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Background: Multiple system atrophy (MSA) is a rare, progressive, neurodegenerative disorder presenting glia pathology. Still, disease etiology and pathophysiology are unknown, but neuro-inflammation and vascular disruption may be contributing factors to the disease progression. Here, we performed an ex vivo deep proteome profiling of the prefrontal cortex of MSA patients to reveal disease-relevant molecular neuropathological processes. Observations were validated in plasma and cerebrospinal fluid (CSF) of novel cross-sectional patient cohorts. Methods: Brains from 45 MSA patients and 30 normal controls (CTRLs) were included. Brain samples were homogenized and trypsinized for peptide formation and analyzed by high-performance liquid chromatography tandem mass spectrometry (LC–MS/MS). Results were supplemented by western blotting, immuno-capture, tissue clearing and 3D imaging, immunohistochemistry and immunofluorescence. Subsequent measurements of glial fibrillary acid protein (GFAP) and neuro-filament light chain (NFL) levels were performed by immunoblotting in plasma of 20 MSA patients and 20 CTRLs. Finally, we performed a proteome profiling of 144 CSF samples from MSA and CTRLs, as well as other parkinsonian disorders. Data were analyzed using relevant parametric and non-parametric two-sample tests or linear regression tests followed by post hoc tests corrected for multiple testing. Additionally, high-throughput bioinformatic analyses were applied. Results: We quantified more than 4,000 proteins across samples and identified 49 differentially expressed proteins with significantly different abundances in MSA patients compared with CTRLs. Pathway analyses showed enrichment of processes related to fibrinolysis and complement cascade activation. Increased fibrinogen subunit β (FGB) protein levels were further verified, and we identified an enriched recognition of FGB by IgGs as well as intra-parenchymal accumulation around blood vessels. We corroborated blood–brain barrier leakage by a significant increase in GFAP and NFL plasma levels in MSA patients that correlated to disease severity and/or duration. Proteome profiling of CSF samples acquired during the disease course, confirmed increased total fibrinogen levels and immune-related components in the soluble fraction of MSA patients. This was also true for the other atypical parkinsonian disorders, dementia with Lewy bodies and progressive supra-nuclear palsy, but not for Parkinson’s disease patients. Conclusion: Our results implicate activation of the fibrinolytic cascade and immune system in the brain as contributing factors in MSA associated with a more severe disease course.

The thalamus is a brain region consisting of anatomical and functional connections between various spinal, subcortical, and cortical regions, which has a putative role in the clinical manifestation of Multiple System Atrophy (MSA). Previous stereological studies have reported significant anatomical alterations in diverse brain regions of MSA patients, including the cerebral cortex, basal ganglia and white matter, but no quantitative studies have examined the thalamus. To establish the extent of thalamic involvement, we applied stereological methods to estimate the total number of neurons and glial cells (oligodendrocytes, astrocytes and microglia) as well as the volume in two thalamic sub-regions, the mediodorsal nucleus (MDT) and the anterior principal nucleus (APn), in brains from ten MSA patients and 11 healthy control subjects. Compared to healthy controls, MSA patients had significantly fewer neurons (26%) in the MDT, but not the APn. We also found significantly more astrocytes (32%) and microglia (54%) in the MDT, with no such changes in the APn. Finally, we saw no group differences in the total number of oligodendrocytes. Our findings show a region-specific loss of thalamic neurons that occurs without loss of oligodendrocytes, whereas thalamic microgliosis seems to occur alongside astrogliosis. These pathological changes in the thalamus may contribute to the cognitive impairment seen in most patients with MSA.

Significance Axons, the brain’s communication cables, have been described as cylinders since their discovery in 1860. Their structure is linked to how fast they conduct signals and is thus indicative of brain health and function. Here, we demonstrate an interplay between the micromorphology of axons and other extra-axonal structures, showing that axons are noncylindrical and exhibit environment-dependent diameter and trajectory variations. The nonspecificity in diameter, and thus conduction velocity, challenges the current knowledge of how axons communicate signals. Diffusion magnetic resonance imaging can be used to measure axon diameter in the living brain in order to explore the brain network and detect potential biomarkers of disease, but we show here that the observed complex morphologies of axons bias these measurements., Axonal conduction velocity, which ensures efficient function of the brain network, is related to axon diameter. Noninvasive, in vivo axon diameter estimates can be made with diffusion magnetic resonance imaging, but the technique requires three-dimensional (3D) validation. Here, high-resolution, 3D synchrotron X-ray nano-holotomography images of white matter samples from the corpus callosum of a monkey brain reveal that blood vessels, cells, and vacuoles affect axonal diameter and trajectory. Within single axons, we find that the variation in diameter and conduction velocity correlates with the mean diameter, contesting the value of precise diameter determination in larger axons. These complex 3D axon morphologies drive previously reported 2D trends in axon diameter and g-ratio. Furthermore, we find that these morphologies bias the estimates of axon diameter with diffusion magnetic resonance imaging and, ultimately, impact the investigation and formulation of the axon structure–function relationship.

Our access to a unique material of postmortem brains obtained from decades of data collection enabled a stereological analysis of the neuron numbers and correlation of results with individual premorbid intelligence quotient (IQ) data. In our sample of 50 brains from men, we find that IQ does not correlate with the number of brain cells in the human neocortex and was only weakly correlated to brain weight. Our stereological examination extended to measures of several other parameters that might be of relevance to intelligence, including numbers of cerebral glial cells (astrocytes, oligodendrocytes, and microglia) and the volume of key areas in the gray and white matter and of the cerebral ventricles, also showing near-zero nonsignificant correlations to IQ.

Multiple system atrophy (MSA) and Parkinson's disease (PD) are synucleinopathies characterized by aggregation of α‐synuclein in brain cells. Recent studies have shown that morphological changes in terms of cerebral nerve cell loss and increase in glia cell numbers, the degree of brain atrophy and molecular and epidemiological findings are more severe in MSA than PD. In the present study, we performed a stereological comparison of cerebellar volumes, granule and Purkinje cells in 13 patients diagnosed with MSA [8 MSA‐P (striatonigral subtype) and 5 MSA‐C (olivopontocerebellar subtype)], 12 PD patients, and 15 age‐matched control subjects. Only brains from MSA‐C patients showed a reduction in the total number of Purkinje cells (anterior lobe) whereas both MSA‐P and MSA‐C patients had reduced Purkinje cell volumes (perikaryons and nuclei volume). The cerebellum of both diseases showed a reduction in the white matter volume compared to controls. The number of granule cells was unaffected in both diseases. Analyses of cell type‐specific mRNA expression supported our structural data. This study of the cerebellum is in line with previous findings in the cerebrum and demonstrates that the degree of morphological changes is more pronounced in MSA‐C than MSA‐P and PD. Further, our results support an explicit involvement of cerebellar Purkinje cells and white matter connectivity in MSA‐C > MSA‐P and points to the potential importance of white matter alterations in PD pathology.

Correlations between differences in animal behavior and brain structures have been used to infer function of those structures. Brain region size has especially been suggested to be important for an animal’s behavioral capability, controlled by specific brain regions. The oval nucleus of the mesopallium (MO) is part of the anterior forebrain vocal learning pathway in the parrot brain. Here, we compare brain volume and total number of neurons in MO of three parrot species (the peach-fronted conure, Eupsittula aurea, the peach-faced lovebird, Agapornis roseicollis, and the budgerigar, Melopsittacus undulatus), relating the total neuron numbers with the vocal response to playbacks of each species. We find that individuals with the highest number of neurons in MO had the shortest vocal latency. The peach-fronted conures showed the shortest vocal latency and largest number of MO neurons, the peach-faced lovebird had intermediary levels of both, and the budgerigar had the longest latency and least number of neurons. These findings indicate the MO nucleus as one candidate region that may be part of what controls the vocal capacity of parrots.

ObjectiveA hallmark of amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase-1 (SOD1) are inclusions containing SOD1 in motor neurons. Here, we searched for SOD1-positive inclusions in 29 patients carrying ALS-linked mutations in six other genes.MethodsA panel of antibodies that specifically recognise misfolded SOD1 species were used for immunohistochemical investigations of autopsy tissue.ResultsThe 18 patients with hexanucleotide-repeat-expansions in C9orf72 had inclusions of misfolded wild type (WT) SOD1WT in spinal motor neurons. Similar inclusions were occasionally observed in medulla oblongata and in the motor cortex and frontal lobe. Patients with mutations in FUS, KIF5A, NEK1, ALSIN or VAPB, carried similar SOD1WT inclusions. Minute amounts of misSOD1WT inclusions were detected in 2 of 20 patients deceased from non-neurological causes and in 4 of 10 patients with other neurodegenerative diseases. Comparison was made with 17 patients with 9 different SOD1 mutations. Morphologically, the inclusions in patients with mutations in C9orf72HRE, FUS, KIF5A, NEK1, VAPB and ALSIN resembled inclusions in patients carrying the wildtype-like SOD1D90A mutation, whereas patients carrying unstable SOD1 mutations (A4V, V5M, D76Y, D83G, D101G, G114A, G127X, L144F) had larger skein-like SOD1-positive inclusions.Conclusions and relevanceAbundant inclusions containing misfolded SOD1WT are found in spinal and cortical motor neurons in patients carrying mutations in six ALS-causing genes other than SOD1. This suggests that misfolding of SOD1WT can be part of a common downstream event that may be pathogenic. The new anti-SOD1 therapeutics in development may have applications for a broader range of patients.

Spreading depolarizations (SDs) occur in 50–60% of patients after surgical treatment of severe traumatic brain injury (TBI) and are independently associated with unfavorable outcomes. Here we performed a pilot study to examine the relationship between SDs and various types of intracranial lesions, progression of parenchymal damage, and outcomes. In a multicenter study, fifty patients (76% male; median age 40) were monitored for SD by continuous electrocorticography (ECoG; median duration 79 h) following surgical treatment of severe TBI. Volumes of hemorrhage and parenchymal damage were estimated using unbiased stereologic assessment of preoperative, postoperative, and post-ECoG serial computed tomography (CT) studies. Neurologic outcomes were assessed at 6 months by the Glasgow Outcome Scale-Extended. Preoperative volumes of subdural and subarachnoid hemorrhage, but not parenchymal damage, were significantly associated with the occurrence of SDs (P’s

BackgroundEfficient interhemispheric integration of neural activity between left and right primary motor cortex (M1) is critical for inter-limb motor control.ObjectiveWe employed optogenetic stimulation to establish a framework for probing transcallosal M1-M1 interactions in rats.MethodsIn male rats, we optogenetically stimulated glutamatergic neurons in right M1 and recorded the transcallosally evoked potential with chronically implanted electrodes in contralateral left M1 during dexmedetomidine anesthesia. We systematically varied the stimulation intensity and duration to characterize the relationship between stimulation parameters in right M1 and the characteristics of the evoked intracortical potentials in left M1.ResultsOptogenetic stimulation of right M1 consistently evoked a transcallosal response in left M1 with a consistent negative peak (N1) that sometimes was preceded by a smaller positive peak (P1). Higher stimulation intensity or longer stimulation duration gradually increased N1 amplitude and reduced N1 variability across trials. Median N1 latencies remained stable, once stimulation elicited a reliable N1 peak and did not display a systematic shortening with increasing stimulation intensity or duration.ConclusionsOptogenetically stimulated glutamatergic neurons in M1 can reliably evoke a transcallosal response in anesthetized rats and can be used to characterize the relationship between “stimulation dose” and “response magnitude” (i.e., the gain function) of transcallosal M1-to-M1 glutamatergic connections. Detailed knowledge of the stimulus-response relationship is needed to optimize the efficacy of optogenetic stimulation. Since transcallosal M1-M1 interactions can also be probed non-invasively with transcranial magnetic stimulation in humans, our optogenetic stimulation approach bears translational potential for studying how unilateral M1 stimulation can induce interhemispheric plasticity.

Introduction Ubiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (α-syn) may play important roles in the pathogenesis of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Recently, we reported reduced high-affinity/avidity anti-α-syn nAbs levels in plasma from MSA and PD patients, along with distinct inter-group immunoglobulin (Ig)G subclass distributions. The extent to which these observations in plasma may reflect corresponding levels in the cerebrospinal fluid (CSF) is unknown. Methods Using competitive and indirect ELISAs, we investigated the affinity/avidity of CSF anti-α-syn nAbs as well as the CSF and plasma distribution of IgG subclasses and IgM nAbs in a cross-sectional cohort of MSA and PD patients. Results Repertoires of high-affinity/avidity anti-α-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-α-syn IgM nAb levels were relatively lower in CSF and plasma from MSA patients but were reduced only in plasma from PD patients. Interestingly, anti-α-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-α-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-α-syn IgG2 and reduced anti-α-syn IgG4 levels. Conclusions Differences in the plasma/CSF distribution of anti-α-syn nAbs seem to be a common feature of synucleinopathies. Our data add further support to the notion that MSA and PD patients may have compromised immune reactivity towards α-syn. The differing α-syn-specific systemic immunological responses may reflect their specific disease pathophysiologies. These results are encouraging for further investigation of these immunological mechanisms in neurodegenerative diseases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The schizophrenia-associated gene, BRD1, encodes an epigenetic regulator in which chromatin interactome is enriched with genes implicated in mental health. Alterations in histone modifications and epigenetic regulation contribute to brain transcriptomic changes in affective disorders and preclinical data supports a role for BRD1 in psychopathology. However, the implication of BRD1 on affective pathology remains poorly understood. In this study, we assess affective behaviors and associated neurobiology in Brd1+/− mice along with their responses to Fluoxetine and Imipramine. This involves behavioral, neurostructural, and neurochemical characterizations along with regional cerebral gene expression profiling combined with integrative functional genomic analyses. We report behavioral changes in female Brd1+/− mice with translational value to depressive symptomatology that can be alleviated by the administration of antidepressant medications. Behavioral changes are accompanied by altered brain morphometry and imbalances in monoaminergic systems. In accordance, gene expression changes across brain tissues reveal altered neurotransmitter signaling and cluster in functional pathways associated with depression including ‘Adrenergic-, GPCR-, cAMP-, and CREB/CREM-signaling’. Integrative gene expression analysis specifically links changes in amygdaloid intracellular signaling activity to the behavioral treatment response in Brd1+/− mice. Collectively, our study highlights the importance of BRD1 as a modulator of affective pathology and adds to our understanding of the molecular mechanisms underlying affective disorders and their treatment response.

Multiple system atrophy (MSA) is a rare disease with a fatal outcome. To date, little is known about the molecular processes underlying disease development. Its clinical overlap with related neurodegenerative movement disorders underlines the importance for expanding the knowledge of pathological brain processes in MSA patients to improve distinction from similar diseases. In the current study, we investigated DNA methylation changes in brain samples from 41 MSA patients and 37 healthy controls. We focused on the prefrontal cortex, a moderately affected area in MSA. Using Illumina MethylationEPIC arrays, we investigated 5-methylcytosine (5mC) as well as 5-hydroxymethylcytosine (5hmC) changes throughout the genome. We identified five significantly different 5mC probes (adj. P AREL1 gene involved in antigen presentation was decreased in MSA patients. This decrease correlated with increased 5hmC levels. Further, we identified functional DNA methylation modules involved in inflammatory processes. As expected, the decreased 5mC levels on AREL1 was concordant with increased gene expression levels of both AREL1 as well as MHC Class I HLA genes in MSA brains. We also investigated whether these changes in antigen-related processes in the brain associated with changes in peripheral mononuclear cells. Using flow cytometry on an independent cohort of MSA patients, we identified a decrease in circulating non-classical CD14+CD16++ blood monocytes, whereas T and NK cell populations were unchanged. Taken together, our results support the view of an active neuroimmune response in brains of MSA patients.

Background: Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder with adult onset and unknown etiology. Clinically it is characterized by autonomic failure, cerebellar ataxia, parkinsonism, and corticospinal dysfunction in any combination and with varying severity. Objectives and Methods: To establish the extent of involvement of the white matter in the disease, we have used stereology to quantify the total number of neurons and glial cells (oligodendrocytes, astrocytes, and microglia) in the brains from 10 MSA patients and 11 controls. Results: The mean total number of white matter interstitial neurons in the patient brains was 0.5 × 109 (coefficient of variation = standard deviation/mean = 0.37), which was significantly lower than the 1.1 × 109 (0.41) in the control brains (P = .001) and equal to a reduction by ∼50%. The patient brains had a significantly higher number of white matter microglia, 1.5 × 109 (0.47) versus 0.7 × 109 (0.39) microglia in the control subjects (P = .003) and equal to an increase by ∼ 100%. There was no significant difference in mean total numbers of white matter oligodendrocytes and astrocytes between the groups. Conclusions: We found widespread microgliosis without concomitant astrogliosis in brain white matter in MSA patients and demonstrated an absence of significant oligodendrocyte degeneration. The exact role of oligodendrocytes in MSA pathogenesis, including neurodegeneration, remains to be elucidated. © 2017 International Parkinson and Movement Disorder Society

Spreading depolarizations (SDs) occur in 50-60% of patients after surgical treatment of severe traumatic brain injury (TBI) and are independently associated with unfavorable outcomes. Here we performed a pilot study to examine the relationship between SDs and various types of intracranial lesions, progression of parenchymal damage, and outcomes.In a multicenter study, fifty patients (76% male; median age 40) were monitored for SD by continuous electrocorticography (ECoG; median duration 79 h) following surgical treatment of severe TBI. Volumes of hemorrhage and parenchymal damage were estimated using unbiased stereologic assessment of preoperative, postoperative, and post-ECoG serial computed tomography (CT) studies. Neurologic outcomes were assessed at 6 months by the Glasgow Outcome Scale-Extended.Preoperative volumes of subdural and subarachnoid hemorrhage, but not parenchymal damage, were significantly associated with the occurrence of SDs (P's 0.05). Parenchymal damage increased significantly (median 34 ml [Interquartile range (IQR) - 2, 74]) over 7 (5, 8) days from preoperative to post-ECoG CT studies. Patients with and without SDs did not differ in extent of parenchymal damage increase [47 ml (3, 101) vs. 30 ml (- 2, 50), P = 0.27], but those exhibiting the isoelectric subtype of SDs had greater initial parenchymal damage and greater increases than other patients (P's 0.05). Patients with temporal clusters of SDs (≥ 3 in 2 h; n = 10 patients), which included those with isoelectric SDs, had worse outcomes than those without clusters (P = 0.03), and parenchymal damage expansion also correlated with worse outcomes (P = 0.01). In multivariate regression with imputation, both clusters and lesion expansion were significant outcome predictors.These results suggest that subarachnoid and subdural blood are important primary injury factors in provoking SDs and that clustered SDs and parenchymal lesion expansion contribute independently to worse patient outcomes. These results warrant future prospective studies using detailed quantification of TBI lesion types to better understand the relationship between anatomic and physiologic measures of secondary injury.

The anterior thalamic nuclei are important for spatial and episodic memory; however, there is surprisingly little information about how these nuclei are affected in many conditions that present with memory impairments, including Down’s syndrome. To assess the status of the anterior thalamic nuclei in Down’s syndrome we quantified neurons and glial cells in the brains from four older patients with this condition. There was a striking reduction in the volume of the anterior thalamic nuclei and this appeared to reflect the loss of approximately 70% of neurons. The number of glial cells was also reduced but to a lesser degree than neurons. The anterior thalamic nuclei appear to be particularly sensitive to effects of aging in Down’s syndrome and the pathology in this region likely contributes to the memory impairments observed. These findings re-affirm the importance of assessing the status of the anterior thalamic nuclei in conditions where memory impairments have been principally assigned to pathology in the medial temporal lobe.

ObjectiveWe hypothesize alterations in the quality and quantity of anti–43-kDa TAR DNA-binding protein (TDP-43) naturally occurring autoantibodies (NAbs) in patients with amyotrophic lateral sclerosis (ALS); therefore, we assessed relative binding properties of anti–TDP-43 NAbs composite in plasma from patients with ALS in comparison with healthy individuals.MethodsELISA competition assay was used to explore the apparent avidity/affinity of anti–TDP-43 NAbs in plasma from 51 normal controls and 30 patients with ALS. Furthermore, the relative levels of anti–TDP-43 NAbs within the immunoglobulin (Ig) classes of IgG (isotype IgG1-4) and IgMs were measured using classical indirect ELISA. The occurring results were hereafter correlated with the measures of disease duration and disease progression.ResultsHigh-avidity/affinity anti–TDP-43 NAbs levels were significantly reduced in plasma samples from patients with ALS. In addition, a significant decrease in relative levels of anti–TDP-43 IgG3 and IgM NAbs and a significant increase in anti–TDP-43 IgG4 NAbs were observed in ALS plasma vs controls. Furthermore, a decrease in global IgM and an increase in IgG4 levels were observed in ALS. These aberrations of humoral immunity correlated with disease duration, but did not correlate with ALS Functional Rating Scale–Revised scores.ConclusionsOur results may suggest TDP-43–specific immune aberrations in patients with ALS. The skewed immune profiles observed in patients with ALS could indicate a deficiency in the clearance capacity and/or blocking of TDP-43 transmission and propagation. The decrease in levels of high affinity/avidity anti-TDP-43 NAbs and IgMs correlates with disease progression and may be disease predictors.

Electroconvulsive stimulation (ECS) is one of the strongest stimulators of hippocampal neurogenesis in rodents that represents a plausible mechanism for the efficacy of electroconvulsive therapy (ECT) in major depressive disorder. Using design-based stereological cell counting, we recently documented an initial 2.6-fold increase in neurogenesis following a clinical relevant schedule of ECS, a treatment also rescuing depression-like behavior in rats. However, these results gave no demonstration of the longevity of newly generated neurons. The present study is a direct continuation of the previous work aiming to test the hypothesis that rats subjected to ECS in combination with chronic restraint stress (CRS) display increased formation of new hippocampal neurons, which have a potential for long-term survival. Furthermore, using mediation analysis, we tested if an ECS-induced increase in neurogenesis facilitates the behavioral outcome of the forced swim test (FST), an animal model of depression. The results showed that ECS in conjunction with CRS stimulates hippocampal neurogenesis, and that a significant quantity of the newly formed hippocampal neurons survives up to 12 months. The new BrdU-positive neurons showed time-dependent attrition of ∼40% from day 1 to 3 months, with no further decline between 3 and 12 months. ECS did not affect the number of pre-existing dentate granule neurons or the volume of the dentate granule cell layer, suggesting no damaging effect of the treatment. Finally, we found that, while ECS increases neurogenesis, this formation of new neurons was not associated to ameliorated immobility in the FST. This implies that other ECS-induced effects than neurogenesis must be part of mediating the antidepressant action of ECS. Taken together, the results of the present study contribute to the basic understanding of the neurogenic effects of ECT, and demonstrate that ECS, neurogenesis and anti-depressant behavior are not directly linked. © 2016 Wiley Periodicals, Inc.

Accumulating evidence suggests neuroinflammation to be an integrated feature of neurodegeneration. Profiling inflammatory mediators across diseases may reveal common and disease-specific signatures. Here, we focused on progressive supranuclear palsy (PSP), a tauopathy presenting motor and cognitive dysfunction. We screened for 21 cytokines and growth factors in the dorsomedial prefrontal cortex of 16 PSP and 16 control brains using different quantitative techniques. We found and validated increased interleukin (IL)-2 protein levels in the PSP group expressed locally by neurons and glia cells. We further investigated central players in neuroinflammatory pathways and found increased mRNA expression of glycogen synthase kinase 3 beta (GSK3B). IL-2 and GSK3B proteins are T and natural killer (NK) cell regulators and have previously been associated with other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and multiple system atrophy. In addition, we identified a shift in peripheral CD4+ and CD8+ T cell populations toward increased numbers of memory and reduced numbers of naive T cells. We also observed increased numbers of CD56+ NK cells, but not of CD56+CD57+ or CD57+ NK cells. Our findings suggest a role for IL-2 in PSP disease processes and point toward active and possibly dysfunctional peripheral immune responses in these patients.

Dr Weimers and colleagues have drawn attention1 to the possibility that our recently published observation of an association between IBD and Parkinson’s disease (PD) in a nationwide Danish cohort study2 may reflect surveillance bias. In a recently published Swedish cohort study, Dr Weimers and colleagues found that adjusting for number of healthcare visits during follow-up of patients with IBD attenuated the risk of developing PD markedly.3 They also found that the risk of future PD was …

We estimated by stereological methods the neocortical volume occupied by plaques and tangles in females dying with severe Alzheimer's disease (AD), age-matched female subjects with severe vascular dementia (VaD), and normal control brains. Stereological investigations include a uniform sampling of the tissue in the whole of neocortex and its subdivisions. Resultant volume estimates provide information about the overall burden of these two pathological changes and their volume fractions and allow for correlational studies between the pathological changes and factors such as the total neocortical neuronal cell numbers, dementia test scores, and age. We estimated the volume of plaques and tangles in the entire neocortex and frontal-, temporal-, parietal-, and occipital cortex in nine female AD brains, four female patients dying with VaD, and six neurologically normal female control brains using point-counting in uniform samples of neocortex. The volume occupied by plaques comprised approximately 1% of neocortex, while the neocortical tangles made up approximately 0.1% of neocortex of AD patients but were scarcely present in the other study groups. The individual tangle and plaque volumes did not correlate to the ultimate dementia score of the AD subjects, despite correlating with reduced neocortical volume. In neocortex of AD patients, the burden of plaques and tangles is much higher than that in patients with severe vascular dementia or normal older women but only occupy a small fraction of the neocortical volume.

The anterior thalamic nuclei are important for spatial and episodic memory, however, surprisingly little is known about the status of these nuclei in neurological conditions that present with memory impairments, such as Down syndrome. We quantified neurons and glial cells in the anterior thalamic nuclei of four older patients with Down syndrome. There was a striking reduction in the volume of the anterior thalamic nuclei and this appeared to reflect the loss of approximately 70% of neurons. The number of glial cells was also reduced but to a lesser degree than neurons. The anterior thalamic nuclei appear to be particularly sensitive to effects of aging in Down syndrome and the pathology in this region likely contributes to the memory impairments observed. These findings reaffirm the importance of examining the status of the anterior thalamic nuclei in conditions where memory impairments have been principally assigned to pathology in the medial temporal lobe., Highlights • Volume of anterior thalamus is markedly reduced in older patients with Down syndrome. • Number of neurons in anterior thalamus are substantially reduced. • Number of glial cells in anterior thalamus are substantially reduced.

Aggregation of α-synuclein is a hallmark of Parkinson's disease and dementia with Lewy bodies. We here investigate the relationship between cytosolic Ca2+ and α-synuclein aggregation. Analyses of cell lines and primary culture models of α-synuclein cytopathology reveal an early phase with reduced cytosolic Ca2+ levels followed by a later Ca2+ increase. Aggregated but not monomeric α-synuclein binds to and activates SERCA in vitro, and proximity ligation assays confirm this interaction in cells. The SERCA inhibitor cyclopiazonic acid (CPA) normalises both the initial reduction and the later increase in cytosolic Ca2+. CPA protects the cells against α-synuclein-aggregate stress and improves viability in cell models and in Caenorhabditis elegans in vivo. Proximity ligation assays also reveal an increased interaction between α-synuclein aggregates and SERCA in human brains affected by dementia with Lewy bodies. We conclude that α-synuclein aggregates bind SERCA and stimulate its activity. Reducing SERCA activity is neuroprotective, indicating that SERCA and down-stream processes may be therapeutic targets for treating α-synucleinopathies.

ObjectiveTo investigate whether spreading depolarization (SD)-related variables at 2 different time windows (days 1–4 and 5–8) after aneurysmal subarachnoid hemorrhage (aSAH) correlate with the stereologically determined volume of early focal brain injury on the preinterventional CT scan.MethodsIn this observational multicenter study of 54 patients, volumes of unaffected brain tissue, ventricles, cerebellum, aSAH, intracerebral hemorrhage, and focal parenchymal hypodensity were stereologically estimated. Patients were electrocorticographically monitored using subdural electrodes for 81.8 hours (median) (interquartile range: 70.6–90.5) during days 1–4 (n = 54) and for 75.9 (59.5–88.7) hours during days 5–8 (n = 51). Peak total SD-induced depression duration of a recording day (PTDDD) and peak numbers of (1) SDs, (2) isoelectric SDs, and (3) spreading depressions of a recording day were determined following the recommendations of the Co-Operative Studies on Brain Injury Depolarizations.ResultsThirty-three of 37 patients with early focal brain injury (intracerebral hemorrhage and/or hypodensity) in contrast to 7 of 17 without displayed SDs during days 1–4 (sensitivity: 89% [95% confidence interval, CI: 75%–97%], specificity: 59% [CI: 33%–82%], positive predictive value: 83% [CI: 67%–93%], negative predictive value: 71% [CI: 42%–92%], Fisher exact test, p < 0.001). All 4 SD-related variables during days 1–4 significantly correlated with the volume of early focal brain injury (Spearman rank order correlations). A multiple ordinal regression analysis identified the PTDDD as the most important predictor.ConclusionsOur findings suggest that early focal brain injury after aSAH is associated with early SDs and further support the notion that SDs are a biomarker of focal brain lesions.

The schizophrenia and bipolar disorder associated gene, BRD1, encodes a scaffold protein that in complex with epigenetic modifiers regulate gene sets enriched for psychiatric disorder risk. Preclinical evidence from male Brd1+/− mice has previously implicated BRD1 with phenotypes of translational relevance to schizophrenia. Here we describe the phenotype of female Brd1+/− mice and report attenuated dendritic architecture and monoaminergic dysregulation accompanied by sex-specific changes in affective behaviors. In accordance, global gene expression profiling reveals regional dysregulation of gene sets enriched with major depressive disorder and schizophrenia risk in female and male Brd1+/− mice, respectively. Independent of sex, however, differentially expressed genes cluster in common functional pathways associated with psychiatric disorders, including mitochondrial dysfunction and oxidative phosphorylation as well as G-protein coupled-, and nuclear receptor mediated signaling. Accordingly, we provide in vitro evidence that BRD1 modulates the transcriptional drive of a subset of nuclear receptors (e.g. the vitamin D and glucocorticoid receptors). Moreover, we demonstrate enrichment of psychiatric disorder risk in the target genes of nuclear receptors, sex-biased expression of several nuclear receptor genes in the adult brain of Brd1+/− mice, and that sex-biased genes in general are enriched with nuclear receptor genes particularly at the earliest developmental stage of the human brain. Overall, our data suggests that the spatio-temporal interaction between BRD1 and subsets of nuclear receptors in the brain is sex-biased and that hampered BRD1 mediated regulation of target genes governed by certain nuclear receptors may significantly contribute to sex differences in psychopathology.