume in individuals with BPD, echoing findings in PTSD. However, the interpretation of this shared neurobiological profile remains contentious, with ongoing debates regarding the independence of these pathologies or the potential exacerbation of diminished hippocampal volume in BPD due to concurrent PTSD. Differential impacts on hippocampal subfields across both disorders may further complicate interpretation, suggesting the volume of hippocampal subfields as a potential discriminant biomarker. This study aims to characterize the multidimensional specific and shared profiles of BPD and PTSD-related alterations, with a particular emphasis on hippocampal subfields during adolescence, a crucial period in BPD development. METHODS: This study focuses on female adolescents, who are more prevalent in the BPD population. Participants are categorized into three groups: BPD, BPD with comorbid PTSD, and a control group of matched healthy individuals. Data collection encompasses clinical, cognitive, and neuroimaging domains commonly affected in both disorders, utilizing various imaging markers (including gray matter macrostructure, white matter microstructural integrity, and regional functional connectivity). DISCUSSION: This study examines adolescent BPD with and without comorbid PTSD on clinical, neuroimaging, and cognitive levels. It is the first to use a comprehensive multi-modal approach within the same sample. Additionally, it uniquely explores hippocampal subfield volume differences in adolescents. Analysis of the relationship between the investigated domains and the effects of PTSD comorbidity will elucidate specific and shared alteration profiles in both disorders. TRIAL REGISTRATION: IDRCB number 2019-A00366-51 / clinicaltrials.gov ID: NCT0485274. Registered on 21/04/2021.

Subsegmentation of the hippocampus in subgroups of migraine with aura patients: advanced structural neuroimaging study.

BACKGROUND: This study investigated for a possible contributing role of hippocampus in the different clinical phenotypic manifestations of migraine aura. METHODS: Herein, patients were categorized as those with pure visual aura (MwAv), those who reported additional somatosensory and dysphasic symptoms (MwAvsd), and healthy controls (HCs). Neuroimaging data obtained using FreeSurfer-based segmentation of hippocampal subfields were compared between HCs and patients with migraine with aura, as well as between HCs and those with MwAv and MwAvsd. The average migraine aura complexity score (MACS) was calculated for each patient to investigate the correlation between hippocampal subfield volume and migraine aura complexity. RESULTS: Herein, 46 patients with migraine with aura (28 MwAvsd and 18 MwAv) and 31 HCs were included. There were no significant differences in the hippocampal subfields between HCs and patients with migraine with aura. The average MACS negatively correlated with the volumes of the left and right hippocampi, Cornu Ammonis (CA) 1, CA3, CA4, molecular layer, left granule cell layer of the dentate gyrus, hippocampal fissure, and hippocampus-amygdala transition area. The MwAvsd subgroup had significantly smaller whole hippocampal volumes in both hemispheres, as well as in both subicula, compared with the MwAv subgroup and HCs. In addition, the left molecular layer, right CA1, and hippocampal fissures were significantly smaller in the MwAvsd group than in the MwAv subgroup and HCs. CONCLUSIONS: Smaller left and right hippocampal volumes, particularly of the subiculum/CA1 area, may play an important role in the pathophysiology of somatosensory and dysphasic symptoms in migraine with aura.

Comprehensive Analysis of the 5xFAD Mouse Model of Alzheimer's Disease Using dMRI, Immunohistochemistry, and Neuronal and Glial Functional Metabolic Mapping.

Alzheimer's disease (AD) is characterized by complex interactions between neuropathological markers, metabolic dysregulation, and structural brain changes. In this study, we utilized a multimodal approach, combining immunohistochemistry, functional metabolic mapping, and microstructure sensitive diffusion MRI (dMRI) to progressively investigate these interactions in the 5xFAD mouse model of AD. Our analysis revealed age-dependent and region-specific accumulation of key AD markers, including amyloid-beta (Aß), GFAP, and IBA1, with significant differences observed between the hippocampal formation and upper and lower regions of the cortex by 6 months of age. Functional metabolic mapping validated localized disruptions in energy metabolism, with glucose hypometabolism in the hippocampus and impaired astrocytic metabolism in the cortex. Notably, increased cortical glutaminolysis suggested a shift in microglial metabolism, reflecting an adaptive response to neuroinflammatory processes. While dMRI showed no significant microstructural differences between 5xFAD and wild-type controls, the study highlights the importance of metabolic alterations as critical events in AD pathology. These findings emphasize the need for targeted therapeutic strategies addressing specific metabolic disturbances and underscore the potential of integrating advanced imaging with metabolic and molecular analyses to advance our understanding of AD progression.

A (sub)field guide to quality control in hippocampal subfield segmentation on high-resolution T2-weighted MRI.

Inquiries into properties of brain structure and function have progressed due to developments in magnetic resonance imaging (MRI). To sustain progress in investigating and quantifying neuroanatomical details in vivo, the reliability and validity of brain measurements are paramount. Quality control (QC) is a set of procedures for mitigating errors and ensuring the validity and reliability of brain measurements. Despite its importance, there is little guidance on best QC practices and reporting procedures. The study of hippocampal subfields in vivo is a critical case for QC because of their small size, inter-dependent boundary definitions, and common artifacts in the MRI data used for subfield measurements. We addressed this gap by surveying the broader scientific community studying hippocampal subfields on their views and approaches to QC. We received responses from 37 investigators spanning 10 countries, covering different career stages, and studying both healthy and pathological development and aging. In this sample, 81% of researchers considered QC to be very important or important, and 19% viewed it as fairly important. Despite this, only 46% of researchers reported on their QC processes in prior publications. In many instances, lack of reporting appeared due to ambiguous guidance on relevant details and guidance for reporting, rather than absence of QC. Here, we provide recommendations for correcting errors to maximize reliability and minimize bias. We also summarize threats to segmentation accuracy, review common QC methods, and make recommendations for best practices and reporting in publications. Implementing the recommended QC practices will collectively improve inferences to the larger population, as well as have implications for clinical practice and public health.

The Effect of Segmentation Method on Medial Temporal Lobe Subregion Volumes in Aging.

Early stages of Alzheimer's disease (AD) are associated with volume reductions in specific subregions of the medial temporal lobe (MTL). Using a manual segmentation method-the Olsen-Amaral-Palombo (OAP) protocol-previous work in healthy older adults showed that reductions in grey matter volumes in MTL subregions were associated with lower scores on the Montreal Cognitive Assessment (MoCA), suggesting atrophy may occur prior to diagnosis of mild cognitive impairment, a condition that often progresses to AD. However, current "gold standard" manual segmentation methods are labour intensive and time consuming. Here, we examined the utility of Automatic Segmentation of Hippocampal Subfields (ASHS) to detect volumetric differences in MTL subregions of healthy older adults who varied in cognitive status as determined by the MoCA. We trained ASHS on the OAP protocol to create the ASHS-OAP atlas and then examined how well automated segmentation replicated manual segmentation. Volumetric measures obtained from the ASHS-OAP atlas were also contrasted against those from the ASHS-PMC atlas, a widely used atlas provided by the ASHS team. The pattern of volumetric results was similar between the ASHS-OAP atlas and manual segmentation for anterolateral entorhinal cortex and perirhinal cortex, suggesting that ASHS-OAP is a viable alternative to current manual segmentation methods for detecting group differences based on cognitive status. Although ASHS-OAP and ASHS-PMC produced varying volumes for most regions of interest, they both identified early signs of neurodegeneration in CA2/CA3/DG and identified marginal differences in entorhinal cortex. Our findings highlight the utility of automated segmentation methods but still underscore the need for a unified and harmonized MTL segmentation atlas.