Topographic Distribution Research Articles

Micropatterns and peptide gradient on the inner surface of a guidance conduit synergistically promotes nerve regeneration in vivo

Both of the surface topographical features and distribution of biochemical cues can influence the cell-substrate interactions and thereby tissue regeneration in vivo. However, they have not been combined simultaneously onto a biodegradable scaffold to demonstrate the synergistic role so far. In this study, a proof-of-concept study is performed to prepare micropatterns and peptide gradient on the inner wall of a poly (D,L-lactide-co-caprolactone) (PLCL) guidance conduit and its advantages in regeneration of peripheral nerve in vivo. After linear ridges/grooves of 20/40 μm in width are created on the PLCL film, its surface is aminolyzed in a kinetically controlled manner to obtain the continuous gradient of amino groups, which are then transferred to CQAASIKVAV peptide density gradient via covalent coupling of glutaraldehyde. The Schwann cells are better aligned along with the stripes, and show a faster migration rate toward the region of higher peptide density. Implantation of the nerve guidance conduit made of the PLCL film having both the micropatterns and peptide gradient can significantly accelerate the regeneration of sciatic nerve in terms of rate, function recovery and microstructures, and reduction of fibrosis in muscle tissues. Moreover, this nerve conduit can also benefit the M2 polarization of macrophages and promote vascularization in vivo.

Olfactory Modulation of the Contingent Negative Variation to Auditory Stimuli

Although pleasantness is intrinsically related to the perception of odors it is difficult to objectively assess odor-induced pleasantness. To evaluate the effects of odors of different valences on the contingent negative variation (CNV) in a younger and an older population. Data from 62 participants (27 men, 35 women) were included. Two age groups with Age group 1 (YOUNG) had 30 subjects within age 18–30 years and age group 2 (OLD) had 32 subjects with age >40 years. Pre-testing was performed to acquaint subjects with the experimental tasks and their environment. Subjects received “Sniffin’ Sticks” odor identification tests and a standardized medical history to ascertain normosmia. In addition, they also took questionnaires relating to importance of the sense of smell and personality traits. CNV was elicited with two auditory stimuli, S1 followed by S2 at an interval of 2.4 s. Subjects were asked to push a button as fast as possible after they perceived S2. EEG was recorded from 4 positions of the 10–20 system (Fp2, Fz, Cz, and Pz). Four odors plus odorless air was presented in randomized order. The following main results emerged: (1) Consistent with the literature CNV showed a typical topographical distribution with the largest amplitude over the front-central recording sites. (2) 69% of subjects had consistent CNV for all conditions. (3) for some odor conditions CNV amplitudes exhibit a weak relation to odor pleasantness and associations with calmness. (4) CNV amplitude correlated negatively with reaction times. Overall, the results suggest the usefulness of CNV as an electrophysiological measure of cognition. However, in the present context, concomitantly applied odors of different hedonic tones exerted only minor effects on CNV. Thus, we conclude that odors have little or no effect on CNV.

Topographic correlates of driver mutations and endogenous gene expression in pediatric diffuse midline gliomas and hemispheric high-grade gliomas

We evaluate the topographic distribution of diffuse midline gliomas and hemispheric high-grade gliomas in children with respect to their normal gene expression patterns and pathologic driver mutation patterns. We identified 19 pediatric patients with diffuse midline or high-grade glioma with preoperative MRI from tumor board review. 7 of these had 500 gene panel mutation testing, 11 patients had 50 gene panel mutation testing and one 343 gene panel testing from a separate institution were included as validation set. Tumor imaging features and gene expression patterns were analyzed using Allen Brain Atlas. Twelve patients had diffuse midline gliomas and seven had hemispheric high-grade gliomas. Three diffuse midline gliomas had the K27M mutation in the tail of histone H3 protein. All patients undergoing 500 gene panel testing had additional mutations, the most common being in ACVR1, PPM1D, and p53. Hemispheric high-grade gliomas had either TP53 or IDH1 mutation and diffuse midline gliomas had H3 K27M-mutation. Gene expression analysis in normal brains demonstrated that genes mutated in diffuse midline gliomas had higher expression along midline structures as compared to the cerebral hemispheres. Our study suggests that topographic location of pediatric diffuse midline gliomas and hemispheric high-grade gliomas correlates with driver mutations of tumor to the endogenous gene expression in that location. This correlation suggests that cellular state that is required for increased gene expression predisposes that location to mutations and defines the driver mutations within tumors that arise from that region.

Extracellular matrix remodeling and inflammatory pathway in human endometrium: insights from uterine leiomyomas

To compare the expression profiles of matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases, TIMPs) in the endometrium of women with and without type 3 leiomyomas and to understand their relationship with inflammatory status. Molecular and in silico studies. University hospital. Patients with type 3 leiomyomas ranging from 3 to 10 cm in diameter (n = 18) and control age-matched women undergoing surgery for ovarian cysts (n = 18) who underwent endometrial biopsies. Endometrial biopsies. To evaluate the expression levels of MMPs and TIMPs in the endometrium, quantitative reverse transcriptase polymerase chain reaction and Western blot were performed. With the use of immunofluorescence analysis, the investigated proteins were localized in the tissues. The expression levels of inflammatory mediators such as IL-1β, IL-6, IL-10, TGF, COX1, COX2, STAT3, and VEGF were evaluated by quantitative reverse transcriptase polymerase chain reaction, and their relationships were detected by the STRING approach. The endometrium of women with type 3 leiomyomas exhibited differential expression of MMPs and TIMPs, particularly MMP2, MMP11, and MMP14, as well as different topographic distribution, suggesting that leiomyomas may influence the endometrial molecular profile. Significant decreases in IL-1β, IL-6, and IL-10 expression, along with increases in COX1 and COX2, as well as VEGF, were highlighted. The STRING approach suggests that this altered gene expression profile may affect the Th17 cell differentiation pathway. The differential expression and localization of MMPs and TIMPs observed in women with type 3 leiomyomas, along with the reported derangement in the expression of key molecules involved in the inflammatory pathway, may contribute to changes in endometrial receptivity in these patients.

The Toll Route to Structural Brain Plasticity.

The human brain can change throughout life as we learn, adapt and age. A balance between structural brain plasticity and homeostasis characterizes the healthy brain, and the breakdown of this balance accompanies brain tumors, psychiatric disorders, and neurodegenerative diseases. However, the link between circuit modifications, brain function, and behavior remains unclear. Importantly, the underlying molecular mechanisms are starting to be uncovered. The fruit-fly Drosophila is a very powerful model organism to discover molecular mechanisms and test them in vivo. There is abundant evidence that the Drosophila brain is plastic, and here we travel from the pioneering discoveries to recent findings and progress on molecular mechanisms. We pause on the recent discovery that, in the Drosophila central nervous system, Toll receptors—which bind neurotrophin ligands—regulate structural plasticity during development and in the adult brain. Through their topographic distribution across distinct brain modules and their ability to switch between alternative signaling outcomes, Tolls can enable the brain to translate experience into structural change. Intriguing similarities between Toll and mammalian Toll-like receptor function could reveal a further involvement in structural plasticity, degeneration, and disease in the human brain.

Molecular Imaging for Thyrotoxicosis and Thyroid Nodules.

After exclusion of exogenous iodine overload, radioiodine uptake (RAIU) testing with 123I or 131I enables the accurate evaluation and quantification of iodine uptake and kinetics within thyroid cells. In addition, scintigraphic evaluation with 123I or 99mTc-pertechnetate (99mTc04-) provides the topographic distribution of thyroid cell activity and allows the detection and localization of ectopic thyroid tissue. Destructive thyrotoxicosis is characterized by abolished or reduced uptake whereas productive thyrotoxicosis (i.e., hyperthyroidism "sensu strictu") is characterized by high RAIU with scintigraphically diffuse (i.e., Graves disease and diffuse thyroid autonomy) or focal (i.e., autonomously functioning thyroid nodules [AFTN]) overactivity. Accordingly, RAIU or thyroid scintigraphy are widely used to differentiate different causes of thyrotoxicosis. In addition, several radiopharmaceuticals are also available to help in differentiating benign from malignant thyroid nodules and inform clinical decision making. In fact, AFTNs can be safely excluded from fine-needle aspiration biopsy while either 99mTc-methoxyisobutylisonitrile (MIBI) and 18F-FDG may complement the work-up of cytologically indeterminate cold nodules and contribute to reducing the need for diagnostic lobectomies/thyroidectomies. Finally, RAIU studies are also useful for calculating the administered therapeutic activity of 131I to treat hyperthyroidism and euthyroid multinodular goiter. All considered, thyroid molecular imaging allows us to characterize molecular/functional aspects of different thyroid diseases, even before clinical symptoms become manifest and remains integral to properly managing such conditions. Our present paper summarizes basic concepts, clinical applications, and potential developments of thyroid molecular imaging in patients affected by thyrotoxicosis and thyroid nodules.

Eyelid Lymphatics: An Anatomical Study by Microdissection.

To obtain further understanding of the eyelid lymphatic anatomy. Thirty-two halves of eyelids from 16 fresh fetus cadavers were studied by microdissection using a mixture of 3% Prussian blue and chloroform to visualize the lymphatic vessels. Three layers of lymphatic plexuses were demonstrated in the eyelids: a superficial or preorbicularis muscle plexus; a pretarsal or postorbicular muscle plexus; and a deep or posttarsal plexus. Furthermore, communicating branches among these plexuses were also spotted. The study results demonstrated the topographic distribution of the eyelid lymphatic vessels and confirmed the existence of communicating branches. This discovery will be conducive to understanding the route and mechanism by which inflammation of the eyelid spreads and cancer disseminates. It also provides anatomical insights to apply during eyelid surgery with regard to the prevention of possible eyelid lymphatic injury.

Retrieval orientation for memories encoded in emotional contexts: An ERP study

Retrieval orientation, which is involved in recognition cue processing, optimizes goal-directed memory retrieval. However, whether the emotionality of encoding context affects subsequent retrieval orientation remains unclear. To clarify this, neutral objects were paired with either emotional or neutral background scenes during the study phase. During recognition test, only neutral objects were presented. The ERP analysis on the correctly rejected new items indicated that at least two processes were modulated by the emotionality of memory: 1) the arousal-modulated effect on the right-frontal scalp, and 2) the posterior-distributed effect, which was found to differentiate between memories with positive and negative valence. Furthermore, the magnitude of posterior-distributed effect was correlated with affective rating. The topographical distribution indicated that retrieval orientation for positive memories involves at least partially different neural circuitries from neutral or negative memories. Our results suggest that the emotionality of encoding context affects subsequent retrieval orientation.

Developing a lateral topographic density model for Brazil

Topographic density distribution models are used in many geodetic and geophysical problems. Due to the difficulty in developing a high-resolution three-dimensional density model, many studies are focusing on the development of lateral density models and, despite the existence of global models, it is understood that these are less detailed and need to be improved to be used in regional and local studies. In this context, this research develops a distribution model of the lateral density of topographic masses for Brazil (LTD_Brazil, with 30 arc-seconds grid spacing), associated with their uncertainties, considering more detailed information from geological maps and apparent density values of rock types. The model results indicated an average density of 2459 kg/m³, ranging from 1625 to 3400 kg/m³, with standard deviations ranging from 8 to 351 kg/m³. This average density value has great influence of large Phanerozoic sedimentary basins (Amazonas/Solimões/Acre, Alto Tapajós, Parecis, Parnaíba and Paraná basins) located in Brazil. Furthermore, comparing the LTD_Brazil with a global model (UNB_TopoDensT), it was possible to suggest that the differences (ranging from −500 to 600 kg/m3), more significant in metamorphic and igneous rocks regions, are associated with greater detail of the lithological units used and accuracy of the model.

Topography of Movement-Related Delta and Theta Brain Oscillations

The aim of this study was to analyse the high density EEG during movement execution guided by visual attention to reveal the detailed topographic distributions of delta and theta oscillations. Twenty right-handed young subjects performed a finger tapping task, paced by a continuously transited repeating visual stimuli. Baseline corrected power of scalp current density transformed EEG was statistically assessed with cluster-based permutation testing. Delta and theta activities revealed differences in their spatial properties at the time of finger tapping execution. Theta synchronization showed a contralateral double activation in the parietal and fronto-central regions, while delta activity appeared in the central contralateral channels. Differences in the spatiotemporal topography between delta and theta activity in the course of movement execution were identified on high density EEG.

Acute Onset Flaccid Paralysis as Presentation of Combined Central and Peripheral Demyelination in a Child: A Case Report

Introduction: Inflammatory demyelinating disease like combined central and peripheral demyelination (CCPD) could have varied clinical presentation depending upon the topographical distribution of neural involvement.
 Case presentation: A seven-year-old child had presented with fever followed by acute onset flaccid paralysis and urinary retention. Weakness in the lower limbs as reported was ascending and symmetric in nature, while no history of trauma, band-like sensation or altered sensorium were documented. Superficial and deep tendon reflexes of both the lower limbs were absent. Routine blood investigations had revealed neutrophilic leucocytosis only. Serum IgM antibody for scrub typhus was found positive. CSF study didn’t show cyto-protein dissociation. NCV had demonstrated absence of F wave and H reflex in the peripheral nerves of lower limbs. Anti-ganglioside antibody profiles were negative. Subsequent investigations including MRI brain and spinal cord had revealed acute onset CCPD.
 Conclusion: Acute onset combined central and peripheral demyelination in a child had presented as acute flaccid paralysis of the lower limbs and the condition was temporally association with scrub typhus.

Brain activity complexity has a nonlinear relation to the level of propofol sedation

BackgroundBrain activity complexity is a promising correlate of states of consciousness. Previous studies have shown higher complexity for awake compared with deep anaesthesia states. However, little attention has been paid to complexity in intermediate states of sedation. MethodsWe analysed the Lempel–Ziv complexity of EEG signals from subjects undergoing moderate propofol sedation, from an open access database, and related it to behavioural performance as a continuous marker of the level of sedation and to plasma propofol concentrations. We explored its relation to spectral properties, to propofol susceptibility, and its topographical distribution. ResultsSubjects who retained behavioural performance despite propofol sedation showed increased brain activity complexity compared with baseline (M=13.9%, 95% confidence interval=7.5–20.3). This was not the case for subjects who lost behavioural performance. The increase was most prominent in frontal electrodes, and correlated with behavioural performance and propofol susceptibility. This effect was positively correlated with high-frequency activity. However, abolishing specific frequency ranges (e.g. alpha or gamma) did not reduce the propofol-induced increase in Lempel–Ziv complexity. ConclusionsBrain activity complexity can increase in response to propofol, particularly during low-dose sedation. Propofol-mediated Lempel–Ziv complexity increase was independent of frequency-specific spectral power manipulations, and most prominent in frontal areas. Taken together, these results advance our understanding of brain activity complexity and anaesthetics. They do not support models of consciousness that propose a direct relation between brain activity complexity and states of consciousness.

The Electrophysiological Correlates of Phoneme Perception in Primary Progressive Aphasia: A Preliminary Case Series.

Aims: This study aimed to investigate phoneme perception in patients with primary progressive aphasia (PPA) by using the event-related potential (ERP) technique. These ERP components might contribute to the diagnostic process of PPA and its clinical variants (NFV: nonfluent variant, SV: semantic variant, LV: logopenic variant) and reveal insights about phoneme perception processes in these patients.Method: Phoneme discrimination and categorization processes were investigated by the mismatch negativity (MMN) and P300 in eight persons with early- and late-stage PPA (3 NFV, 2 LV, 2 SV, and 1 PPA-NOS; not otherwise specified) and 30 age-matched healthy adults. The mean amplitude, the onset latency, and the topographic distribution of both components in each patient were compared to the results of the control group.Results: The MMN was absent or the onset latency of the MMN was delayed in the patients with the NFV, LV, and PPA-NOS in comparison to the control group. In contrast, no differences in mean amplitudes and onset latencies of the MMN were found between the patients with the SV and the control group. Concerning the P300, variable results were found in the patients with the NFV, SV, and PPA-NOS, but the P300 of both patients with the LV was delayed and prolonged with increased mean amplitude in comparison to the control group.Conclusion: In this preliminary study, phoneme discrimination deficits were found in the patients with the NFV and LV, and variable deficits in phoneme categorization processes were found in all patients with PPA. In clinical practice, the MMN might be valuable to differentiate the SV from the NFV and the LV and the P300 to differentiate the LV from the NFV and the SV. Further research in larger and independent patient groups is required to investigate the applicability of these components in the diagnostic process and to determine the nature of these speech perception deficits in the clinical variants of PPA.

Geometric deep learning on brain shape predicts sex and age.

The complex relationship between the shape and function of the human brain remains elusive despite extensive studies of cortical folding over many decades. The analysis of cortical gyrification presents an opportunity to advance our knowledge about this relationship, and better understand the etiology of a variety of pathologies involving diverse degrees of cortical folding abnormalities. Hypothesis-driven surface-based approaches have been shown to be particularly efficient in their ability to accurately describe unique features of the folded sheet topology of the cortical ribbon. However, the utility of these approaches has been blunted by their reliance on manually defined features aiming to capture the relevant geometric properties of cortical folding. In this paper, we propose an entirely novel, data-driven deep-learning based method to analyze the brain's shape that eliminates this reliance on manual feature definition. This method builds on the emerging field of geometric deep-learning and uses traditional convolutional neural network architecture uniquely adapted to the surface representation of the cortical ribbon. This method is a complete departure from prior brain MRI CNN investigations, all of which have relied on three dimensional MRI data and interpreted features of the MRI signal for prediction. MRI data from 6410 healthy subjects obtained from 11 publicly available data repositories were used for analysis. Ages ranged from 6 to 89 years. Both inner and outer cortical surfaces were extracted using Freesurfer and then registered into MNI space. For purposes of method development, both a classification and regression challenge were introduced for network learning including sex and age prediction, respectively. Two independent graph convolutional neural networks (gCNNs) were trained, the first of which to predict subject's self-identified sex, the second of which to predict subject's age. Class Activation Maps (CAM) and Regression Activation Maps (RAM) were constructed respectively to map the topographic distribution of the most influential brain regions involved in the decision process for each gCNN. Using this approach, the gCNN was able to predict a subject's sex with an average accuracy of 87.99 % and achieved a Person's coefficient of correlation of 0.93 with an average absolute error 4.58 years when predicting a subject's age. We believe this shape-based convolutional classifier offers a novel, data-driven approach to define biomedically relevant features from the brain at both the population and single subject levels and therefore lays a critical foundation for future precision medicine applications.

IncobotulinumtoxinA Efficacy/Safety in Upper-Limb Spasticity in Pediatric Cerebral Palsy: Randomized Controlled Trial

BackgroundThis randomized phase 3 study with double-blind main period (MP) and open-label extension (OLEX; NCT02002884) assessed incobotulinumtoxinA safety and efficacy for pediatric upper-limb spasticity treatment in ambulant/nonambulant (Gross Motor Function Classification System [GMFCS] I-V) patients, with the option of combined upper- and lower-limb treatment. MethodsPatients were aged two to 17 years with unilateral or bilateral spastic cerebral palsy (CP) and Ashworth Scale (AS) score ≥2 in treatment-selected clinical patterns. In the MP, patients were randomized (2:1:1) to incobotulinumtoxinA 8, 6, or 2 U/kg body weight (maximum 200, 150, 50 U/upper limb), with optional lower-limb injections in one of five topographical distributions (total body dose ≤16 to 20 U/kg, maximum 400 to 500 U, depending on body weight and GMFCS level). In the OLEX, patients received three further treatment cycles, at the highest MP doses (8 U/kg/upper limb group). Outcomes included AS, Global Impression of Change Scale (GICS), and adverse events (AEs). ResultsAS scores improved from baseline to week 4 in all MP dose groups (n = 350); patients in the incobotulinumtoxinA 8 U/kg group had significantly greater spasticity improvements versus the 2 U/kg group (least-squares mean [standard error] for upper-limb main clinical target pattern −1.15 [0.06] versus −0.93 [0.08]; P = 0.017). Investigator's, child/adolescent's, and parent/caregiver's GICS scores showed improvements in all groups. Treatment benefits were sustained over further treatment cycles. AE incidence did not increase with dose or repeated treatment across GMFCS levels. ConclusionsData provide evidence for sustained efficacy and safety of multipattern incobotulinumtoxinA treatment in children and adolescents with upper-limb spasticity.

From Remote Sensing to Species Distribution Modelling: An Integrated Workflow to Monitor Spreading Species in Key Grassland Habitats

Remote sensing (RS) has been widely adopted as a tool to investigate several biotic and abiotic factors, directly and indirectly, related to biodiversity conservation. European grasslands are one of the most biodiverse habitats in Europe. Most of these habitats are subject to priority conservation measure, and several human-induced processes threaten them. The broad expansions of few dominant species are usually reported as drivers of biodiversity loss. In this context, using Sentinel-2 (S2) images, we investigate the distribution of one of the most spreading species in the Central Apennine: Brachypodium genuense. We performed a binary Random Forest (RF) classification of B. genuense using RS images and field-sampled presence/absence data. Then, we integrate the occurrences obtained from RS classification into species distribution models to identify the topographic drivers of B. genuense distribution in the study area. Lastly, the impact of B. genuense distribution in the Natura 2000 (N2k) habitats (Annex I of the European Habitat Directive) was assessed by overlay analysis. The RF classification process detected cover of B. genuense with an overall accuracy of 94.79%. The topographic species distribution model shows that the most relevant topographic variables that influence the distribution of B. genuense are slope, elevation, solar radiation, and topographic wet index (TWI) in order of importance. The overlay analysis shows that 74.04% of the B. genuense identified in the study area falls on the semi-natural dry grasslands. The study highlights the RS classification and the topographic species distribution model’s importance as an integrated workflow for mapping a broad-expansion species such as B. genuense. The coupled techniques presented in this work should apply to other plant communities with remotely recognizable characteristics for more effective management of N2k habitats.

Degenerative nuclear atypia in pleomorphic adenoma of salivary glands: Histological and immunohistochemical observations

The occurrence and topographical distribution of nuclear changes regarded as degenerative were examined in 84 salivary pleomorphic adenomas (PAs). Haematoxylin and eosin-stained sections from them were light-microscopically studied for unusual variations in size, shape and chromatin pattern of tumour-cell nuclei. Selected cases were further examined by immunohistochemical techniques valuable in characterising cell phenotypes in PA, and cell cycle antigens. A single case (female, 26 years, palate; 1.2 %) showed prominent cells with eosinophilic cytoplasm and variably enlarged or giant, irregularly shaped and occasionally multi-vacuolated nuclei with condensed or stippled chromatin and no mitoses. These cells were variably dyscohesive and did not line lumina; were cytokeratins 5/6, 7 and 14 (+, cytoplasmic), smooth muscle actin (+, cytoplasmic), p63 (+, nuclear), S-100 protein (+, nuclear and cytoplasmic), and WT1 and podoplanin (+/−, cytoplasmic); and did not stain for DOG1, CD63, p16 or Ki67. The nuclear vacuoles were cytokeratin and WT1 (+) - hence, interpreted as cytoplasmic inclusions. Degenerative nuclear atypia in PA seems rare, associated with non-cycling, non-luminal cells of myomatous (‘myoepithelial’) or schwannomatous phenotype and not related to malignant transformation. The particular phenotype of the affected cells suggests similarities to the degenerative nuclear atypia in pleomorphic leiomyoma and ancient schwannoma.

Improvement in callosal disconnection syndrome with recovery of callosal connectivity

ABSTRACT Recent advancements in radiological techniques have enabled the observation of the topographic distribution of the human corpus callosum. However, its functional connectivity remains to be elucidated. The symptoms of callosal disconnection syndrome (CDS) can potentially reveal the functional connections between the cerebral hemispheres. Herein, we report a patient with CDS, whose callosal lesion was restricted to the posterior midbody, isthmus, and an anterior part of the dorsal splenium. A 53-year-old right-handed woman demonstrated CDS following cerebral infarction associated with subarachnoid hemorrhage. She exhibited CDS including ideomotor apraxia, and tactile anomia with the left hand, cross-replication of hand postures, cross-localization of the fingers, and constructional impairment with the right hand. Six months after onset, the left-handed ideomotor apraxia on imitation improved, but that to command did not, which indicated the difference in the nature of the transcallosal connections between ideomotor apraxia on imitation and ideomotor apraxia to command. Longitudinal CDS observation and corpus callosum tractography will prove useful in expanding our understanding of the nature of the organization of interhemispheric information transference.

Changes in the Brain Extracellular Matrix Sulfation Code in Alzheimer's Disease

Alzheimer's Disease (AD) is a neurodegenerative disorder associated with synapse dysfunction and neurocircuit hyperactivation. Neural networks involved in memory and cognition are regulated by extracellular matrices known as perineuronal nets (PNNs), and these unique matrix structures are reduced in the human AD brain. PNNs are comprised of chondroitin sulfate glycosaminoglycan (CS-GAG) lattices that consist of five differentially-sulfated CS isomers (CS-A, -C, -D, -E and -O), with their relative abundance comprising a “sulfation code” that controls key biological functions including neuroplasticity (CS-A), protein-glycan binding (CS-O, CS-D), and neuroinflammation (CS-C, CS-E). Although changes in CS-GAGs promote PNN dysfunction, synapse reorganization, and neurocircuit hyperactivation in rodents, it is unknown if such changes are features in human AD brain. Using LC-MS/MS analysis, we report a decrease in the nonsulfated ΔO (p=0.0002) in the middle frontal gyrus (MFG) of human AD brain compared to controls. This effect was offset by an increase in the monosulfated ΔC (p=0.024) and trending increase in the disulfated ΔE (p=0.067), which yielded an increase in overall CS-GAG sulfation (p<0.0001). We next sought to determine whether changes in CS-GAGs in AD also associate with Braak stage and topographic distribution of neurofibrillary tangles including phosphorylated tau (P-tau). We found that more advanced Braak stage associated with a decrease in the non-sulfated ΔO (p<0.0001), increases in the sulfated ΔC (p=0.011) and ΔE (p=0.047), and a trending increase in the ΔD (p=0.093), which yielded a Braak stage-dependent increase in overall CS-GAG sulfation (p<0.0001). Antibody labeling against P-tau S396 showed robust accumulation within layer V of the MFG neocortex of AD patients, and whereas P-tau burden was inversely correlated with ΔO (p=0.0017), it was positively correlated with ΔC (p=0.0037), ΔD (p=0.0189), ΔE (p=0.0014), as well as with overall CS sulfation (p<0.0001). Finally, as the increase in Braak stage and P-tau accumulation associate with cognitive decline in AD, we correlated cognitive function (assessed using the Mini-Mental State Examination-MMSE) with changes in CS-GAG sulfation patterns within the MFG. We report that MMSE scoring correlated positively with ΔO (p<0.0006) and negatively with ΔE (p=0.0062) and CS sulfation (p<0.0001) but did not associate with changes in ΔC, ΔD, or ΔA isomer abundance. Since the changes in CS-GAG sulfation reported herein were present prior to the regional onset of classical AD pathology (e.g. Braak III/IV, prior to tangle formation in the MFG), they may play an active role to initiate and/or progress underlying degenerative processes and thus represents a novel target for the prevention and treatment of AD.

Elevated and Slowed EEG Oscillations in Patients with Post-Concussive Syndrome and Chronic Pain Following a Motor Vehicle Collision.

(1) Background: Mild traumatic brain injury produces significant changes in neurotransmission including brain oscillations. We investigated potential quantitative electroencephalography biomarkers in 57 patients with post-concussive syndrome and chronic pain following motor vehicle collision, and 54 healthy nearly age- and sex-matched controls. (2) Methods: Electroencephalography processing was completed in MATLAB, statistical modeling in SPSS, and machine learning modeling in Rapid Miner. Group differences were calculated using current-source density estimation, yielding whole-brain topographical distributions of absolute power, relative power and phase-locking functional connectivity. Groups were compared using independent sample Mann–Whitney U tests. Effect sizes and Pearson correlations were also computed. Machine learning analysis leveraged a post hoc supervised learning support vector non-probabilistic binary linear kernel classification to generate predictive models from the derived EEG signatures. (3) Results: Patients displayed significantly elevated and slowed power compared to controls: delta (p = 0.000000, r = 0.6) and theta power (p < 0.0001, r = 0.4), and relative delta power (p < 0.00001) and decreased relative alpha power (p < 0.001). Absolute delta and theta power together yielded the strongest machine learning classification accuracy (87.6%). Changes in absolute power were moderately correlated with duration and persistence of symptoms in the slow wave frequency spectrum (<15 Hz). (4) Conclusions: Distributed increases in slow wave oscillatory power are concurrent with post-concussive syndrome and chronic pain.