The magnetization transfer ratio of the post-mortem canine intervertebral disk is positively correlated to Pfirrmann grading on high field 3.0T MRI: a pilot study.

Objective: Intervertebral disk (IVD) degeneration usually occurs earlier in chondrodystrophic dog breeds than in other breeds. Spinal cord compression secondary to IVD degeneration is the most common cause of myelopathy in these dogs. Standard magnetic resonance imaging (MRI) sequences permit the identification of IVD degeneration and its consequences on adjacent neurological structures. In human medicine, quantitative MRI sequences, such as magnetization transfer ratio (MTR) sequences, are developed and used to detect early IVD degeneration. This prospective randomized post-mortem comparative study aimed to evaluate the correlation between a qualitative Pfirrmann MRI grading and the MTR values of the IVD in chondrodystrophic dogs. Materials and methods: Vertebral columns of eight canine cadavers were frozen and thawed prior to imaging with T2-weighted and MTR sequences using a 3.0 T high-field MRI. These sequences were reviewed by two observers. A Spearman correlation coefficient was calculated in order to compare the MTR values with the Pfirrmann grade. Pearson correlation coefficients were calculated to evaluate the inter-observer agreement of the delineation of the region of interest (ROI) around the NP and the MTR values. A Wilcoxon-Mann-Whitney test was used to conclude on the significance of the correlation between the MTR values and the Pfirrmann grades. Results: There were 138 intervertebral disks analyzed: 29/138 (21.0%) IVD were grade I, 74/138 (53.6%) grade II, and 35/138 (25.4%) grade III. No grades IV and V were present in this study. Inter-observer agreement for delineation of IVD ROI was fair (r = 0.54) but inter-observer agreement of mean MTR value within the ROI was very good (r = 0.89). Mean MTR values were 16.459% (10.0305-21.0950%) for grade I, 18.888% (10.0750-27.2400%) for grade II, and 22.813% (12.5700-31.7600%) for grade III. The mean MTR value was significantly different between each Pfirrmann grade: between grades I and II (p < 0.005), grades II and III (p < 0.05), and grades I and III (p < 0.005). There was a significant moderate positive correlation between Pfirrmann grading and mean MTR values (r = 0.516). Conclusion: The magnetization transfer ratio seems to be an objective method to detect early intervertebral disk degeneration via quantitative analysis.

Progressive Brain Atrophy in Multiple System Atrophy: A Longitudinal, Multicenter, Magnetic Resonance Imaging Study.

OBJECTIVE: To determine the rates of brain atrophy progression in vivo in patients with multiple system atrophy (MSA). BACKGROUND: Surrogate biomarkers of disease progression are a major unmet need in MSA. Small-scale longitudinal studies in patients with MSA using magnetic resonance imaging (MRI) to assess progression of brain atrophy have produced inconsistent results. In recent years, novel MRI post-processing methods have been developed enabling reliable quantification of brain atrophy in an automated fashion. METHODS: Serial 3D-T1-weighted MRI assessments (baseline and after 1 year of follow-up) of 43 patients with MSA were analyzed and compared to a cohort of early-stage Parkinson's disease (PD) patients and healthy controls (HC). FreeSurfer's longitudinal analysis stream was used to determine the brain atrophy rates in an observer-independent fashion. RESULTS: Mean ages at baseline were 64.4 ± 8.3, 60.0 ± 7.5, and 59.8 ± 9.2 years in MSA, PD patients and HC, respectively. A mean disease duration at baseline of 4.1 ± 2.5 years in MSA patients and 2.3 ± 1.4 years in PD patients was observed. Brain regions chiefly affected by MSA pathology showed progressive atrophy with annual rates of atrophy for the cerebellar cortex, cerebellar white matter, pons, and putamen of -4.24 ± 6.8%, -8.22 ± 8.8%, -4.67 ± 4.9%, and - 4.25 ± 4.9%, respectively. Similar to HC, atrophy rates in PD patients were minimal with values of -0.41% ± 1.8%, -1.47% ± 4.1%, -0.04% ± 1.8%, and -1.54% ± 2.2% for cerebellar cortex, cerebellar white matter, pons, and putamen, respectively. CONCLUSIONS: Patients with MSA show significant brain volume loss over 12 months, and cerebellar, pontine, and putaminal volumes were the most sensitive to change in mid-stage disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The long-term impact of irradiation on functional connectivity in brain circuits involved in memory processes after pediatric posterior fossa tumor.

PURPOSE: Memory is one of the main specific cognitive domains impaired with attention and processing speed after a pediatric brain tumor. This work explored the long-term impact of radiotherapy in children with posterior fossa tumor (PFT) on brain connectivity in neural circuits involved in memory using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: A total of 20 irradiated and 15 non-irradiated PFT survivors, and 21 healthy controls, prospectively included in the IMPALA study (NCT04324450), performed memory tests assessing episodic, procedural, and working memories and were subjected to an rs-fMRI. We manually contoured main structures involved in memory to explore connectivity at rest in a seed-to-voxel analysis. The groups were compared and differences in connectivity were correlated with behavioral scores and irradiation doses. RESULTS: The performance of all mnesic tasks was lower in PFT survivors with a greater alteration in working and episodic memory in irradiated patients. Irradiated survivors had atypical connectivities in all memory circuits compared to controls and in cortico-caudate and cortico-cerebellar circuits compared to non-irradiated survivors. Non-irradiated survivors had only atypical connectivities in the cortico-cerebellar circuits compared to controls. In irradiated survivors, atypical connectivities in cortico-hippocampal circuits were linked with episodic memory scores and dose of irradiation to the left hippocampus and in cortico-striatal circuits with procedural memory scores and dose of irradiation to the striatum. CONCLUSION: The results of this study highlight that irradiation has a long-term impact on brain connectivity in brain circuits involved in memory after pediatric PFT with a specific radiation-dose effect in supratentorial structures.

Diffusion tensor imaging tractography in the one-humped camel (Camelus dromedarius) brain.

Introduction: Tractography is a technique used to trace the pathways of the brain using noninvasive diffusion tensor imaging (DTI) data. It is becoming increasingly popular for investigating the brains of domestic mammals and other animals with myelinated fibers but the principle of DTI can also apply for those with unmyelinated fibers. In the case of camels, DTI tractography is a promising method for enhancing current knowledge of the brain's structural connectivity and identifying white-matter tract changes potentially linked to neurodegenerative pathologies. The present study was therefore designed to describe representative white-matter tracts in the one-humped camel DTI tractography. Methods: Post mortem DTI was used to obtain images of two one-humped camel brains using a 3 Tesla system. T2-weighted images were also acquired to identify regions of interest for each fiber tract and a fiber dissection technique was used to complement the DT images. The main association, commissural, and projection fibers were reconstructed and superimposed on T2-weighted images or fractional anisotropy maps. Results: The results of the present study show the reconstruction of the most representative tracts, ie the cingulum, the corpus callosum and the internal capsule, in the one-humped camel brain using DTI data acquired post mortem. These DTI results were compared to those from fiber dissection. Discussion: Anatomy of the cingulum, corpus callosum and internal capsule correlates well with the description in anatomical textbooks and appears to be similar to fibers describe in large animals. Further research will be required to improve and validate these findings and to generate a tractography atlas based on MRI and histological data, as such an atlas would be a valuable resource for future neuroimaging research.

Tomodensitometric and histological age-related changes in the normal feline middle and inner ear.

Deafness in cats may be due to acquired causes such as aging. Similar age-related morphological changes in the cochlea have been noted in several animal species. However, little is known about the effects of age on the morphology of the middle and inner ear in cats. The aim of the present study was to compare these structures in middle-aged and geriatric cats using computed tomography and histological morphometric analysis. Data were obtained from 28 cats, aged 3-18 years, with no hearing or neurological disorders. Computed tomography showed an increase in tympanic bulla (middle ear) volume with aging. Histological morphometric analysis revealed thickening of the basilar membrane and atrophy of the stria vascularis (inner ear) in older cats, similar to what has been observed in older humans and dogs. Nevertheless, histological procedures could be improved to provide more data for comparison with different forms of presbycusis in humans.

Volumetric assessment and longitudinal changes of subcortical structures in formalinized Beagle brains.

High field MRI is an advanced technique for diagnostic and research purposes on animal models, such as the Beagle dog. In this context, studies on neuroscience applications, e.g. aging and neuro-pathologies, are currently increasing. This led to a need for reference values, in terms of volumetric assessment, for the structures typically involved. Nowadays, several canine brain MRI atlases have been provided. However, no reports are available regarding the measurements' reproducibility and little is known about the effect of formalin on MRI segmentation. Here, we assessed the segmentation variability of selected structures among operators (two operators segmented the same data) in a sample of 11 Beagle dogs. Then, we analyzed, for one Beagle dog, the longitudinal volumetric changes of these structures. We considered four conditions: in vivo, post mortem (after euthanasia), ex vivo (brain extracted and studied after 1 month in formalin, and after 12 months). The MRI data were collected with a 3 T scanner. Our findings suggest that the segmentation procedure was overall reproducible since only slight statistical differences were detected. In the post mortem/ ex vivo comparison, most structures showed a higher contrast, thereby leading to greater reproducibility between operators. We observed a net increase in the volume of the studied structures. This could be justified by the intrinsic relaxation time changes observed because of the formalin fixation. This led to an improvement in brain structure visualization and segmentation. To conclude, MRI-based segmentation seems to be a useful and accurate tool that allows longitudinal studies on formalin-fixed brains.

Ex vivo susceptibility-weighted imaging anatomy of canine brain-comparison of imaging and histological sections.

Now that access of large domestic mammals to high-field MRI becomes more common, techniques initially implemented for human patients can be used for the structural and functional study of the brain of these animals. Among them, susceptibility-weighted imaging (SWI) is a recent technique obtained from gradient echo (GE) imaging that allow for an excellent anatomical tissue contrast and a non-invasive assessment of brain iron content. The goal of this study was to design an optimal GE SWI imaging protocol to be used in dogs undergoing an MRI examination of the brain in a 3-Tesla scanner. This imaging protocol was applied to ex vivo brains from four dogs. The imaging protocol was validated by visual inspection of the SWI images that provided a high anatomical detail, as demonstrated by their comparison with corresponding microscopic sections. As resolvable brain structures were labeled, this study is the first to provide an anatomic description of SWI images of the canine brain. Once validated in living animals, this GE SWI imaging protocol could be easily included in routine neuroimaging protocols to improve the diagnosis of various intracranial diseases of dogs, or be used in future comparative studies aiming at evaluating brain iron content in animals.

Insular functional connectivity in migraine with aura.

INTRODUCTION: Insula plays an integrating role in sensory, affective, emotional, cognitive and autonomic functions in migraine, especially in migraine with aura (MA). Insula is functionally divided into 3 subregions, the dorsoanterior, the ventroanterior and the posterior insula respectively related to cognition, emotion, and somatosensory functions. This study aimed at investigating functional connectivity of insula subregions in MA. METHODS: Twenty-one interictal patients with MA were compared to 18 healthy controls (HC) and 12 interictal patients with migraine without aura (MO) and were scanned with functional MRI during the resting state. Functional coupling of the insula was comprehensively tested with 12 seeds located in the right and left, dorsal, middle, ventral, anterior and posterior insula, by using a seed-to-voxel analysis. RESULTS: Seed-to-voxel analysis revealed, in MA, a strong functional coupling of the right and left antero-dorsal insula with clusters located in the upper cerebellum. The overlap of these cerebellar clusters corresponded to the vermis VI. These functional couplings were not correlated to duration of MA, frequency of MA attacks nor time since last MA attack, and were not found in MO. DISCUSSION: The anterior insula and superior cerebellum, including vermis VI, are components of the central Autonomic Nervous System (ANS) network. As these regions are involved in the control of cardiovascular parasympathetic tone, we hypothesize that this connectivity may reflect the cardiovascular features of MA. CONCLUSION: The anterior dorsal insula is connected with vermis VI in MA patients in the resting state. This connectivity may reflect the cardiovascular features of MA. TRIAL REGISTRATION: NCT02708797.

A prospective behavioral and imaging study exploring the impact on long-term memory of radiotherapy delivered for a brain tumor in childhood and adolescence.

BACKGROUND: Posterior fossa tumors represent two thirds of brain tumors in children. Although progress in treatment has improved survival rates over the past few years, long-term memory impairments in survivors are frequent and have an impact on academic achievement. The hippocampi, cerebellum and cerebellar-cortical networks play a role in several memory systems. They are affected not only by the location of the tumor itself and its surgical removal, but also by the supratentorial effects of complementary treatments, particularly radiotherapy. The IMPALA study will investigate the impact of irradiation doses on brain structures involved in memory, especially the hippocampi and cerebellum. METHODS/DESIGN: In this single-center prospective behavioral and neuro-imaging study, 90 participants will be enrolled in three groups. The first two groups will include patients who underwent surgery for a posterior fossa brain tumor in childhood, who are considered to be cured, and who completed treatment at least 5 years earlier, either with radiotherapy (aggressive brain tumor; Group 1) or without (low-grade brain tumor; Group 2). Group 3 will include control participants matched with Group 1 for age, sex, and handedness. All participants will perform an extensive battery of neuropsychological tests, including an assessment of the main memory systems, and undergo multimodal 3 T MRI. The irradiation dose to the different brain structures involved in memory will be collected from the initial radiotherapy dosimetry. DISCUSSION: This study will provide long-term neuropsychological data about four different memory systems (working memory, episodic memory, semantic memory, and procedural memory) and the cognitive functions (attention, language, executive functions) that can interfere with them, in order to better characterize memory deficits among the survivors of brain tumors. We will investigate the correlations between neuropsychological and neuroimaging data on the structural (3DT1), microstructural (DTI), functional (rs-fMRI), vascular (ASL) and metabolic (spectroscopy) impact of the tumor and irradiation dose. This study will thus inform the setting of dose constraints to spare regions linked to the development of cognitive and memory functions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04324450, registered March 27, 2020, updated January 25th, 2021. Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT04324450.

Iron distribution in the lentiform nucleus: A post-mortem MRI and histology study.

Iron plays an important role in many neurobiological processes, especially in the basal ganglia, the brain structures with the highest concentration. Composed of the pallidum and putamen, the lentiform nucleus plays a key role in the basal ganglia circuitry. With MRI advances, iron-based sequences such as R2* and quantitative susceptibility mapping (QSM) are now available for detecting and quantifying iron in different brain structures. Since their validation using classic iron detection techniques (histology or physical techniques), these sequences have attracted growing clinical attention, especially in the field of extrapyramidal syndromes that particularly affect the basal nuclei. Accurate mapping of iron in these nuclei and their connections is needed to gain a better understanding of this specific anatomy, before considering its involvement in the physiopathological processes. We performed R2* and QSM along with Perls histology, to gain new insights into the distribution of iron in the lentiform nucleus and its surrounding structures, based on four specimens obtained from voluntary donors. We found that iron is preferentially distributed in the anterior part of the globus pallidus externus and the posterior part of the putamen. The lateral wall of the putamen is iron-poor, compared with the lateral medullary lamina and intraputaminal fibers. The relevance of perivascular iron concentration, along with pallido- and putaminofugal iron-rich fibers, is discussed.

Modern Brainstem MRI Techniques for the Diagnosis of Parkinson's Disease and Parkinsonisms.

The brainstem is the earliest vulnerable structure in many neurodegenerative diseases like in Multiple System Atrophy (MSA) or Parkinson's disease (PD). Up-to-now, MRI studies have mainly focused on whole-brain data acquisition. Due to its spatial localization, size, and tissue characteristics, brainstem poses particular challenges for MRI. We provide a brief overview on recent advances in brainstem-related MRI markers in Parkinson's disease and Parkinsonism's. Several MRI techniques investigating brainstem, mainly the midbrain, showed to be able to discriminate PD patients from controls or to discriminate PD patients from atypical parkinsonism patients: iron-sensitive MRI, nigrosome imaging, neuromelanin-sensitive MRI, diffusion tensor imaging and advanced diffusion imaging. A standardized multimodal brainstem-dedicated MRI approach at high resolution able to quantify microstructural modification in brainstem nuclei would be a promising tool to detect early changes in parkinsonian syndromes.

Diffusion Tensor Imaging Tractography of White Matter Tracts in the Equine Brain.

Tractography, a noninvasive technique tracing brain pathways from diffusion tensor magnetic resonance imaging (DTI) data, is increasingly being used for brain investigation of domestic mammals. In the equine species, such a technique could be useful to improve our knowledge about structural connectivity or to assess structural changes of white matter tracts potentially associated with neurodegenerative diseases. The goals of the present study were to establish the feasibility of DTI tractography in the equine brain and to provide a morphologic description of the most representative tracts in this species. Postmortem DTI and susceptibility-weighted imaging (SWI) of an equine brain were acquired with a 3-T system using a head coil. Association, commissural, and projection fibers, the three fiber groups typically investigated in tractography studies, were successfully reconstructed and overlaid on SWI or fractional anisotropy maps. The fibers derived from DTI correlate well with their description in anatomical textbooks. Our results demonstrate the feasibility of using postmortem DTI data to reconstruct the main white matter tracts of the equine brain. Further DTI acquisitions and corresponding dissections of equine brains will be necessary to validate these findings and create an equine stereotaxic white matter atlas that could be used in future neuroimaging research.

Neuromelanin Locus Coeruleus MRI Contrast in Migraine With Aura.

INTRODUCTION: The locus coeruleus (LC) is one of the brainstem nuclei that may be activated during migraine attack. As LC contains neuromelanin, a by-product of norepinephrine synthesis, it can be delineated in vivo using neuromelanin sensitive magnetic resonance imaging (MRI). The neuromelanin content in LC has been suggested to reflect previous LC activation. We investigated LC MRI contrast in patients with migraine with aura (MWA) and its correlation with migraine features. METHODS: This matched cohort study compared 23 MWA patients aged 30-55 and without comorbidity, to 23 sex- and age-matched healthy controls. The study was conducted in a University Hospital. LC contrast was measured with T1 neuromelanin-sensitive-weighted 3T MRI. Voxels were manually selected by 2 independent researchers and comparison was made twice using intersection and union of the voxels selected by the 2 observers. RESULTS: No difference was found in neuromelanin LC contrast between MWA patients and controls with both the INTER method (0.224 ± 0.042 vs 0.228 ± 0.048; difference: 0.0001 (95%CI: -0.032 to 0.026), P = .799) and UNION method (0.218 ± 0.043 vs 0.222 ± 0.047; difference: -0.0012 (95%CI: -0.031 to 0.026), P = .775). Global LC volume was also similar between the 2 groups with INTER method (15.087 ± 3.965 vs 13.739 ± 3.583; difference: 2 (95%CI: -1 to 4), P = .233) and UNION method (17.522 ± 4.440 vs 16.087 ± 4.274; difference: 1 (95%CI: -2 to 4), P = .270). Moreover, no correlations were found between neuromelanin LC contrast and migraine features (duration of migraine and frequency of attacks). CONCLUSION: These negative findings do not support the use of neuromelanin LC contrast as a biomarker of MA.

Quantitative MRI markers in Parkinson's disease and parkinsonian syndromes.

PURPOSE OF REVIEW: In Parkinson's disease and parkinsonian disorders, the differential diagnosis is still challenging. We aim to review current developments in MRI quantitative markers and their potential in a clinical and neuroscientific setting. RECENT FINDINGS: There have been efforts to improve MRI acquisition methods and to explore new promising biomarkers. In parallel, technological advances in data analysis (i.e. deep learning) open new ways to use these biomarkers. The MRI markers may differ according to the brain structure investigated. Even if the newly adopted acquisition protocols served mainly the development of brainstem-related biomarkers (neuromelanin MRI, nigrosome sensitive MRI), more established markers (e.g. morphometric values) in basal ganglia, cortex and cerebellum demonstrate their relevance especially to differential diagnosis in parkinsonian syndromes. SUMMARY: We provide an overview on recent advances in MRI quantitative markers of Parkinson's disease that we divide for didactic purposes in three anatomical levels - cortical/cerebellum structures, basal ganglia and brainstem. We show the complementarity of new biomarkers sensitive to brain tissue properties to established morphometrics.

Matching ex vivo MRI With Iron Histology: Pearls and Pitfalls.

Iron levels in the brain can be estimated using newly developed specific magnetic resonance imaging (MRI) sequences. This technique has several applications, especially in neurodegenerative disorders like Alzheimer's disease or Parkinson's disease. Coupling ex vivo MRI with histology allows neuroscientists to better understand what they see in the images. Iron is one of the most extensively studied elements, both by MRI and using histological or physical techniques. Researchers were initially only able to make visual comparisons between MRI images and different types of iron staining, but the emergence of specific MRI sequences like R2* or quantitative susceptibility mapping meant that quantification became possible, requiring correlations with physical techniques. Today, with advances in MRI and image post-processing, it is possible to look for MRI/histology correlations by matching the two sorts of images. For the result to be acceptable, the choice of methodology is crucial, as there are hidden pitfalls every step of the way. In order to review the advantages and limitations of ex vivo MRI correlation with iron-based histology, we reviewed all the relevant articles dealing with the topic in humans. We provide separate assessments of qualitative and quantitative studies, and after summarizing the significant results, we emphasize all the pitfalls that may be encountered.

Substantia nigra locations of iron-content, free-water and mean diffusivity abnormalities in moderate stage Parkinson's disease.

BACKGROUND: Prior work demonstrated that free water in the posterior substantia nigra (SN) was elevated in Parkinson's disease (PD) compared to healthy controls (HC) across single- and multi-site cohorts, and increased over 1 year in Parkinson's disease but not in relation with the iron deposition in SN with the relaxometry T2*. OBJECTIVES: The main objective of the present study was to evaluate changes in the SN using relaxometry T2*, single- and bi-tensor models of diffusion magnetic resonance imaging between PD patients and HC. METHODS: 39 subjects participated in this study, including 21 HCs and 18 PD patients, in moderate stage (7 years), whose data were collected at two visits separated by approximately 2 years, underwent 3-T MRI comprising: T2*-weighted, T1-weighted and diffusion tensor imaging (DTI) scans. Relaxometry T2*, bi-tensor free water (FW), free-water-corrected fractional anisotropy, free-water-corrected mean diffusivity, single-tensor fractional anisotropy, and single-tensor mean diffusivity were computed for the anterior, posterior and whole substantia nigra. RESULTS: In the anterior SN, relaxometry T2* values were greater for PD patients than HCs. In the posterior SN, free water, single- and bi-tensor mean diffusivity values were greater for PD patients than HCs. No significant change were found over time in FW/MD/R2* maps for PD patients with moderate stage. CONCLUSION: The specific increase of R2* in the anterior SN concomitant with the specific increase of FW in posterior SN suggests a complementary aspect of the two parameters and, perhaps, different underlying pathophysiological processes.

Imaging grafted cells with [18F]FHBG using an optimized HSV1-TK mammalian expression vector in a brain injury rodent model.

INTRODUCTION: Cell transplantation is an innovative therapeutic approach after brain injury to compensate for tissue damage. To have real-time longitudinal monitoring of intracerebrally grafted cells, we explored the feasibility of a molecular imaging approach using thymidine kinase HSV1-TK gene encoding and [18F]FHBG as a reporter probe to image enzyme expression. METHODS: A stable neuronal cell line expressing HSV1-TK was developed with an optimised mammalian expression vector to ensure long-term transgene expression. After [18F]FHBG incubation under defined parameters, calibration ranges from 1 X 104 to 3 X 106 Neuro2A-TK cells were analysed by gamma counter or by PET-camera. In parallel, grafting with different quantities of [18F]FHBG prelabelled Neuro2A-TK cells was carried out in a rat brain injury model induced by stereotaxic injection of malonate toxin. Image acquisition of the rats was then performed with PET/CT camera to study the [18F]FHBG signal of transplanted cells in vivo. RESULTS: Under the optimised incubation conditions, [18F]FHBG cell uptake rate was around 2.52%. In-vitro calibration range analysis shows a clear linear correlation between the number of cells and the signal intensity. The PET signal emitted into rat brain correlated well with the number of cells injected and the number of surviving grafted cells was recorded via the in-vitro calibration range. PET/CT acquisitions also allowed validation of the stereotaxic injection procedure. Technique sensitivity was evaluated under 5 X 104 grafted cells in vivo. No [18F]FHBG or [18F]metabolite release was observed showing a stable cell uptake even 2 h post-graft. CONCLUSION: The development of this kind of approach will allow grafting to be controlled and ensure longitudinal follow-up of cell viability and biodistribution after intracerebral injection.