Glutamatergic synapse in autism: a complex story for a complex disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathophysiological mechanisms are still unclear. Hypotheses suggest a role for glutamate dysfunctions in ASD development, but clinical studies investigating brain and peripheral glutamate levels showed heterogenous results leading to hypo- and hyper-glutamatergic hypotheses of ASD. Recently, studies proposed the implication of elevated mGluR5 densities in brain areas in the pathophysiology of ASD. Thus, our objective was to characterize glutamate dysfunctions in adult subjects with ASD by quantifying (1) glutamate levels in the cingulate cortex and periphery using proton magnetic resonance spectroscopy and metabolomics, and (2) mGluR5 brain density in this population and in a validated animal model of ASD (prenatal exposure to valproate) at developmental stages corresponding to childhood and adolescence in humans using positron emission tomography. No modifications in cingulate Glu levels were observed between individuals with ASD and controls further supporting the difficulty to evaluate modifications in excitatory transmission using spectroscopy in this population, and the complexity of its glutamate-related changes. Our imaging results showed an overall increased density in mGluR5 in adults with ASD, that was only observed mostly subcortically in adolescent male rats prenatally exposed to valproic acid, and not detected in the stage corresponding to childhood in the same animals. This suggest that clinical changes in mGluR5 density could reflect the adaptation of the glutamatergic dysfunctions occurring earlier rather than being key to the pathophysiology of ASD.

Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study.

Nitrous oxide (N2O) has recently emerged as a potential fast-acting antidepressant but the cerebral mechanisms involved in this effect remain speculative. We hypothesized that the antidepressant response to an Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) would be associated with changes in cerebral connectivity and brain tissue pulsations (BTP). Thirty participants (20 with a major depressive episode resistant to at least one antidepressant and 10 healthy controls-HC, aged 25-50, only females) were exposed to a 1-h single session of EMONO and followed for 1 week. We defined response as a reduction of at least 50% in the MADRS score 1 week after exposure. Cerebral connectivity of the Anterior Cingulate Cortex (ACC), using ROI-based resting state fMRI, and BTP, using ultrasound Tissue Pulsatility Imaging, were compared before and rapidly after exposure (as well as during exposure for BTP) among HC, non-responders and responders. We conducted analyses to compare group × time, group, and time effects. Nine (45%) depressed participants were considered responders and eleven (55%) non-responders. In responders, we observed a significant reduction in the connectivity of the subgenual ACC with the precuneus. Connectivity of the supracallosal ACC with the mid-cingulate also significantly decreased after exposure in HC and in non-responders. BTP significantly increased in the three groups between baseline and gas exposure, but the increase in BTP within the first 10 min was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the subgenual ACC-precuneus, nodes within the default mode network, in depressed participants responders to EMONO. In addition, larger increases in BTP, associated with a significant rise in cerebral blood flow, appear to promote the antidepressant response, possibly by facilitating optimal drug delivery to the brain. Our study identified potential cerebral mechanisms related to the antidepressant response of N2O, as well as potential markers for treatment response with this fast-acting antidepressant.

Neural correlates of mindfulness meditation and hypnosis on magnetic resonance imaging: similarities and differences. A scoping review.

BACKGROUND: Mindfulness meditation (MM) and hypnosis practices are gaining interest in mental health, but their physiological mechanisms remain poorly understood. This study aimed to synthesize the functional, morphometric and metabolic changes associated with each practice using magnetic resonance imaging (MRI), and to identify their similarities and differences. METHODS: MRI studies investigating MM and hypnosis in mental health, specifically stress, anxiety, and depression, were systematically screened following PRISMA guidelines from four research databases (PubMed, Web of Science, Embase, PsycINFO) between 2010 and 2022. RESULTS: In total, 97 references met the inclusion criteria (84 for MM and 13 for hypnosis). This review showed common and divergent points regarding the regions involved and associated brain connectivity during MM practice and hypnosis. The primary commonality between mindfulness and hypnosis was decreased default mode network intrinsic activity and increased central executive network - salience network connectivity. Increased connectivity between the default mode network and the salience network was observed in meditative practice and mindfulness predisposition, but not in hypnosis. CONCLUSIONS: While MRI studies provide a better understanding of the neural basis of hypnosis and meditation, this review underscores the need for more rigorous studies.

Connectivity patterns of the core resting-state networks associated with apathy in late-life depression.

BACKGROUND: Apathy is associated with reduced antidepressant response and dementia in late-life depression (LLD). However, the functional cerebral basis of apathy is understudied in LLD. We investigated the functional connectivity of 5 resting-state networks (RSN) hypothesized to underlie apathy in LLD. METHODS: Resting-state functional MRI data were collected from individuals with LLD who did not have dementia as well as healthy older adults between October 2019 and April 2022. Apathy was evaluated using the diagnostic criteria for apathy (DCA), the Apathy Evaluation Scale (AES) and the Apathy Motivation Index (AMI). Subnetworks whose connectivity was significantly associated with each apathy measure were identified via the threshold-free network-based statistics. Regions that were consistently associated with apathy across the measures were reported as robust findings. RESULTS: Our sample included 39 individuals with LLD who did not have dementia and 26 healthy older adults. Compared with healthy controls, individuals with LLD had an altered intra-RSN and inter-RNS connectivity in the default mode, the cingulo-opercular and the frontoparietal networks. All 3 apathy measurements showed associations with modified intra-RSN connectivity in these networks, except for the DCA in the cingulo-opercular network. The AMI scores showed stronger associations with the cingulo-opercular and frontoparietal networks, whereas the AES had stronger associations with the default mode network and the goal-oriented behaviour network. LIMITATIONS: The study was limited by the small number of participants without apathy according to the DCA, which may have reduced the statistical power of between-group comparisons. Additionally, the reliance on specific apathy measures may have influenced the observed overlap in brain regions. CONCLUSION: Our findings indicate that apathy in LLD is consistently associated with changes in both intra-RSN and inter-RSN connectivity of brain regions implicated in goal-oriented behaviours. These results corroborate previous findings of altered functional RSN connectivity in severe LLD.

Imaging of dopamine transporter with [18F]LBT-999: initial evaluation in healthy volunteers.

BACKGROUND: The aim of this study was to evaluate in healthy human brain the distribution, uptake, and kinetics of [18F]LBT-999, a PET ligand targeting the dopamine transporter, to assess its ability to explore dopaminergic innervation, using a shorter protocol, more convenient for patients than currently with [123I]ioflupane. METHODS: After intravenous injection of [18F]LBT-999, 8 healthy subjects (53-80y) underwent a dynamic PET-scan. Venous samples were concomitantly obtained for metabolites analysis. Time activity curves (TACs) were generated for several ROIs (caudate, putamen, occipital cortex, substantia nigra and cerebellum). Cerebellum was used as reference region to calculate binding potentials (BPND). RESULTS: No adverse events or detectable pharmacological effects were reported. [18F]LBT-999 PET revealed a good cerebral distribution, with an intense and symmetric uptake in both putamen and caudate (BPND of 6.75±1.17 and 6.30±1.17, respectively), without other brain abnormal tracer accumulation. Regional TACs showed a plateau from the maximal uptake, 20min pi, to the end of the acquisition for both caudate and putamen, whereas uptake in substantia nigra decreased progressively. A faster clearance and lowest BPND values were observed in both cortex and cerebellum. Ratios to the cerebellum exhibit value of about 3 in substantia nigra, close to 10 for both caudate and putamen, and remained around the value of 1 in cortex. The parent fraction of [18F]LBT-999 in plasma was 80%, 60% and 45% at 15, 30 and 45 min pi, respectively. CONCLUSIONS: These findings support the usefulness of [18F]LBT-999 for a quantitative clinical evaluation of presynaptic dopaminergic innervation.

Neurocognitive, emotional and neuroendocrine correlates of exposure to sexual assault in women.

BACKGROUND: Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women. METHODS: Twenty-seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities. RESULTS: Relative to the control group, the survivors group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivors group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivors group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories. LIMITATIONS: The small sample size was the main limitation of this study. CONCLUSION: Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved.

Neurocognitive, emotional and neuroendocrine correlates of exposure to sexual assault in women.

BACKGROUND: Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women. METHODS: Twenty-seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities. RESULTS: Relative to the control group, the survivor group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivor group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivor group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories. LIMITATIONS: The small sample size was the main limitation of this study. CONCLUSION: Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved.

Brain tissue pulsatility mediates cognitive and electrophysiological changes in normal aging: Evidence from ultrasound tissue pulsatility imaging (TPI).

Aging is characterized by a cognitive decline of fluid abilities and is also associated with electrophysiological changes. The vascular hypothesis proposes that brain is sensitive to vascular dysfunction which may accelerate age-related brain modifications and thus explain age-related neurocognitive decline. To test this hypothesis, cognitive performance was measured in 39 healthy participants from 20 to 80 years, using tests assessing inhibition, fluid intelligence, attention and crystallized abilities. Brain functioning associated with attentional abilities was assessed by measuring the P3b ERP component elicited through an auditory oddball paradigm. To assess vascular health, we used an innovative measure of the pulsatility of deep brain tissue, due to variations in cerebral blood flow over the cardiac cycle. Results showed (1) a classical effect of age on fluid neurocognitive measures (inhibition, fluid intelligence, magnitude and latency of the P3b) but not on crystallized measures, (2) that brain pulsatility decreases with advancing age, (3) that brain pulsatility is positively correlated with fluid neurocognitive measures and (4) that brain pulsatility strongly mediated the age-related variance in cognitive performance and the magnitude of the P3b component. The mediating role of the brain pulsatility in age-related effect on neurocognitive measures supports the vascular hypothesis of cognitive aging.

In vivo MR spectroscopy of human breast tissue: quantification of fatty acid composition at a clinical field strength (3 T).

OBJECTIVE: To evaluate the feasibility of in vivo measurement of the fatty acid (FA) composition of breast adipose tissue by MRS on a clinical platform. MATERIAL AND METHODS: MRS experiments were performed at 3 T, using a STEAM sequence, on 25 patients diagnosed with breast cancer. MR spectra, acquired on healthy breast tissue, were analysed with the LCModel. RESULTS: The measured values of the saturated fatty acid (SFA), mono-unsaturated fatty acid (MUFA) and poly-unsaturated fatty acid (PUFA) fractions were 23.8 ± 7.1%, 55.4 ± 6.8% and 20.8 ± 4.4%, respectively. The values of SFA, MUFA and PUFA observed in the current study are in the same range as those found in two previous studies performed at 7 T. CONCLUSION: The results of the current study show that it is possible to quantify the fatty acid composition of breast tissue in vivo in a clinical setting (3 T).

FIBRASCAN: a novel method for 3D white matter tract reconstruction in MR space from cadaveric dissection.

INTRODUCTION: Diffusion tractography relies on complex mathematical models that provide anatomical information indirectly, and it needs to be validated. In humans, up to now, tractography has mainly been validated by qualitative comparison with data obtained from dissection. No quantitative comparison was possible because Magnetic Resonance Imaging (MRI) and dissection data are obtained in different reference spaces, and because fiber tracts are progressively destroyed by dissection. Here, we propose a novel method and software (FIBRASCAN) that allow accurate reconstruction of fiber tracts from dissection in MRI reference space. METHOD: Five human hemispheres, obtained from four formalin-fixed brains were prepared for Klingler's dissection, placed on a holder with fiducial markers, MR scanned, and then dissected to expose the main association tracts. During dissection, we performed iterative acquisitions of the surface and texture of the specimens using a laser scanner and two digital cameras. Each texture was projected onto the corresponding surface and the resulting set of textured surfaces was coregistered thanks to the fiducial holders. The identified association tracts were then interactively segmented on each textured surface and reconstructed from the pile of surface segments. Finally, the reconstructed tracts were coregistered onto ex vivo MRI space thanks to the fiducials. Each critical step of the process was assessed to measure the precision of the method. RESULTS: We reconstructed six fiber tracts (long, anterior and posterior segments of the superior longitudinal fasciculus; Inferior fronto-occipital, Inferior longitudinal and uncinate fasciculi) from cadaveric dissection and ported them into ex vivo MRI reference space. The overall accuracy of the method was of the order of 1mm: surface-to-surface registration=0.138mm (standard deviation (SD)=0.058mm), deformation of the specimen during dissection=0.356mm (SD=0.231mm), and coregistration surface-MRI=0.6mm (SD=0.274mm). The spatial resolution of the method (distance between two consecutive surface acquisitions) was 0.345mm (SD=0.115mm). CONCLUSION: This paper presents the robustness of a novel method, FIBRASCAN, for accurate reconstruction of fiber tracts from dissection in the ex vivo MR reference space. This is a major step toward quantitative comparison of MR tractography with dissection results.

Paraffin embedding of the whole human cerebral hemisphere to assess arterial distribution territories.

Commonly used to decode the human brain's structural complexity, ex vivo dissection focuses on a given structure or region but cannot depict the whole brain organization (for example, its arterial distribution territories). Where dissection reaches its limit, the combination of tissue sectioning and 3D reconstruction may provide a volume for the assessment of structures from any view angle, following them dynamically to understand their spatial relationships. However, to produce sections, standard histological tissue processing protocols for paraffin embedding cannot be applied to a cerebral hemisphere as the latter is extensively larger than the conventional specimens. This paper presents a protocol for paraffin embedding of the whole human cerebral hemisphere and a method to reconstruct 3D volumes from serially sectioned and photographed paraffin blocks containing embedded hemispheres. Seven ex vivo whole human cerebral hemispheres were included, two were serially sectioned. Main cerebral arteries were injected with colored media to label arterial territories. A detailed description of every step, from tissue processing to image acquisition of cut blockfaces and volume reconstruction, is provided. Tissue processing and section cutting were reproducible, and the former provided complete and homogeneous paraffin wax impregnation. 3D visualization of the reconstructed whole human cerebral hemisphere successfully showed the distribution territories of the main cerebral arteries. In addition, we discuss the challenges we faced and overcame while developing the presented method and highlight its originality.

Doing more with less: Realistic stereoscopic three-dimensional anatomical modeling from smartphone photogrammetry.

Traditional teaching methods struggle to convey three-dimensional concepts effectively. While 3D virtual models and virtual reality platforms offer a promising approach to teaching anatomy, their cost and specialized equipment pose limitations, especially in disadvantaged areas. A simpler alternative is to use virtual 3D models displayed on regular screens, but they lack immersion, realism, and stereoscopic vision. To address these challenges, we developed an affordable method utilizing smartphone-based 360° photogrammetry, virtual camera recording, and stereoscopic display (anaglyph or side-by-side technique). In this study, we assessed the feasibility of this method by subjecting it to various specimen types: osteological, soft organ, neuroanatomical, regional dissection, and a dedicated 3D-printed testing phantom. The results demonstrate that the 3D models obtained feature a complete mesh with a high level of detail and a realistic texture. Mesh and texture resolutions were estimated to be approximately 1 and 0.2 mm, respectively. Additionally, stereoscopic animations were both feasible and effective in enhancing depth perception. The simplicity and affordability of this method position it as a technique of choice for creating easily photorealistic anatomical models combined with stereoscopic depth visualization.

Direct Inside-Out Observation of Superficial White Matter Fasciculi in the Human Brain.

Background: Recent methodological advances in the study of the cerebral white matter have left short association fibers relatively underexplored due to their compact and juxtacortical nature, which represent significant challenges for both post-mortem post-cortex removal dissection and magnetic resonance-based diffusion imaging. Objective: To introduce a novel inside-out post-mortem fiber dissection technique to assess short association fiber anatomy. Methods: Six cerebral specimens were obtained from a body donation program and underwent fixation in formalin. Following two freezing and thawing cycles, a standardized protocol involving peeling fibers from deep structures towards the cortex was developed. Results: The inside-out technique effectively exposed the superficial white matter. The procedure revealed distinguishable intergyral fibers, demonstrating their dissectability and enabling the identification of their orientation. The assessment of layer thickness was possible through direct observation and ex vivo morphological magnetic resonance imaging. Conclusion: The inside-out fiber technique effectively demonstrates intergyral association fibers in the post-mortem human brain. It adds to the neuroscience armamentarium, overcoming methodological obstacles and offering an anatomical substrate essential for neural circuit modeling and the evaluation of neuroimaging congruence. Impact statement The inside-out fiber dissection technique enables a totally new perception of cerebral connectivity as the observer navigates inside the parenchyma and looks toward the cerebral surface with the subcortical white matter and the cortical mantle in place. This approach has proven very effective for exposing intergyral association fibers, which have shown to be much more distinguishable from an inner perspective. It gave rise to unprecedented images of the human superficial white matter and allowed, for the first time, direct observation of this vast mantle of fascicles on entire cerebral hemisphere aspects.

Quantifying Apathy in Late-Life Depression: Unraveling Neurobehavioral Links Through Daily Activity Patterns and Brain Connectivity Analysis.

BACKGROUND: Better understanding apathy in late-life depression would help improve prediction of poor prognosis of diseases such as dementia. Actimetry provides an objective and ecological measure of apathy from patients' daily motor activity. We aimed to determine whether patterns of motor activity were associated with apathy and brain connectivity in networks that underlie goal-directed behaviors. METHODS: Resting-state functional magnetic resonance imaging and diffusion magnetic resonance imaging were collected from 38 nondemented participants with late-life depression. Apathy was evaluated using the diagnostic criteria for apathy, Apathy Evaluation Scale, and Apathy Motivation Index. Functional principal components (fPCs) of motor activity were derived from actimetry recordings taken for 72 hours. Associations between fPCs and apathy were estimated by linear regression. Subnetworks whose connectivity was significantly associated with fPCs were identified via threshold-free network-based statistics. The relationship between apathy and microstructure metrics was estimated along fibers by diffusion tensor imaging and a multicompartment model called neurite orientation dispersion and density imaging via tractometry. RESULTS: We found 2 fPCs associated with apathy: mean diurnal activity, negatively associated with Apathy Evaluation Scale scores, and an early chronotype, negatively associated with Apathy Motivation Index scores. Mean diurnal activity was associated with increased connectivity in the default mode, cingulo-opercular, and frontoparietal networks, while chronotype was associated with a more heterogeneous connectivity pattern in the same networks. We did not find significant associations between microstructural metrics and fPCs. CONCLUSIONS: Our findings suggest that mean diurnal activity and chronotype could provide indirect ambulatory measures of apathy in late-life depression, associated with modified functional connectivity of brain networks that underlie goal-directed behaviors.

Glutamate levels of the right and left anterior cingulate cortex in autistics adults.

BACKGROUND: The neurobiology of Autism Spectrum Disorder (ASD) is still unknown. Alteration in glutamate metabolism might translate into an imbalance of the excitation/inhibition equilibrium of cortical networks that in turn are related to autistic symptoms, but previous studies using voxel located in bilateral anterior cingulate cortex (ACC) failed to show abnormalities in total glutamate level. Due to the functional differences in the right and left ACC, we sought to determine whether a difference between right and left ACC glutamate levels could be found when comparing ASD patients and control subjects. METHODS: Using single-voxel proton magnetic resonance spectroscopy (1H-MRS), we analyzed the glutamate + glutamine (Glx) concentrations in the left and right ACC of 19 ASD patients with normal IQs and 25 matched control subjects. RESULTS: No overall group differences in Glx were shown, in the left ACC (p = 0.24) or in the right ACC (p = 0.11). CONCLUSIONS: No significant alterations in Glx levels were detected in the left and right ACC in high-functioning autistic adults. In the excitatory/inhibitory imbalance framework, our data reinforce the critical need to analyze the GABAergic pathway, for better understanding of basic neuropathology in autism.

Working memory processing of traumatic material in women with posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with medial frontal and amygdala functional alterations during the processing of traumatic material and frontoparietal dysfunctions during working memory tasks. This functional magnetic resonance imaging (fMRI) study investigated the effects of trauma-related words processing on working memory in patients with PTSD. METHODS: We obtained fMRI scans during a 3-back task and an identity task on both neutral and trauma-related words in women with PTSD who had been sexually abused and in healthy, nonexposed pair-matched controls. RESULTS: Seventeen women with PTSD and 17 controls participated in the study. We found no behavioural working memory deficit for the PTSD group. In both tasks, deactivation of posterior parietal midline regions was more pronounced in patients than controls. Additionally, patients with PTSD recruited the left dorsolateral frontal sites to a greater extent during the processing of trauma-related material than neutral material. LIMITATIONS: This study included only women and did not include a trauma-exposed non-PTSD control group; the results may, therefore, have been influenced by sex or by effects specific to trauma exposure. CONCLUSION: Our results broadly confirm frontal and parietal functional variations in women with PTSD and suggest a compensatory nature of these variations with regard to the retreival of traumatic memories and global attentional deficits, respectively, during cognitively challenging tasks.

Maternal deprivation and milk replacement affect the integrity of gray and white matter in the developing lamb brain.

The psychoendocrine evaluation of lamb development has demonstrated that maternal deprivation and milk replacement alters health, behavior, and endocrine profiles. While lambs are able to discriminate familiar and non-familiar conspecifics (mother or lamb), only lambs reared with their mother develop such clear social discrimination or preference. Lambs reared without mother display no preference for a specific lamb from its own group. Differences in exploratory and emotional behaviors between mother-reared and mother-deprived lambs have also been reported. As these behavioural abilities are supported by the brain, we hypothesize that rearing with maternal deprivation and milk replacement leads to altered brain development and maturation. To test this hypothesis, we examined brain morphometric and microstructural variables extracted from in vivo T1-weighted and diffusion-weighted magnetic resonance images acquired longitudinally (1 week, 1.5 months, and 4.5 months of age) in mother-reared and mother-deprived lambs. From the morphometric variables the caudate nuclei volume was found to be smaller for mother-deprived than for mother-reared lambs. T1-weighted signal intensity and radial diffusivity were higher for mother-deprived than for mother-reared lambs in both the white and gray matters. The fractional anisotropy of the white matter was lower for mother-deprived than for mother-reared lambs. Based on these morphometric and microstructural characteristics we conclude that maternal deprivation delays and affects lamb brain growth and maturation.

Benzodiazepine use and neuroimaging markers of Alzheimer's disease in nondemented older individuals: an MRI and 18F Florbetapir PET study in the MEMENTO cohort.

Recent evidence suggests an association between benzodiazepines (BZDs) use and lower brain amyloid load, a hallmark of AD pathophysiology. Other AD-related markers include hippocampal atrophy, but the effect of BZDs on hippocampal volume remains unclear. We aimed at 1) replicating findings on BZDs use and brain amyloid load and 2) investigating associations between BZDs use and hippocampal volume, in the MEMENTO clinical cohort of nondemented older adults with isolated memory complaint or light cognitive impairment at baseline. Total Standardized Uptake Value Ratio (SUVR) of brain amyloid load and hippocampal volume (HV) were obtained, respectively, from 18F Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI), and compared between BZD chronic users and nonusers using multiple linear regressions adjusted for age, sex, educational level, ApoE ε4 genotype, cognitive and neuropsychiatric assessments, history of major depressive episodes and antidepressant intake. BZD users were more likely to manifest symptoms of depression, anxiety and apathy. In the MRI subgroup, BZD users were also more frequently females with low education and greater clinical impairments as assessed with the clinical dementia rating scale. Short- versus long-acting BZDs, Z-drugs versus non-Z-drugs BZDs, as well as dose and duration of BZD use, were also considered in the analyses. Total SUVR and HV were significantly lower and larger, respectively, in BZD users (n = 38 in the PET subgroup and n = 331 in the MRI subgroup) than in nonusers (n = 251 in the PET subgroup and n = 1840 in the MRI subgroup), with a medium (Cohen's d = -0.43) and low (Cohen's d = 0.10) effect size, respectively. Short-acting BZDs and Z-drugs were more significantly associated with larger HV. We found no effect of dose and duration of BZD use. Our results support the involvement of the GABAergic system as a potential target for blocking AD-related pathophysiology, possibly via reduction in neuronal activity and neuroinflammation. Future longitudinal studies may confirm the causal effect of BZDs to block amyloid accumulation and hippocampal atrophy.

Proton MR spectroscopic imaging of basal ganglia and thalamus in neurofibromatosis type 1: correlation with T2 hyperintensities.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is frequently associated with hyperintense lesions on T2-weighted images called "unidentified bright objects" (UBO). To better characterize the functional significance of UBO, we investigate the basal ganglia and thalamus using spectroscopic imaging in children with NF1 and compare the results to anomalies observed on T2-weighted images. METHODS: Magnetic resonance (MR) data of 25 children with NF1 were analyzed. On the basis of T2-weighted images analysis, two groups were identified: one with normal MR imaging (UBO- group; n = 10) and one with UBO (UBO+ group; n = 15). Within the UBO+ group, a subpopulation of patients (n = 5) only had lesions of the basal ganglia. We analyzed herein seven regions of interest (ROIs) for each side: caudate nucleus, capsulo-lenticular region, lateral and posterior thalamus, thalamus (lateral and posterior voxels combined), putamen, and striatum. For each ROI, a spectrum of the metabolites and their ratio was obtained. RESULTS: Patients with abnormalities on T2-weighted images had significantly lower NAA/Cr, NAA/Cho, and NAA/mI ratios in the lateral right thalamus compared with patients with normal T2. These abnormal spectroscopic findings were not observed in capsulo-lenticular regions that had UBO but in the thalamus region that was devoid of UBO. CONCLUSION: Multivoxel spectroscopic imaging using short-time echo showed spectroscopic abnormalities in the right thalamus of NF1 patients harboring UBO, which were mainly located in the basal ganglia. This finding could reflect the anatomical and functional interactions of these regions.