Topographic Distribution Research Articles

The feasibility and technical aspects of trigemino-cervical reflex elicitation in humans under general anesthesia

ObjectiveTo analyze the feasibility, neurophysiological aspects, stimulation patterns, and topographic distribution of trigemino-cervical reflex (TCR) components in humans under general anesthesia. MethodsThis prospective observational study enrolled 20 participants who underwent posterior fossa surgery, surgical proceduresin thecraniovertebral junction,or spinal cord surgery. TCR responses were simultaneously recorded in the sternocleidomastoid (SCM) and trapezius muscles after electrical stimulation of the supraorbital and infraorbital nerves. TCR responses were recorded preoperatively and intraoperatively using single-pulse and multipulse (trains of 2–7 electrical stimuli) stimulation, respectively. Two stimulus duration patterns were evaluated: 0.2–0.5 ms and 0.5–1.0 ms. ResultsIntraoperatively, short- and long-latency TCR components were obtained in the SCM ipsilateral to the stimulation with variable recordability. Short-latency responses were the most commonly recorded components. A longer stimulus duration (0.5–1.0 ms) seems to favor the elicitation of TCR responses under general anesthesia. ConclusionsShort-latency components recorded in the SCM ipsilateral to the stimulation could be regularly elicited under general anesthesia when a larger stimulus duration (0.5–1.0 ms) was applied. SignificanceThis is the first study to demonstrate the elicitation of TCR components in humans under general anesthesia. This neurophysiological technique can potentially optimize intraoperative neurophysiological monitoring during brainstem surgery.

Histologic tau lesions and magnetic resonance imaging biomarkers differ across two progressive supranuclear palsy variants.

Progressive supranuclear palsy is a neurodegenerative disease characterized by the deposition of four-repeat tau in neuronal and glial lesions in the brainstem, cerebellar, subcortical and cortical brain regions. There are varying clinical presentations of progressive supranuclear palsy with different neuroimaging signatures, presumed to be due to different topographical distributions and burden of tau. The classic Richardson syndrome presentation is considered a subcortical variant, whilst progressive supranuclear palsy with predominant speech and language impairment is considered a cortical variant, although the pathological underpinnings of these variants are unclear. In this case-control study, we aimed to determine whether patterns of regional tau pathology differed between these variants and whether tau burden correlated with neuroimaging. Thirty-three neuropathologically confirmed progressive supranuclear palsy patients with either the Richardson syndrome (n = 17) or speech/language (n = 16) variant and ante-mortem magnetic resonance imaging were included. Tau lesion burden was semi-quantitatively graded in cerebellar, brainstem, subcortical and cortical regions and combined to form neuronal and glial tau scores. Regional magnetic resonance imaging volumes were converted to Z-scores using 33 age- and sex-matched controls. Diffusion tensor imaging metrics, including fractional anisotropy and mean diffusivity, were calculated. Tau burden and neuroimaging metrics were compared between groups and correlated using linear regression models. Neuronal and glial tau burden were higher in motor and superior frontal cortices in the speech/language variant. In the subcortical and brainstem regions, only the glial tau burden differed, with a higher burden in globus pallidus, subthalamic nucleus, substantia nigra and red nucleus in Richardson's syndrome. No differences were observed in the cerebellar dentate and striatum. Greater volume loss was observed in the motor cortex in the speech/language variant and in the subthalamic nucleus, red nucleus and midbrain in Richardson's syndrome. Fractional anisotropy was lower in the midbrain and superior cerebellar peduncle in Richardson's syndrome. Mean diffusivity was greater in the superior frontal cortex in the speech/language variant and midbrain in Richardson's syndrome. Neuronal tau burden showed associations with volume loss, lower fractional anisotropy and higher mean diffusivity in the superior frontal cortex, although these findings did not survive correction for multiple comparisons. Results suggest that a shift in the distribution of tau, particularly neuronal tau, within the progressive supranuclear palsy network of regions is driving different clinical presentations in progressive supranuclear palsy. The possibility of different disease epicentres in these clinical variants has potential implications for the use of imaging biomarkers in progressive supranuclear palsy.

Alkali induced changes in spatial distribution of functional groups in carboxymethylated cellulose

The aim of the work was to investigate treatment parameters that exert most influence on performance of cellulose fibers carboxymethylated from aqueous solutions. Viscose fibers were carboxymethylated in alkaline solutions of sodium monochloroacetate at two temperatures (30 °C, 50 °C) and with different levels of alkali (0.5 mol/L and 4 mol/L NaOH). The degree of carboxymethylation was assessed with both back titration and conductometric titration methods, and the performance of carboxymethylated fibers was assessed from their propensity for sorption of the cationic dye methylene blue, a putative wastewater contaminant. Higher degrees of carboxymethylation were generally observed for fibers carboxymethylated in 4 mol/L NaOH, but in dye sorption propensities, the fibers carboxymethylated in 0.5 mol/L NaOH performed better. A combination of observations from dye sorption, color measurement and conductometric titration suggested that dye permeation was greater through fibers carboxymethylated in 0.5 mol/L NaOH as compared to 4 mol/L NaOH. As permeability differences were evinced in cases also where the degrees of carboxymethylation were very similar, it appears that the reaction conditions (i.e., alkali content during carboxymethylation), in addition to degree of carboxymethylation, affected fiber performance. The effect of alkali may stem from their influence on the topographical distribution of the substituted carboxymethyl functional groups.

Exploration of the influence of the quantification method and reference scheme on feedback-related negativity and standardized measurement error of feedback-related negativity amplitudes in a trust game

Various approaches have been taken over the years to quantify event-related potential (ERP) responses and these approaches may vary in their utility connecting empirical research and scientific claims. In this work we compared different quantification methods as well as the influence of three reference methods (linked mastoids, average reference, and current source density) on the resulting ERP amplitude. We use the experimental effects and effect sizes (Cohen's d) to evaluate the different methodological variants and we calculate intraclass correlation coefficients (ICC). In addition, the bootstrapped standard error of the means (SME, Luck et al., 2021), which was recently suggested as a quality criterion for ERP research, is used for this purpose. Our example for an ERP is the feedback-related negativity (FRN) to feedback about trustee behavior in a trust game with participants in the trustor position. We found that the quantification methods concerning the FRN influenced the absolute value of condition effects in the experimental paradigm. Yet, the patterns of effects were detected by all chosen methods, except for the ‘individual difference wave’-based peak window approach. In addition, our findings stress the importance of checking the reference electrodes concerning effects of the experimental conditions. Furthermore, interactions of topographical distribution and reference choice should be considered. Finally, we were able to show that the SME is lower for more datapoints that are given in the quantification period of the FRN, and higher for more negative FRN amplitudes. These biases may lead to divergence of SME and effect size detection. Therefore, if the SME was used to compare different processing choices one should consider controlling for these important aspects of the data and possibly include other quality criteria like effect sizes.

Iron Deposition and Distribution Across the Hippocampus Is Associated with Pattern Separation and Pattern Completion in Older Adults at Risk for Alzheimer's Disease.

Elevated iron deposition in the brain has been observed in older adult humans and persons with Alzheimer's disease (AD), and has been associated with lower cognitive performance. We investigated the impact of iron deposition, and its topographical distribution across hippocampal subfields and segments (anterior, posterior) measured along its longitudinal axis, on episodic memory in a sample of cognitively unimpaired older adults at elevated familial risk for AD (N = 172, 120 females, 52 males; mean age = 68.8 ± 5.4 years). MRI-based quantitative susceptibility maps were acquired to derive estimates of hippocampal iron deposition. The Mnemonic Similarity Task was used to measure pattern separation and pattern completion, two hippocampally mediated episodic memory processes. Greater hippocampal iron load was associated with lower pattern separation and higher pattern completion scores, both indicators of poorer episodic memory. Examination of iron levels within hippocampal subfields across its long axis revealed topographic specificity. Among the subfields and segments investigated here, iron deposition in the posterior hippocampal CA1 was the most robustly and negatively associated with the fidelity memory representations. This association remained after controlling for hippocampal volume and was observed in the context of normal performance on standard neuropsychological memory measures. These findings reveal that the impact of iron load on episodic memory performance is not uniform across the hippocampus. Both iron deposition levels as well as its spatial distribution, must be taken into account when examining the relationship between hippocampal iron and episodic memory in older adults at elevated risk for AD.

Diffusion Magnetic Resonance Imaging Tractography Guides Investigation of the Zona Incerta: A Novel Target for Deep Brain Stimulation

BackgroundThe zona incerta (ZI) is a subcortical structure primarily investigated in rodents that is implicated in various behaviors, ranging from motor control to survival-associated activities, partly due to its integration in multiple neural circuits. In the current study, we used diffusion magnetic resonance imaging tractography to segment the ZI and gain insight into its connectivity in various circuits in humans. MethodsWe performed probabilistic tractography in 7T diffusion MRI on 178 participants from the Human Connectome Project to validate the ZI’s anatomical subdivisions and their respective tracts. K-means clustering segmented the ZI based on each voxel’s connectivity profile. We further characterized the connections of each ZI subregion using probabilistic tractography with each subregion as a seed. ResultsWe identified 2 dominant clusters that delineated the whole ZI into rostral and caudal subregions. The caudal ZI primarily connected with motor regions, while the rostral ZI received a topographic distribution of projections from prefrontal areas, notably the anterior cingulate and medial prefrontal cortices. We generated a probabilistic ZI atlas that was registered to a patient-participant’s magnetic resonance imaging scan for placement of stereoencephalographic leads for electrophysiology-guided deep brain stimulation to treat their obsessive-compulsive disorder. Rostral ZI stimulation improved the patient’s core symptoms (mean improvement 21%). ConclusionsWe present a tractography-based atlas of the rostral and caudal ZI subregions constructed using high-resolution diffusion magnetic resonance imaging from 178 healthy participants. Our work provides an anatomical foundation to explore the rostral ZI as a novel target for deep brain stimulation to treat refractory obsessive-compulsive disorder and other disorders associated with dysfunctional reward circuitry.

Prevalence, distribution, and severity of cerebral amyloid angiopathy differ between Lewy body diseases and Alzheimer’s disease

Dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and Parkinson’s disease (PD) collectively known as Lewy body diseases (LBDs) are neuropathologically characterised by α-synuclein deposits (Lewy bodies and Lewy neurites). However, LBDs also exhibit pathology associated with Alzheimer’s disease (AD) (i.e. hyperphosphorylated tau and amyloid β (Aβ). Aβ can be deposited in the walls of blood vessels in the brains of individuals with AD, termed cerebral amyloid angiopathy (CAA). The aim of this study was to investigate the type and distribution of CAA in DLB, PDD, and PD and determine if this differs from AD. CAA type, severity, and topographical distribution was assessed in 94 AD, 30 DLB, 17 PDD, and 11 PD cases, and APOE genotype evaluated in a subset of cases where available. 96.3% AD cases, 70% DLB cases and 82.4% PDD cases exhibited CAA (type 1 or type 2). However only 45.5% PD cases had CAA. Type 1 CAA accounted for 37.2% of AD cases, 10% of DLB cases, and 5.9% of PDD cases, and was not observed in PD cases. There was a hierarchical topographical distribution in regions affected by CAA where AD and DLB displayed the same distribution pattern that differed from PDD and PD. APOE ε4 was associated with severity of CAA in AD cases. Topographical patterns and severity of CAA in DLB more closely resembled AD rather than PDD, and as type 1 CAA is associated with clinical dementia in AD, further investigations are warranted into whether the increased presence of type 1 CAA in DLB compared to PDD are related to the onset of cognitive symptoms and is a distinguishing factor between LBDs. Possible alignment of the the topographical distribution of CAA and microbleeds in DLB warrants further investigation. CAA in DLB more closely resembles AD rather than PDD or PD, and should be taken into consideration when stratifying patients for clinical trials or designing disease modifying therapies.

Topographic Distribution of miRNAs (miR-30a, miR-223, miR-let-7a, miR-let-7f, miR-451, and miR-486) in the Plasma Extracellular Vesicles.

There are many articles on the quantitative analysis of miRNAs contained in a population of EVs of different sizes under various physiological and pathological conditions. For such analysis, it is important to correctly quantify the miRNA contents of EVs. It should be considered that quantification is skewed depending on the isolation protocol, and different miRNAs are degraded by nucleases with different efficiencies. In addition, it is important to consider the contribution of miRNAs coprecipitating with the EVs population, because the amount of miRNAs in the EVs population under study is skewed without appropriate enzymatic treatment. By studying a population of EVs from the blood plasma of healthy donors, we found that the absolute amount of miRNA inside the vesicles is commensurate with the amount of the same type of miRNA adhered to the outside of the EVs. The inside/outside ratio ranged from 1.02 to 2.64 for different investigated miRNAs. According to our results, we propose the hypothesis that high occupancy of miRNAs on the outer surface of EVs influence on the transporting RNA repertoire no less than the inner cargo received from the host cell.

Perfil epidemiológico, clínico y alérgico en pacientes con psoriasis. Evaluación del Registro Español de Dermatitis de Contacto (REIDAC)

BackgroundPsoriasis is a chronic inflammatory dermatosis whose clinical and topographic distribution requires differential diagnosis, or the possible association with allergic contact dermatitis (ACD), requiring patch testing (PT) as part of the diagnostic procedure. ObjectivesTo describe the epidemiological, clinical, and allergic profile of patients with a primary or secondary diagnosis of psoriasis undergoing PT and compare them with patients with a diagnosis of ACD at the end of the diagnostic process. MethodsCross-sectional study with data from REIDAC from 2018 through 2023 of selected patients with a diagnosis of psoriasis and/or ACD. ResultsA total of 11 502 patients were included, 513 of whom had been diagnosed with primary or secondary psoriasis, 3640 with ACD, and 108 with both diseases. Men were more predominant in the groups of patients with psoriasis, psoriasis+ACD, and lesions were more predominantly seen in the hands with little association with atopic factors vs the ACD group. The rate of positivity in PT to the 2022 Spanish battery of allergens was lower in the group with psoriasis only in 27% of the patients. The most common allergens found in the psoriasis group were also the most common ones found in the overall ACD population. ConclusionsOverall, 36.2% of psoriatic patients tested positive in PT to the 2022 Spanish battery of allergens, which proved that this association is not uncommon. Overall, psoriatic patients had a higher mean age, were more predominantly men, and showed more hand involvement.

Relationship of Topographic Distribution of Macular Atrophy Secondary to Neovascular AMD and Reading Performance.

The purpose of this study was to provide a topographical assessment of macular atrophy in successfully treated neovascular age-related macular degeneration (AMD) eyes to investigate determinants of monocular reading performance. A total of 60 participants (60 eyes) with previously treated neovascular AMD and absence of optical coherence tomography (OCT) signs of exudation were enrolled. Reading performance was assessed monocularly using Radner charts. The following variables were obtained: (i) the reading acuity was defined as the logarithm of the reading acuity determination (LogRAD), at the smallest sentence, a patient is able to read in less than 30 seconds; (ii) the maximum reading speed was defined as the fastest time achieved and is calculated in words per minute (wpm). OCT images were reviewed for the presence of macular atrophy within the central, 4 inner and 4 outer Early Treatment Diabetic Retinopathy Study (ETDRS) grid subfields. Contributory factors affecting reading performance were examined using univariable and multivariable linear mixed model considering reading acuity and reading speed as dependent variables. Median (interquartile range [IQR]) values were 0.53 (IQR = 0.17) LogRAD for reading acuity, and 144 (60) wpm for maximum reading speed. Thirty-five out of 60 (58.3%) eyes were characterized by the presence of macular atrophy. In multiple regression analysis, reading acuity was significantly associated with presence of macular atrophy in the foveal central circle (P = 0.024). Conversely, the maximum reading speed was associated with presence of macular atrophy in the inner-right ETDRS subfield (P = 0.005). We showed a significant relationship between presence and location of macular atrophy and reading performance in neovascular AMD.

Variation of Wormian and Inca Bones in Adult Skulls

Objective: Irregular and abnormal small additional bones called Wormian bones can be encountered between the skull bones. This study aimed to investigate the incidence, topographical distribution, morphology, and interrelationship of the Wormian and Inca bones in Central Anatolia Region dry adult skulls. Methods: In the study, 119 adult skulls were examined. The location and frequency of additional bones (Wormian) in the sutures in the cranium were determined. Skulls with Inca bones were identified. The Inca bones were typified in accordance with the literature and their dimensions in the transverse and sagittal axis were measured with a digital caliper. Results: Wormian bone was present in 33 of 119 adult skulls (27.7%). Of the 33 bones, 22 were detected in the male (66.66%) and 11 female (33.34%) skulls. The locations of the Wormian bones in the order of decreasing incidence were the lambdoid suture (16.0%, 19/119), pterion (16.0%, 19/119), lambda (7.6%, 9/119), asterion (2.5%, 3/119), and bregma (1.7%, 2/119). Nine Inca bones were found in the lambdoid region (27.3%, 9/33). Six of these bones (66.7%) were in the male skull. We found that two of these bones were incomplete lateral asymmetric, two were complete symmetric bipartite, two were incomplete asymmetric bipartite and three were incomplete median type. We found that 13 (10.9%) of the skulls in the study had metopic sutures and 0.8% had craniosynostosis. When the craniums with metopic suture were evaluated, it was found that 8 of them (61.5%) had additional bone. 50% of the Wormian bones were found in the lambdoid suture. Conclusion: It has been found that the incidence of Wormian bone increases with suture variations. It was determined that the frequency of Inca bone variation may vary depending on regional differences.

En Face Optical Coherence Tomography Illustrates the Trizonal Distribution of Drusen and Subretinal Drusenoid Deposits in the Macula

PurposeTo analyze the topographic distribution of macular drusen and subretinal drusenoid deposits (SDD) using single capture en face spectral domain optical coherence tomography (SD-OCT) imaging. DesignRetrospective case series. MethodsAnalysis of 33 eyes of 20 patients with evidence of SDD. Structural en face OCT images were reconstructed using a 40µ thick slab positioned from 48 to 88 µm above Bruch's membrane. The Early Treatment of Diabetic Retinopathy Study (ETDRS) grid and a rod/cone density map were overlaid upon the en face OCT images and the distribution of different subtypes of SDD and macular drusen were assessed. ResultsA total of 31 eyes (94%) showed a trizonal distribution pattern of drusen and SDD. Whereas small to large drusen tended to aggregate in the central circle, dot SDD predominated in the inner ring and the inner portion of the outer ring of the ETDRS grid and ribbon SDD localized to the outer ring and outside the ETDRS grid. Of note, drusen colocalized to the region of greatest cone density, while ribbon SDD colocalized to the area of greatest rod density. The dot SDD mapped to the intermediate region with mixed rod and cone representation. ConclusionDot and ribbon subtypes of SDD and macular drusen show a characteristic trizonal distribution. The locations of these lesions co-localize according to the different densities of the cones and rods in the retina and may reflect varying pathophysiological activities of these photoreceptor subtypes.

Forensic pilot application of rehydrating solutions on human cadaveric skin: what are the effects on hemorrhagic infiltrates?

The microscopic evaluation of hemorrhagic infiltrates is crucial in forensic diagnostics, but it proves challenging in corificated and mummified cadavers. In these cases, pre-treatment with rehydrating solutions is recommended, although their effects on the hemorrhagic infiltrate are not well understood. In this pilot study, we microscopically investigated the effect of two different rehydrating solutions-Sandison's solution and fabric softener-on well-preserved human cadaveric skin samples taken from areas affected by an ecchymotic lesion, comparing them with direct fixation in formalin. Specifically, we examined the topographic distribution of the hemorrhagic infiltrate in each layer of the skin by assigning a semi-quantitative score, conducted mutual comparisons, and performed statistical analysis. Histologically, compared to direct fixation in formalin, a slight and statistically non-significant reduction in the hemorrhagic infiltrate was observed in samples pre-treated with fabric softener. On the other hand, a more pronounced and statistically significant decrease in scores was observed in samples pre-treated with Sandison's solution. This effect is likely due to the fact that Sandison's solution, due to its components, exerts an osmotic effect, partially inducing osmotic lysis of red blood cells. Overall, extensive areas of hemorrhagic infiltrates were preserved, although to a lesser extent, while smaller foci were markedly reduced, sometimes even disappearing. The findings suggest that Sandison's solution has a detrimental effect on cutaneous hemorrhagic infiltrates, emphasizing the importance of being cautious and conducting dual sampling, using both formalin and a rehydrating solution, for forensic examination of mummified or corificated skin samples.

Morpho-phenotypic characterization of melanoma brain metastases immune microenvironment: A multicentre retrospective study

IntroductionThe recent rise of immunotherapy for melanoma brain metastases (MBM) has enhanced the interest in characterizing the composition of local immune microenvironment. Despite the central nervous system (CNS) is well known for harbouring a peculiar immunological milieu, its role in MBM is only partially understood. The aim of our study was to characterize tumour-infiltrating lymphocytes (TILs) and tumour-associated macrophages (TAMs) distribution and density in a cohort of MBM and their potential relevance as prognostic biomarkers. Materials and methodsNinety-four MBM patients were retrospectively evaluated for morphological, molecular features and follow-up data. Formalin-fixed and paraffin-embedded (FFPE) tissue sections were immunostained with the following antibodies: CD4, CD8, FoxP3 CD68, CD163, PD-L1, HLA-ABC. Semiquantitative assessment of TILs and TAMs density and spatial distribution was performed and statistical analysis for prognostic correlations was carried out. ResultsThe distribution of CD4+ TILs was higher in the intratumoral region (p=0.012) while CD163+ TAMs in the peritumoral (p=0.016). An association was also found between tumour-associated astrogliosis (TAA) and CD163+ TAMs (p=0.021). Increased CD68+ TAMs correlated with BRAF V600 mutation (p=0.038). CD4+ TILs were significantly higher in PD-L1 <1 % group (p=0.030). CD68+ high expression group significantly correlated with PD-L1 ≥1 % (p=0.029). Median HLA-ABC H-score was significantly associated with intratumoral CD4+ (p=0.005) and peritumoral CD8+ infiltration (p=0.048). CD68+ TAMs intratumoral high expression showed a favorable association with OS in patients with multiple MBM (p=0.017), whereas a high HLA-ABC H-score with a prolonged OS in those with single MBM (p=0.007). ConclusionsOur findings suggest a peculiar topographical distribution of immune cells in both intratumoral and peritumoral areas, and correlations with both BRAF V600 mutation and PD-L1 expression in a large cohort of MBM. Moreover, CD68+ TAMs distribution and HLA-ABC favourably impacted prognosis in patients with multiple and single brain metastases, respectively.

Chronic intermittent hypoxia remodels catecholaminergic nerve innervation in mouse atria.

Chronic intermittent hypoxia (CIH, a model for sleep apnoea) is a major risk factor for several cardiovascular diseases. Autonomic imbalance (sympathetic overactivity and parasympathetic withdrawal) has emerged as a causal contributor of CIH-induced cardiovascular disease. Previously, we showed that CIH remodels the parasympathetic pathway. However, whether CIH induces remodelling of the cardiac sympathetic innervation remains unknown. Mice (male, C57BL/6J, 2-3months) were exposed to either room air (RA, 21% O2 ) or CIH (alternating 21% and 5.7% O2 , every 6min, 10 hday-1 ) for 8-10weeks. Flat-mounts of their left and right atria were immunohistochemically labelled for tyrosine hydroxylase (TH, a sympathetic marker). Using a confocal microscope (or fluorescence microscope) and Neurlocudia 360digitization and tracing system, we scanned both the left and right atria and quantitatively analysed the sympathetic axon density in both groups. The segmentation data was mapped onto a 3D mouse heart scaffold. Our findings indicated that CIH significantly remodelled the TH immunoreactive (-IR) innervation of the atria by increasing its density at the sinoatrial node, the auricles and the major veins attached to the atria (P < 0.05, n=7). Additionally, CIH increased the branching points of TH-IR axons and decreased the distance between varicosities. Abnormal patterns of TH-IR axons around intrinsic cardiac ganglia were also found following CIH. We postulate that the increased sympathetic innervation may further amplify the effects of enhanced CIH-induced central sympathetic drive to the heart. Our work provides an anatomical foundation for the understanding of CIH-induced autonomic imbalance. KEY POINTS: Chronic intermittent hypoxia (CIH, a model for sleep apnoea) causes sympathetic overactivity, cardiovascular remodelling and hypertension. We determined the effect of CIH on sympathetic innervation of the mouse atria. In vivo CIH for 8-10weeks resulted in an aberrant axonal pattern around the principal neurons within intrinsic cardiac ganglia and an increase in the density, branching point, tortuosity of catecholaminergic axons and atrial wall thickness. Utilizing mapping tool available from NIH (SPARC) Program, the topographical distribution of the catecholaminergic innervation of the atria were integrated into a novel 3D heart scaffold for precise anatomical distribution and holistic quantitative comparison between normal and CIH mice. This work provides a unique neuroanatomical understanding of the pathophysiology of CIH-induced autonomic remodelling.

Ultrastructural Details of Epiretinal Membrane Foveoschisis

Introduction: The aim of this study was to describe differences in the vitreomacular interface (VMI) in idiopathic epiretinal membrane (ERM) foveoschisis compared to macular pseudohole (MPH) and lamellar macular hole (LMH). Methods: We analysed surgically excised epiretinal material and internal limiting membrane (ILM) specimens obtained from 16 eyes of 16 patients with ERM foveoschisis (6 eyes), MPH (5 eyes), and LMH (5 eyes) during standard pars plana vitrectomy (PPV) with membrane peeling. The three entities were classified according to the newly introduced optical coherence tomography (OCT) terminology. Transmission electron microscopy (TEM) was used to describe the ultrastructural features. Results: We found fibrocellular epiretinal tissues in all samples analysed. However, the cell and collagen composition of the VMI differed between groups. Eyes with ERM foveoschisis were characterized by a higher number of cells, multilayered membranes, and thick strands of vitreous collagen embedding the major cell types of myofibroblasts compared to MPH. Eyes with MPH also showed a predominance of myofibroblasts, but these were located directly on the ILM with no collagen between the cells and the ILM. Eyes with LMH showed a thick, multilayered epiretinal proliferation consisting mainly of non-tractional glial cells, corresponding to hypodense epiretinal proliferation on OCT. Eyes with ERM foveoschisis and MPH were more likely to have incomplete PVD compared to LMH in terms of posterior hyaloid status. Discussion/Conclusion: Tractional ERMs in eyes with ERM foveoschisis and MPH differ in their ultrastructure. The main difference is in the amount and topographical distribution of vitreous collagen. However, the epiretinal cell types are predominantly myofibroblasts in both entities. This highlights the importance of distinguishing ERM foveoschisis from both MPH and LMH in terms of pathogenesis and surgical peeling procedures.

Cholinergic and Nadph-δ neurons in the pedunculopontine and laterodorsal tegmental nuclei of human and nonhuman primates.

The brainstem pedunculopontine (PPN) and laterodorsal tegmental (LDTg) nuclei are involved in multifarious activities, including motor control. Yet, their exact cytoarchitectural boundaries are still uncertain. We therefore initiated a comparative study of the topographical and neurochemical organization of the PPN and LDTg in cynomolgus monkeys (Macaca fascicularis) and humans. The distribution and morphological characteristics of neurons expressing choline acetyltransferase (ChAT) and/or nicotinamide adenine dinucleotide phosphate diaphorase (Nadph-δ) were documented. The number and density of the labeled neurons were obtained by stringent stereological methods, whereas their topographical distribution was reported upon corresponding magnetic resonance imaging (MRI) planes. In both human and nonhuman primates, the PPN and LDTg are populated by three neurochemically distinct types of neurons (ChAT-/Nadph-δ+, ChAT+/Nadph-δ-, and ChAT+/Nadph-δ+), which are distributed according to a complex spatial interplay. Three-dimensional reconstructions reveal that ChAT+ neurons in the PPN and LDTg form a continuum with some overlaps with pigmented neurons of the locus coeruleus, dorsally, and of the substantia nigra (SN) complex, ventrally. The ChAT+ neurons in the PPN and LDTg are -two to three times more numerous in humans than in monkeys but their density is -three to five times higher in monkeys than in humans. Neurons expressing both ChAT and Nadph-δ have a larger cell body and a longer primary dendritic arbor than singly labeled neurons. Stereological quantification reveals that 25.6% of ChAT+ neurons in the monkey PPN are devoid of Nadph-δ staining, a finding that questions the reliability of Nadph-δ as a marker for cholinergic neurons in primate brainstem.

Association between topographic distribution of dilated perivascular spaces and Alzheimer’s disease pathologies measured by 18F‐florbetaben and PI‐2620 PET

AbstractBackgroundDilated perivascular spaces (DPVS) has been hypothesized to be implicated in the development and/or progression Alzheimer’s disease (AD). However, evidence of a relationship between its topographic distribution and burden of AD pathologies has not been well‐established. We thus aimed to evaluate whether beta‐amyloid (Aβ) and tau burdens measured in positron emission tomography (PET) are associated with topographic distribution of DPVS.MethodFifty‐one patients with amnestic mild cognitive impairment or mild dementia due to possible AD were recruited. Aβ burden was measured as Centiloid (CL) scale from 18F‐florbetaben PET. Burden of tau on regions comprising Braak stage III‐IV of neurofibrillary pathology (Braak H, et al. 2006) was measured as standardized uptake value ratio (SUVR) from tau tracer PI‐2620 PET. DPVS were assessed in the basal ganglia (BG‐DPVS) and in the subcortical white matter (WM‐DPVS) in T1‐sequences of brain MRI. DPVS severities were rated by an established 4‐point semiquantitative score and were then classified as high degree (score&gt;2) or low degree (score≤2) (Martinez‐Ramirez, et al. 2013). The patients were further categorized into 3 groups including patients with higher, equal, and lower score of BG‐DPVS compared to WM‐DPVS (BG&gt;WM, BG = WM, and BG&lt;WM, respectively) (Thanprasertsuk, et al. 2014). Multivariate analyses controlling for age, sex, and MoCA score were applied to ensure independent relationships of DPVS to Aβ‐CL and tau‐SUVR.ResultPatients with high degree of WM‐DPVS (n = 18), compared to ones with the low degree (n = 33), had higher burdens of both Aβ‐CL (median[IQR], 74.29[55.90‐102.02] versus 35.06[11.34‐57.57], p&lt;0.001) and tau‐SUVR (1.46[1.24‐2.15] versus 1.16[1.07‐1.49], p = 0.001). Based on DPVS category, there were differences in both Aβ‐CL (p = 0.001) and tau‐SUVR (p = 0.009) among the BG&gt;WM (n = 20), BG = WM (n = 13), and BG&lt;WM (n = 18) groups, with apparently high disease‐specific pathologies of AD in the BG&lt;WM group (Aβ‐CL = 74.29[46.60‐105.20], and tau‐SUVR = 1.50[1.24‐2.14]). There were no differences in Aβ‐CL and tau‐SUVR between patients with low and high degree of BG‐DPVS.ConclusionOur results suggest that WM‐DPVS is associated with the deposition of Aβ and tau in AD patients, while BG‐DPVS appears to have less substantial association.

Mapping changes in synaptic vesicle protein 2A (SV2A) in neurodegenerative diseases

AbstractBackgroundSynaptic loss is an early feature of neurodegenerative diseases and the best correlate of clinical decline. Synaptophysin is a pre‐synaptic protein used as a marker of synaptic integrity. Although no biomarker is available to measure synaptic integrity in the clinical setting, various potential PET‐scan tracers are under development. Tracers to detect synaptic vesicle protein 2A (SV2A), an integral glycoprotein in the membrane of synaptic vesicles, are among the most promising among those in development. However, the topographical distribution of SV2A in the human brain and the degree of regional changes in different neurodegenerative conditions are unclear, making it challenging to establish the utility of SV2A tracers in clinical practice. To close this gap, we mapped the density of SV2A in five areas vulnerable to age‐related neuropathology in postmortem brain tissue of subjects with four different types of neurodegenerative disease and healthy controls. Furthermore, we compared SV2A maps to synaptophysin maps obtained from adjacent slides.MethodTable 1 details the subjects' features. The regions of interest include middle and inferior frontal gyri, inferior temporal gyrus, angular gyrus, and CA1 sector/entorhinal cortex. 8 µm thick FFPE adjacent slides underwent immunohistochemistry for SV2A (1:150, Atlas Antibodies, rabbit polyclonal) or synaptophysin (1:75, Atlas Antibodies, rabbit polyclonal). All slides were scanned using a calibrated Zeiss Axioscan and quantified using the Zen software. Density was measured in 40 cortical ROIs (20 white &amp; 20 gray matter) per area/case, randomly distributed. Values were normalized for white matter intensity.ResultSVA2 loss was present in all disease conditions. The pattern of change was region and disease‐specific (Fig 1). Interestingly, the correlation between SV2A and synaptophysin density was poor to moderate (Fig 2).ConclusionReduced SV2A expression/level in all diseases indicates that SV2A is a potential marker to detect neurodegeneration. However, the lack of correlation between synaptophysin and SV2A level changes suggests that these markers signal different pathways. Additional research is needed to investigate the relationship between regional loss of SV2A and its potential significance as a marker for neurodegenerative disorders. We are performing Western blotting and autoradiography in the same samples to confirm the immunohistochemistry findings.

Tau pathway‐based gene analysis in the Alzheimer’s disease continuum identifies CLU and FYN associated with tau deposition on PET in a Korean Cohort

AbstractBackgroundAbnormal tau protein aggregation and spreading in the brain is closely linked to cognitive impairment and neurodegeneration in Alzheimer’s disease (AD). The role of genetic variation in brain tau aggregation has not been fully elucidated. Here, we performed pathway‐based candidate gene association analysis to identify novel genes associated with brain tau deposition on PET in a well‐characterized Korean AD continuum Cohort.MethodWe analyzed data for 145 older adults (69 cognitively normal (CN), 38 mild cognitive impairment (MCI), and 38 AD) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE). We selected 15 candidate genes related to both tau pathways and AD, curated from existing pathway databases, literature mining, and genome‐wide association study findings. We performed gene‐based association analysis of tau deposition measured by 18F‐AV‐1451 PET scans using PLINK. In addition, we performed whole brain voxel‐wise association analysis of identified single nucleotide polymorphisms (SNPs) to investigate their topographic distributions of differences in tau deposition across the whole brain using SPM12. We examined the interaction of the identified SNPs with APOE ε4 carrier status.ResultGene‐based analysis identified CLU and FYN as significantly associated with tau deposition after adjusting for multiple testing. The most significant signals originated from rs149413552 in CLU and rs57650567 in FYN. A voxel‐wise analysis for the two SNPs showed that individuals carrying at least one minor allele demonstrated greater tau throughout the temporal, parietal, and frontal lobes than individuals having no minor alleles (Fig. 1). The two SNPs were associated with greater cortical atrophy of AD‐signature regions and worse global cognition. rs149413552 in CLU was also associated with longitudinal decline in global cognition and immediate verbal memory over two years. APOE ε4 and the two SNPs appeared to exert additive effects on tau levels (Fig. 2). An interaction between rs57650567 in FYN and APOE ε4 carrier status was observed (Fig. 2)Conclusion CLU and FYN may play a specific role in tau pathophysiology. These risk genes may prove useful for biomarker and therapeutic development. Larger and multiethnic studies are needed to confirm these findings and to determine generalizability across populations.