Olivary Nucleus Research Articles

Radiological Hypertrophic Olivary Degeneration Following Posterior Fossa Tumor Surgery

Hypertrophic olivary degeneration is a rare form of transsynaptic degeneration, caused by injury to the Dentato-rubro-olivary pathway (DROP). Radiologically this manifests as T2 hyperintensity, with or without enlargement of the inferior olivary nucleus (ION). The purpose of the study was to evaluate the incidence, associated imaging characteristics, potential etiologies, latency period, and temporal progression of HOD in patients undergoing surgical resection of posterior fossa tumors (PFTs). A retrospective analysis of patients with PFTs and post-surgical MRI scans was conducted. HOD was diagnosed based on ION signal abnormalities and size changes. Demographics, tumor characteristics, time to HOD onset, involved DROP components, and clinical symptoms were recorded. HOD was seen in 40 (6.2%) patients following PFT surgery. 26 patients were aged 17 or less while the rest were older than 17 years. Medulloblastoma was the most frequently diagnosed tumor type (n=25), followed by pilocytic astrocytoma (n=8), ependymoma (n=6), and high grade glioma (n=1). No statistical association was found between the development of HOD and tumor grade (p=0.882). Ataxia was the most commonly reported clinical symptom (n=15). The time elapsed between surgery and the diagnosis of HOD varied, with median intervals of 1 month, 5 months, and 37 months for different stages. Dentate nucleus was the most commonly affected component of the DROP (n=36). HOD is a frequently overlooked postoperative complication following PFT resection. Increased recognition of HOD by neuroradiologists is essential for timely diagnosis and avoidance of unnecessary diagnostic procedures.

Neuropathologic Findings and Electrolyte Abnormalities in a Case of Lennox-Gastaut Syndrome (SCN2a- related) Encountered at Autopsy

Abstract Introduction/Objective Lennox-Gastaut syndrome is a severe form of childhood epilepsy which may be due to several conditions, including sodium channelopathies which alter neuronal firing patterns. We present a case of a 6-year-old female with Lennox-Gastaut syndrome (SCN2A-related) complicated by developmental delay, spastic quadriplegia, and gastrojejunostomy tube dependence who was referred for medicolegal autopsy due to death subsequent to becoming unresponsive during a supervised bath. Methods/Case Report A complete autopsy was performed, including gross and microscopic examination of all primary organ systems, formal neuropathologic examination, and postmortem microbiology, toxicology, and vitreous electrolyte studies. The decedent showed evidence of developmental delay and flexion contractures of the extremities. No significant traumatic injuries were identified. A postmortem nasopharyngeal swab was positive for Rhinovirus/Enterovirus and Influenza A H3. A postmortem vitreous electrolyte panel demonstrated a dehydration pattern, including markedly elevated sodium and chloride and elevated urea nitrogen. Gross examination of the brain showed a thin corpus callosum, small hippocampi, as well as abnormal cerebellar dentate and inferior olivary nuclei. Microscopic examination of the brain tissue supported the gross findings, including dentato-olivary dysplasia. The cause of death was certified as dehydration complicating Lennox-Gastaut syndrome (SCN2a-related). Rhinovirus/Enterovirus and Influenza A H3 infections were considered contributory to death. The manner of death remained undetermined, since it was unknown if the decedent’s natural diseases, issues following a scheduled gastrojejunostomy feeding regimen, neglect, or some combination thereof caused the dehydration. Results (if a Case Study enter NA) NA Conclusion This case highlights unique and rarely documented neuropathologic findings and electrolyte abnormalities that may be seen in Lennox-Gastaut syndrome associated with an SCN2A mutation in addition to demonstrating the challenges of cause and manner death certification in cases of severe developmental disorders of childhood related to sodium channelopathies.

Electrophysiological correlates of divergent projections in the avian superior olivary nucleus.

The physiological diversity of inhibitory neurons provides ample opportunity to influence a wide range of computational roles through their varied activity patterns, especially via feedback loops. In the avian auditory brainstem, inhibition originates primarily from the superior olivary nucleus (SON) and so it is critical to understand the intrinsic physiological properties and processing capabilities of these neurons. Neurons in the SON receive ascending input via the cochlear nuclei: directly from the intensity-coding cochlear nucleus angularis (NA) and indirectly via the interaural timing nucleus laminaris (NL), which itself receives input from cochlear nucleus magnocellularis. Two distinct populations of SON neurons provide either inhibitory feedback to ipsilateral NA, NL, and the timing cochlear nucleus NM, or to the contralateral SON. To determine whether these populations correspond to distinct response types, we investigated their electrophysiology in brain stem slices using patch clamp electrophysiology. We identified three phenotypes: single spiking, chattering tonic, and regular tonic neurons. The two tonic phenotypes displayed distinct firing patterns and different membrane properties. Fluctuating "noisy" currents used to probe the capability of SON neurons to encode temporal features showed that each phenotype differed in sensitivity to temporally modulated input. By using cell fills and anatomical reconstructions, we could correlate the firing phenotypes with their axonal projection patterns. We found that SON axons exited via three fiber tracts with each tract composed of specific phenotypes. These results provide a basis for understanding the role of specific inhibitory cell types in auditory function and elucidate the organization of the SON outputs.

Early-onset palatal myoclonus in Wernekinck commissure syndrome secondary to caudal paramedian midbrain infarction: A case report and a mini review of the literature

IntroductionWernekinck commissure syndrome (WCS) is an extremely rare midbrain syndrome, which selectively destroys the decussation of the superior cerebellar peduncle and the central tegmental tract, which commonly presents with bilateral cerebellar ataxia, dysarthria, and internuclear ophthalmoplegia. Palatal myoclonus in Wernekinck commissure syndrome is uncommon and often occurs as a late phenomenon due to hypertrophic degeneration of bilateral inferior olivary nuclei. Material and methodA patient with WCS, admitted to our hospital from December 2023, was chosen for this study, and the syndrome's clinical manifestations, imaging features, and etiology were retrospectively analyzed based on the literature. A 68-year-old right-handed East Asian man presented with dizziness, slurred speech, difficulty with swallowing and walking, and rhythmic contractions of the soft palate. He had several risk factors for ischemic cerebrovascular diseases (age, sex, dyslipidemia, hypertension and smoking history). Brain magnetic resonance imaging showed hyperintensity of DWI and hypointensity of ADC at the caudal midbrain which was around the paramedian mesencephalic tegmentum anterior to the aqueduct of midbrain. ResultsHe was diagnosed with Wernekinck commissure syndrome (WCS) secondary to caudal paramedian midbrain infarction. He was started on dual antiplatelet therapy (aspirin and clopidogrel) and intensive statin therapy. Blood pressure and glucose were also adjusted. His symptoms improved rapidly, and he walked steadily and speak clearly after 7 days of treatment. ConclusionsPalatal myoclonus is known to occur as a late phenomenon due to hypertrophic degeneration of bilateral inferior olivary nuclei. However, Our case suggests that palatal myoclonus can occur in the early stages in WCS.

Understanding subcortical projections to the lateral posterior thalamic nucleus and its subregions using retrograde neural tracing.

The rat lateral posterior thalamic nucleus (LP) is composed of the rostromedial (LPrm), lateral (LPl), and caudomedial parts, with LPrm and LPl being areas involved in information processing within the visual cortex. Nevertheless, the specific differences in the subcortical projections to the LPrm and LPl remain elusive. In this study, we aimed to reveal the subcortical regions that project axon fibers to the LPl and LPrm using a retrograde neural tracer, Fluorogold (FG). After FG injection into the LPrm or LPl, the area was visualized immunohistochemically. Retrogradely labeled neurons from the LPrm were distributed in the retina and the region from the diencephalon to the medulla oblongata. Diencephalic labeling was found in the reticular thalamic nucleus (Rt), zona incerta (ZI), ventral lateral geniculate nucleus (LGv), intergeniculate leaflet (IGL), and hypothalamus. In the midbrain, prominent labeling was found in the periaqueductal gray (PAG) and deep layers of the superior colliculus. Additionally, retrograde labeling was observed in the cerebellar and trigeminal nuclei. When injected into the LPl, several cell bodies were labeled in the visual-related regions, including the retina, LGv, IGL, and olivary pretectal nucleus (OPT), as well as in the Rt and anterior pretectal nucleus (APT). Less labeling was found in the cerebellum and medulla oblongata. When the number of retrogradely labeled neurons from the LPrm or LPl was compared as a percentage of total subcortical labeling, a larger percentage of subcortical inputs to the LPl included projections from the APT, OPT, and Rt, whereas a large proportion of subcortical inputs to the LPrm originated from the ZI, reticular formation, and PAG. These results suggest that LPrm not only has visual but also multiple sensory-and motor-related functions, whereas the LPl takes part in a more visual-specific role. This study enhances our understanding of subcortical neural circuits in the thalamus and may contribute to our exploration of the mechanisms and disorders related to sensory perception and sensory-motor integration.

Label-free photoacoustic computed tomography of visually evoked responses in the primary visual cortex and four subcortical retinorecipient nuclei of anesthetized mice.

Many techniques exist for screening retinal phenotypes in mouse models in vision research, but significant challenges remain for efficiently probing higher visual centers of the brain. Photoacoustic computed tomography (PACT), with optical sensitivity to hemodynamic response (HR) in brain and ultrasound resolution, provides unique advantages in comprehensively assessing higher visual function in the mouse brain. We aim to examine the reliability of PACT in the functional phenotyping of mouse models for vision research. A PACT-ultrasound (US) parallel imaging system was established with a one-dimensional (1D) US transducer array and a tunable laser. Imaging was performed at three coronal planes of the brain, covering the primary visual cortex and the four subcortical nuclei, including the superior colliculus, the dorsal lateral geniculate nucleus, the suprachiasmatic nucleus, and the olivary pretectal nucleus. The visual-evoked HR was isolated from background signals using an impulse-based data processing protocol. rd1 mice with rod/cone degeneration, melanopsin-knockout (mel-KO) mice with photoreceptive ganglion cells that lack intrinsic photosensitivity, and wild-type mice as controls were imaged. The quantitative characteristics of the visual-evoked HR were compared. Quantitative analysis of the HRs shows significant differences among the three mouse strains: (1)rd1 mice showed both smaller and slower responses compared with wild type ( , ) and (2)mel-KO mice had lower amplitude but not significantly delayed photoresponses than wild-type mice ( , ). These results agree with the known visual deficits of the mouse strains. PACT demonstrated sufficient sensitivity to detecting post-retinal functional deficits.

IMG-01. LONGITUDINAL SIGNAL CHANGES IN THE DENTATE AND INFERIOR OLIVARY NUCLEI IN PATIENTS WITH CEREBELLAR MUTISM SYNDROME

Abstract BACKGROUND Cerebellar mutism syndrome (CMS) is a complication of posterior fossa surgery with an acute impairment in speech, and long-term neurocognitive deficits. Lesion mapping studies suggest the cognitive symptoms are associated with dentatorubrolivary damage1. We hypothesize that CMS patients will demonstrate more longitudinal MRI signal abnormalities in the dentate and inferior olivary nuclei as compared to non-CMS patients. METHODS MRI brains on 40 pediatric medulloblastoma patients between 2013-2015 were retrospectively reviewed by a neuroradiologist blinded to the diagnosis at pre-operative and immediate, 6-month, 12 month and most recent post-operative time points. The dentate and inferior olivary nuclei were scored for restricted diffusion, T1 and T2 hypo-and hyperintensity. A linear regression with different scores on CMS status (YES vs NO) was applied, after adjusting for age. RESULTS In the dentate nuclei, there was significantly higher T2 hypointensity in the CMS group on immediate (difference is 0.4084, p=0.0467) and most recent (difference is 0.7190, p=0.0386) post-operative MRIs. The CMS group had significantly higher T1 hyperintensity on the 1-year (difference is 0.9254, p=0.0108) and most recent (difference is 1.3291, p<0.001) post-operative MRIs. In the inferior olivary nuclei, there was significantly higher T2 hyperintensity on the 6-month (difference is 0.71, p=0.0045) and 1-year (difference is 0.6356, p=0.0162) post-operative MRIs. CONCLUSION The immediate post-operative findings are suggestive of a hemorrhagic, rather than an ischemic process in the dentate nuclei. On long-term follow up, the signal changes in the dentate and the inferior olivary nuclei represent dystrophic mineralization and hypertrophic degeneration, due to inflammation and axonal degeneration within the dentatorubroolivary tract2

Hypertrophic olivary degeneration following head injury: a case report

BackgroundHypertrophic olivary degeneration (HOD) is a unique type of neuronal degeneration presenting as hypertrophy, in contrast to atrophy as seen in most cases. It presents with classical characteristic clinical features due to involvement of dentate-rubral-olivary pathway, also described as triangle of Guillain and Mollaret formed in midbrain, pons and cerebellum. It can be idiopathic or secondary to infarction, bleeding, tumours, trauma or demyelination. However, the mechanism is still unclear. Herein, we present a case of HOD that had developed after post-traumatic pontine and midbrain haemorrhagic contusion.Case presentationA young male patient presented with progressively increasing tremors of both hands, inability to walk and multiple cranial nerve palsy. Magnetic resonance imaging demonstrated bilateral inferior olivary nucleus enlargement and signal changes seen as T2 and T2-FLAIR hyperintensities and non-enhancing T1 iso-intensities. Based on these features, diagnosis of HOD was made. Patient was kept on conservative management and his condition improved.ConclusionsHypertrophic olivary degeneration is a unique neuronal degeneration with typical clinical manifestations and distinct imaging features. Proper and early recognition and multidisciplinary treatment approach can result in the best outcomes for the patient.

Hypertrophy of the inferior olivary nucleus in corticobasal degeneration: A neuropathological study.

Corticobasal degeneration (CBD) is a rare neurodegenerative disorder. The status of the inferior olivary nucleus (ION) in CBD has been inadequately investigated. In this study, we conducted a pathological investigation of the ION in CBD. We reviewed the data of Japanese patients with pathologically confirmed CBD who underwent consecutive autopsies between 1985 and 2020 at our institute. We retrospectively examined clinical data from medical records and clinicopathological conferences and semi-quantitatively assessed the ION, central tegmental tract, superior cerebellar peduncle, and dentate nucleus. Of the 32 patients included, 14 (43.8%) had hypertrophy of the ION (HION), of whom 6 showed laterality. In the 14 HION cases, with or without laterality, except in 1 unevaluable case, atrophy/myelin pallor of the central tegmental tract was observed on the same side as the hypertrophy. Ten patients with HION, with or without laterality, had atrophy/myelin pallor of the superior cerebellar peduncle on the contralateral side to the hypertrophy. The ION presents with hypertrophic changes in CBD. The lesion is a primary degeneration in CBD and is related to the degeneration of the Guillain-Mollaret triangle. This finding contributes to the elucidation of the specific pathological characteristics of CBD.

Comparison of the connectivity of the posterior intralaminar thalamic nucleus and peripeduncular nucleus in rats and mice.

The posterior intralaminar thalamic nucleus (PIL) and peripeduncular nucleus (PP) are two adjoining structures located medioventral to the medial geniculate nucleus. The PIL-PP region plays important roles in auditory fear conditioning and in social, maternal and sexual behaviors. Previous studies often lumped the PIL and PP into single entity, and therefore it is not known if they have common and/or different brain-wide connections. In this study, we investigate brain-wide efferent and afferent projections of the PIL and PP using reliable anterograde and retrograde tracing methods. Both PIL and PP project strongly to lateral, medial and anterior basomedial amygdaloid nuclei, posteroventral striatum (putamen and external globus pallidus), amygdalostriatal transition area, zona incerta, superior and inferior colliculi, and the ectorhinal cortex. However, the PP rather than the PIL send stronger projections to the hypothalamic regions such as preoptic area/nucleus, anterior hypothalamic nucleus, and ventromedial nucleus of hypothalamus. As for the afferent projections, both PIL and PP receive multimodal information from auditory (inferior colliculus, superior olivary nucleus, nucleus of lateral lemniscus, and association auditory cortex), visual (superior colliculus and ectorhinal cortex), somatosensory (gracile and cuneate nuclei), motor (external globus pallidus), and limbic (central amygdaloid nucleus, hypothalamus, and insular cortex) structures. However, the PP rather than PIL receives strong projections from the visual related structures parabigeminal nucleus and ventral lateral geniculate nucleus. Additional results from Cre-dependent viral tracing in mice have also confirmed the main results in rats. Together, the findings in this study would provide new insights into the neural circuits and functional correlation of the PIL and PP.

483 Radiographic Changes in the Auditory Pathway to Predict Outcomes of Children with Hearing Loss

OBJECTIVES/GOALS: Early diagnosis of congenital sensorineural hearing loss (SNHL) is of paramount importance in preventing speech and language impairment.Diffusion tensor imaging (DTI) MRI can identify brain microstructural changes that may potentially contribute towards prognosticating rehabilitation. METHODS/STUDY POPULATION: We retrospectively reviewed pediatric patients with SNHL who obtained DTI MRI between 2011 and 2019, identifying 16 pediatric patients (age <18 years) with at least moderate asymmetric/bilateral SNHL., and gender-matched controlswithout neurological, developmental, or MRI-based brain macrostructural abnormalities. The following brainstem regions and tracts of the auditory pathway were assessed: superior olivary nucleus (SON), inferior colliculus (IC), ipsilateral tracts between the inferior colliculus and superior olivary nucleus (IC-SON). Diffusion values for bilateral regions and tracts were generated, then averaged to calculate a mean value for fractional anisotropy (FA) and mean diffusivity (MD) for each subject. RESULTS/ANTICIPATED RESULTS: Significant differences were identified in FA values of the SON between the SNHL cohort and controls (0.377±0.056 vs 0.422±0.052; p=0.009). No other FA or MD values were significantly different. In children £5 years, MD was significantly decreased in the SNHL cohort compared to controls in the IC (0.918±0.051 vs 1.120±0.142; p<0.001). In children >5 years, there were no significant differences in MD (1.124±0.198 vs 0.997±0.103; p = 0.119). There were no significant differences in MD or FA in the white matter fibers of the IC-SON tract [applewebdata%3A//720AAF0C-C4CF-459C-A42A-6BAA56C4E4CA#_msocom_2]. DISCUSSION/SIGNIFICANCE: This is the first study to assess microstructural changes in brainstem auditory pathway regions among children with SNHL. Longitudinal studies are warranted to assess the predictive value of DTI imaging for long-term outcomes and prognosticating intervention.

Marked IDO2 expression and activity related to autophagy and apoptosis in brain tissue of fatal tuberculous meningitis

In about 1% of tuberculosis (TB) patients, Mycobacterium tuberculosis (M. tuberculosis) can disseminate to the meninges, causing tuberculous meningitis (TBM) with mortality rate up to 60%.Chronic granulomatous inflammation (non-necrotizing and necrotizing) in the brain is the histological hallmark of TBM. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and the generated kynurenine metabolites exert major effector functions relevant to TB granuloma functioning. Here we have assessed immunohistochemically IDO1 expression and activity and its effector function and that of its isoform, IDO2, in post-mortem brain tissue of patients that demised with neurotuberculosis. We also related these findings to brain tissue of fatal/severe COVID-19. In this study, IDO1 and IDO2 were abundantly expressed and active in tuberculoid granulomas and were associated with the presence of M. tuberculosis as well as markers of autophagy and apoptosis. Like in fatal/severe COVID-19, IDO2 was also prominent in specific brain regions, such as the inferior olivary nucleus of medulla oblongata and cerebellum, but not associated with granulomas or with M. tuberculosis. Spatially associated apoptosis was observed in TBM, whereas in fatal COVID-19 autophagy dominated. Together, our findings highlight IDO2 as a potentially relevant effector enzyme in TBM, which may relate to the symptomology of TBM.

Microstructural Changes in the Brainstem Auditory Pathway in Children With Hearing Loss.

To assess the utility of diffusion tensor imaging of the auditory pathway in children with sensorineural hearing loss (SNHL). Retrospective cohort study. A single academic tertiary children's hospital. Sixteen pediatric patients with bilateral SNHL of at least moderate severity in the poorer ear (eight male; mean age, 5.3 ± 4.9 yrs). Controls consisted of age- and sex-matched children with normal hearing who were imaged for nonotologic, non-neurologic medical concerns and found to have normal magnetic resonance imaging (MRI). Three Tesla MRI scanners were used for diffusion tensor imaging. Quantitative diffusion tensor metrics were extracted from the superior olivary nucleus (SON), inferior colliculus (IC), and ipsilateral fiber tracts between the SON and IC delineated by tractography. We identified differences in fractional anisotropy of the SON between the SNHL cohort and controls (0.377 ± 0.056 vs. 0.422 ± 0.052; p = 0.009), but not in the IC. There were no differences in the mean diffusivity (MD) values in the IC and SON. Among younger children (≤5 yrs), MD was decreased in the SNHL cohort compared with controls in the IC (0.918 ± 0.051 vs. 1.120 ± 0.142; p < 0.001). However, among older children (>5 yrs), there were no differences in MD (1.124 ± 0.198 vs. 0.997 ± 0.103; p = 0.119). There were no differences in MD or fractional anisotropy in the white matter fibers of the IC-SON tract. Our results suggest abnormal neural tracts along the central auditory pathway among children with SNHL. Longitudinal studies should assess the prognostic value of these MRI-based findings for assessing long-term outcomes and determining intervention efficacy.

Olivary body exposure through far lateral and lower retrosigmoid approaches. Comparative analysis of the exposed surface and angle of attack

ObjectivesThroughout neurosurgical history, the treatment of intrinsic lesions located in the brainstem has been subject of much controversy. The brainstem is the anatomical structure of the central nervous system (CNS) that presents the highest concentration of nuclei and fibers, and its simple manipulation can lead to significant morbidity and mortality. Once one of the safe entry points at the medulla oblongata has been established, we wanted to evaluate the safest approach to the olivary body (the most used safe entry zone on the anterolateral surface of the medulla oblongata). The proposed objective was to evaluate the working channel from the surface of each of the far lateral and retrosigmoid approaches to the olivary body: distances, angles of attack and channel content. Material and methodsTo complete this work, a total of 10 heads injected with red/blue silicone were used. A total of 40 approaches were made in the 10 heads used (20 retrosigmoid and 20 far lateral). After completing the anatomical study and obtaining the data referring to all the approaches performed, it was decided to expand the sample of this research study by using 30 high-definition magnetic resonance imaging of anonymous patients without cranial or cerebral pathology. The reference points used were the same ones defined in the anatomical study. After defining the working channels in each of the approaches, the working distances, angle of attack, exposed surface, and the number of neurovascular structures present in the central trajectory were analyzed. ResultsThe distances to the cranial and medial region of the olivary body were 52.71 mm (SD 3.59) from the retrosigmoid approach and 27.94 mm (SD 3.99) from the far lateral; to the most basal region of the olivary body, the distances were 49.93 (SD 3.72) from the retrosigmoid approach and 18.1 mm (SD 2.5) from the far lateral. The angle of attack to the caudal region was 19.44° (SD 1.3) for the retrosigmoid approach and 50.97° (SD 8.01) for the far lateral approach; the angle of attack to the cranial region was 20.3° (SD 1.22) for the retrosigmoid and 39.9° (SD 5.12) for the far lateral. Regarding neurovascular structures, the probability of finding an arterial structure is higher for the lateral far, whereas a neural structure will be more likely from a retrosigmoid approach. ConclusionsAs conclusions of this work, we can say that far lateral approach presents more favorable conditions for the microsurgical treatment of intrinsic bulbar and bulbomedullary lesions approached through the caudal half of the olivary body. In those cases of bulbar and pontine-bulbar lesions approached through the cranial half of the olivary body, the retrosigmoid approach can be considered for selected cases.

Uniparental Disomy as a Mechanism for Combined Oxidative Phosphorylation Deficiency Associated with MRPS34 Gene.

Mitochondrial oxidative phosphorylation (OXPHOS) is a cellular process that generates most of the cellular energy required by the body. Disorders affecting OXPHOS are multisystem diseases caused by pathogenic variants in more than 50 genes. In 2017, biallelic variants in the MRPS34 gene were shown to cause combined oxidative phosphorylation deficiency type 32 (COPD32) (OMIM#617664); however, only 7 patients have been reported in the literature up to this moment. COPD32 is characterized mainly by a severe Leigh-like syndrome. Whole-exome sequencing identified a homozygous pathogenic variant in the MRPS34 gene, c.322-10G>A. Only the mother was heterozygous for this variant. SNP-array analysis was performed, which revealed a region of absence of heterozygosity in variant 16q with 9.8Mb, compatible with maternal uniparental disomy. We report the case of an 18-year-old female with unremarkable family history. The pregnancy was complicated by oligohydramnios, and the neonatal period was unremarkable. She evolved with low weight, mild-moderate developmental delay/intellectual disability, and hypogonadotropic hypogonadism. On examination, she had slender habitus, joint laxity, and kyphoscoliosis. The cardiac evaluation was normal, and the head MRI showed bilateral olivary nucleus degeneration that was not confirmed subsequently. Extensive metabolic studies documented only mild lactate and pyruvate elevation, and the chromosomal microarray was normal. We have reported the case of the first patient with COPD32 due to partial maternal uniparental disomy of chromosome 16, being first in Portugal and seventh in the literature. Contrarily to previous patients, who died in the first months of life or survived with severe DD/ID, and had a Leigh-like syndrome, this case is significantly milder, contributing to a better characterization of the phenotypic spectrum. Recurrence risk is unexpectedly low in this instance. This case illustrates the importance of segregation analysis in patients with homozygous recessive mutations.

Chromatic pupillometry for evaluating melanopsin retinal ganglion cell function in Alzheimer's disease and other neurodegenerative disorders: a review.

The evaluation of pupillary light reflex (PLR) by chromatic pupillometry may provide a unique insight into specific photoreceptor functions. Chromatic pupillometry refers to evaluating PLR to different wavelengths and intensities of light in order to differentiate outer/inner retinal photoreceptor contributions to the PLR. Different protocols have been tested and are now established to assess in-vivo PLR contribution mediated by melanopsin retinal ganglion cells (mRGCs). These intrinsically photosensitive photoreceptors modulate the non-image-forming functions of the eye, which are mainly the circadian photoentrainment and PLR, via projections to the hypothalamic suprachiasmatic and olivary pretectal nucleus, respectively. In this context, chromatic pupillometry has been used as an alternative and non-invasive tool to evaluate the mRGC system in several clinical settings, including hereditary optic neuropathies, glaucoma, and neurodegenerative disorders such as Parkinson's disease (PD), idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD), and Alzheimer's disease (AD). The purpose of this article is to review the key steps of chromatic pupillometry protocols for studying in-vivo mRGC-system functionality and provide the main findings of this technique in the research setting on neurodegeneration. mRGC-dependent pupillary responses are short-wavelength sensitive, have a higher threshold of activation, and are much slower and sustained compared with rod- and cone-mediated responses, driving the tonic component of the PLR during exposure to high-irradiance and continuous light stimulus. Thus, mRGCs contribute mainly to the tonic component of the post-illumination pupil response (PIPR) to bright blue light flash that persists after light stimulation is switched off. Given the role of mRGCs in circadian photoentrainment, the use of chromatic pupillometry to perform a functional evaluation of mRGcs may be proposed as an early biomarker of mRGC-dysfunction in neurodegenerative disorders characterized by circadian and/or sleep dysfunction such as AD, PD, and its prodromal phase iRBD. The evaluation by chromatic pupillometry of mRGC-system functionality may lay the groundwork for a new, easily accessible biomarker that can be exploited also as the starting point for future longitudinal cohort studies aimed at stratifying the risk of conversion in these disorders.

Motor neuron symptoms and pathology burden in de medulla oblongata of FTLD‐TDP brain donors

AbstractBackgroundmotor neuron symptoms (MNS) are the hallmark of amyotrophic lateral sclerosis (ALS), which is clinically and pathologically related to frontotemporal dementia (FTD). Up to 20% of FTD patients are diagnosed with ALS (1). However, MNS are observed in a larger proportion of FTD patients (FTD‐MNS), which do not fulfill clinical diagnostic criteria for concomitant ALS (FTD‐ALS) (2). The burden of TDP‐43 pathology in the hypoglossal nucleus (HN) is higher in FTD‐ALS compared to pure FTD brain donors (3), but little is known about the distribution of TDP‐43 pathology in the medulla oblongata in FTD‐MNS.MethodMNS occurring at any disease stage were assessed from the records of FTLD‐TDP brain donors from the Netherlands Brain Bank (n = 38). The total amount of neurons and the percentage of neurons showing TDP‐43 pathology were counted in the HN, nucleus ambiguus (NA) and inferior olivary nucleus (ION). ANOVA was performed between pure FTD, FTD‐ALS, and FTD‐MNS.Resulta pure FTD syndrome was recorded in 12/38 FTLD‐TDP brain donors. A concomitant FTD‐ALS diagnosis had been established during life for 4/38 brain donors, while 16/38 had FTD‐MNS. The most common MNS were dysphagia (63%), spasticity (29%) and wasting (24%). A higher TDP‐43 burden in the HN and NA was observed in FTD‐ALS compared to FTD (p &lt; 0.05). TDP‐43 burden in the HN and in the ION was significantly higher in FTD‐MNS compared to FTD brain donors (p &lt; 0.05).ConclusionMNS are common in FTD, even in the absence of ALS. MNS in FTD are linked to TDP‐43 burden in the HN, NA and ION.

Visualization of small brain nuclei with a high-spatial resolution, clinically available whole-body PET scanner

ObjectiveTo verify the visibility of physiological 18F-fluorodeoxyglucose (18F-FDG) uptake in nuclei in and around the brainstem by a whole-body (WB) silicon photomultiplier positron emission tomography (SiPM-PET) scanner with point-spread function (PSF) reconstruction using various iteration numbers.MethodsTen healthy subjects (5 men, 5 women; mean age, 56.0 ± 5.0 years) who underwent 18F-FDG PET/CT using a WB SiPM-PET scanner and magnetic resonance imaging (MRI) of the brain including a spin-echo three-dimensional sampling perfection with application-optimized contrasts using different flip angle evolutions fluid-attenuated inversion recovery (3D-FLAIR) and a 3D-T1 magnetization-prepared rapid gradient-echo (T1-MPRAGE) images were enrolled. Each acquired PET image was reconstructed using ordered-subset expectation maximization (OSEM) with iteration numbers of 4, 16, 64, and 256 (subset 5 fixed) + time-of-flight (TOF) + PSF. The reconstructed PET images and 3D-FLAIR images for each subject were registered to individual T1-MPRAGE volumes using normalized mutual information criteria. For each MR-coregistered individual PET image, the pattern of FDG uptake in the inferior olivary nuclei (ION), dentate nuclei (DN), midbrain raphe nuclei (MRN), inferior colliculi (IC), mammillary bodies (MB), red nuclei (RN), subthalamic nuclei (STN), lateral geniculate nuclei (LGN), medial geniculate nuclei (MGN), and superior colliculi (SC) was visually classified into the following three categories: good, clearly distinguishable FDG accumulation; fair, obscure contour of FDG accumulation; poor, FDG accumulation indistinguishable from surrounding uptake.ResultsAmong individual 18F-FDG PET images with OSEM iterations of 4, 16, 64, and 256 + TOF + PSF, the iteration numbers that showed the best visibility in each structure were as follows: ION, MRN, LGN, MGN, and SC, iteration 64; DN, iteration 16; IC, iterations 16, 64, and 256; MB, iterations 64 and 256; and RN and STN, iterations 16 and 64, respectively. Of the four iterations, the 18F-FDG PET image of iteration 64 visualized FDG accumulation in small structures in and around the brainstem most clearly (good, 98 structures; fair, 2 structures).ConclusionsA clinically available WB SiPM-PET scanner is useful for visualizing physiological FDG uptake in small brain nuclei, using a sufficiently high number of iterations for OSEM with TOF and PSF reconstructions.

Brainstem anatomy with 7-T MRI: in vivo assessment and ex vivo comparison

Background The brainstem contains grey matter nuclei and white matter tracts to be identified in clinical practice. The small size and the low contrast among them make their in vivo visualisation challenging using conventional magnetic resonance imaging (MRI) sequences at high magnetic field strengths. Combining higher spatial resolution, signal- and contrast-to-noise ratio and sensitivity to magnetic susceptibility (χ), susceptibility-weighted 7-T imaging could improve the assessment of brainstem anatomy.MethodsWe acquired high-resolution 7-T MRI of the brainstem in a 46-year-old female healthy volunteer (using a three-dimensional multi-echo gradient-recalled-echo sequence; spatial resolution 0.3 × 0.3 × 1.2 mm3) and in a brainstem sample from a 48-year-old female body donor that was sectioned and stained. Images were visually assessed; nuclei and tracts were labelled and named according to the official nomenclature.ResultsThis in vivo imaging revealed structures usually evaluated through light microscopy, such as the accessory olivary nuclei, oculomotor nucleus and the medial longitudinal fasciculus. Some fibre tracts, such as the medial lemniscus, were visible for most of their course. Overall, in in vivo acquisitions, χ and frequency maps performed better than T2*-weighted imaging and allowed for the evaluation of a greater number of anatomical structures. All the structures identified in vivo were confirmed by the ex vivo imaging and histology.ConclusionsThe use of multi-echo GRE sequences at 7 T allowed the visualisation of brainstem structures that are not visible in detail at conventional magnetic field and opens new perspectives in the diagnostic and therapeutical approach to brain disorders.Relevance statementIn vivo MR imaging at UHF provides detailed anatomy of CNS substructures comparable to that obtained with histology. Anatomical details are fundamentals for diagnostic purposes but also to plan a direct targeting for a minimally invasive brain stimulation or ablation.Key points• The in vivo brainstem anatomy was explored with ultrahigh field MRI (7 T).• In vivo T2*-weighted magnitude, χ, and frequency images revealed many brainstem structures.• Ex vivo imaging and histology confirmed all the structures identified in vivo.• χ and frequency imaging revealed more brainstem structures than magnitude imaging.Graphical

Degeneration of olivospinal tract in the upper cervical spinal cord of multiple system atrophy patients: Reappraisal of Helweg's triangular tract.

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder that presents with variable combinations of autonomic dysfunction, cerebellar ataxia, parkinsonism, and pyramidal signs. The inferior olivary nucleus is targeted in MSA, with a phenotype of olivopontocerebellar atrophy in particular, and involvement of the olivocerebellar tract is well known. However, degeneration of the olivospinal tract has not been studied in MSA. We examined 97 spinal cords from consecutively autopsied patients with MSA. Myelin staining revealed that 22 cords (22.7%) had small, bilateral, triangular-shaped tract degeneration in the boundary of the anterior and lateral funiculi, which appeared continuously from C1 to C5. The anatomical pathway of the degenerated tract was consistent with the description of the olivospinal tract provided by Helweg in 1888. The MSA patients showing degeneration of this tract were younger at disease onset (average: 56.4 ± 8.7 years, range: 42-74), and had longer disease duration (average: 10.1 ± 4.8 years, range: 2-25) and more severe olivopontocerebellar changes compared to other MSA patients. Quantitative analyses revealed that patients with olivospinal tract degeneration had a lower neuronal density in the inferior olivary nucleus compared to other patients. Microglial density in this tract was negatively correlated with the neuronal density in the inferior olivary nucleus. The densities of glial cytoplasmic inclusions in the inferior olivary nucleus and in the olivospinal tract were strongly correlated with each other. Neurologically healthy controls (n = 22) and disease controls with Lewy body disease (n = 30), amyotrophic lateral sclerosis (n = 30), and progressive supranuclear palsy (n = 30) did not present the olivospinal tract degeneration. Our results indicate an impairment of the neural connection between the inferior olivary nucleus and the spinal cord in MSA patients, which may develop in a descending manner.