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Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aβ deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque’s association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aβ-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aβ-positive cases ( n  = 74), including non-demented cases ( n  = 15), early-onset (EO)AD ( n  = 38), and late-onset (LO)AD cases ( n  = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque’s neuritic component (pTau, APP, PrP C ), Aβ isoform composition (Aβ 40 , Aβ 42 , Aβ N3pE , pSer8Aβ), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of Aβ 40 . Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular Aβ 40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent Aβ plaque-type associated with EOAD. Differences in Aβ processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aβ deposits. Disentangling specific Aβ deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the amyloid β (Aβ) protein in the cerebral vasculature and poses a major risk factor for the development of intracerebral haemorrhages (ICH). However, only a minority of patients with CAA develops ICH (CAA-ICH), and to date it is unclear which mechanisms determine why some patients with CAA are more susceptible to haemorrhage than others. We hypothesized that an imbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) contributes to vessel wall weakening. MMP9 plays a role in the degradation of various components of the extracellular matrix as well as of Aβ and increased MMP9 expression has been previously associated with CAA. TIMP3 is an inhibitor of MMP9 and increased TIMP3 expression in cerebral vessels has also been associated with CAA. In this study, we investigated the expression of MMP9 and TIMP3 in occipital brain tissue of CAA-ICH cases ( n  = 11) by immunohistochemistry and compared this to the expression in brain tissue of CAA cases without ICH (CAA-non-haemorrhagic, CAA-NH, n  = 18). We showed that MMP9 expression is increased in CAA-ICH cases compared to CAA-NH cases. Furthermore, we showed that TIMP3 expression is increased in CAA cases compared to controls without CAA, and that TIMP3 expression is reduced in a subset of CAA-ICH cases compared to CAA-NH cases. In conclusion, in patients with CAA, a disbalance in cerebrovascular MMP9 and TIMP3 expression is associated with CAA-related ICH.

Alzheimer's disease (AD) is characterized by amyloid-beta (A[beta]) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical A[beta] deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque's association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø [almost equal to] 80 [micro]m) deposit, characterized as having multiple cores and A[beta]-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of A[beta]-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE [epsilon]4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque's neuritic component (pTau, APP, PrP.sup.C), A[beta] isoform composition (A[beta].sub.40, A[beta].sub.42, A[beta].sub.N3pE, pSer8A[beta]), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of A[beta].sub.40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular A[beta].sub.40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent A[beta] plaque-type associated with EOAD. Differences in A[beta] processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other A[beta] deposits. Disentangling specific A[beta] deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

Objective Elevated levels of anti‐amyloid‐β (anti‐Aβ) autoantibodies in cerebrospinal fluid (CSF) have been proposed as a diagnostic biomarker for cerebral amyloid angiopathy‐related inflammation (CAA‐RI). We aimed to independently validate the immunoassay for quantifying these antibodies and evaluate its diagnostic value for CAA‐RI. Methods We replicated the immunoassay to detect CSF anti‐Aβ autoantibodies using CSF from CAA‐RI patients and non‐CAA controls with unrelated disorders and further characterized its performance. Moreover, we conducted a literature review of CAA‐RI case reports to investigate neuropathological and CSF evidence of the nature of the inflammatory reaction in CAA‐RI. Results The assay demonstrated a high background signal in CSF, which increased and corresponded with higher total immunoglobulin G (IgG) concentration in CSF (rsp = 0.51, p = 0.02). Assay levels were not elevated in CAA‐RI patients (n = 6) compared to non‐CAA controls (n = 20; p = 0.64). Literature review indicated only occasional presence of B‐lymphocytes and plasma cells (i.e., antibody‐producing cells), alongside the abundant presence of activated microglial cells, T‐cells, and other monocyte lineage cells. CSF analysis did not convincingly indicate intrathecal IgG production. Interpretation We were unable to reproduce the reported elevation of anti‐Aβ autoantibody concentration in CSF of CAA‐RI patients. Our findings instead support nonspecific detection of IgG levels in CSF by the assay. Reviewed CAA‐RI case reports suggested a widespread cerebral inflammatory reaction. In conclusion, our findings do not support anti‐Aβ autoantibodies as a diagnostic biomarker for CAA‐RI.

Background: In dementia with Lewy bodies (DLB), co-existence of Alzheimer's disease (AD) pathology, i.e. amyloid-β plaques and tau tangles, has been associated with a more rapid disease progression. In post-mortem DLB brains, we examined the association between AD copathology and regional load and morphology of α-synuclein pathology. Also, we compared regional load and morphology of AD copathology in DLB to pathology in AD. Methods: We included 50 autopsy-confirmed DLB donors with a clinical DLB phenotype, categorized as having no/low levels of AD copathology (pure DLB, n = 15), or intermediate/high levels of AD copathology (mixed DLB+AD, n = 35), and autopsy-confirmed pure AD donors (n = 14) without α-synuclein pathology. We used percentage area of immunopositivity for quantitative assessment of pathology load, and visual scores for semi-quantitative assessment of different morphologies of α-synuclein, amyloid-β and phosphorylated tau (p-tau) pathology in fifteen neocortical, limbic and brainstem regions. Results: Mixed DLB+AD compared to pure DLB showed a shorter disease duration (6 ± 3 versus 8 ± 3 years, p = 0.021) and higher frequency of APOE-ε4 alleles. A-synuclein load was higher in neocortical regions (temporal, parietal and occipital), but not in brainstem and limbic regions, which was based upon an increase of Lewy bodies, α-synuclein-positive astrocytes and α-synuclein-positive plaques in these regions. A-synuclein load was most strongly correlated to amyloid-β and p-tau load in temporal (r = 0.38 and r = 0.50 respectively) and occipital regions (r = 0.43 and r = 0.42 respectively). Compared to pure AD, mixed DLB+AD showed a lower amyloid-β load in temporal cortex, CA3 and CA4 region, and lower p-tau loads in frontal and parietal cortex, based both upon presence of fewer neuritic plaques as well as neurofibrillary tangles. Conclusions: In DLB brains, AD copathology was associated with more neocortical α-synuclein pathology, consisting not only of Lewy bodies and plaques, but also of astroglial α-synuclein. AD pathology in DLB cases is less than in AD cases, reflecting less advanced pathological stages. Astroglial α-synuclein and its relation with AD copathology in DLB should be further studied, as this may play a role in accelerating clinical decline.Competing Interest StatementThe authors have declared no competing interest.

Background Procalcitonin (PCT) and C-reactive protein (CRP) were previously shown to have value for the detection of secondary infections in critically ill COVID-19 patients. However, since the introduction of immunomodulatory therapy, the value of these biomarkers is unclear. We investigated PCT and CRP kinetics in critically ill COVID-19 patients treated with dexamethasone with or without tocilizumab, and assessed the value of these biomarkers to detect secondary bacterial infections. Methods In this prospective study, 190 critically ill COVID-19 patients were divided into three treatment groups: no dexamethasone, no tocilizumab (D−T−) , dexamethasone, no tocilizumab (D + T−) , and dexamethasone and tocilizumab (D + T + ) . Serial data of PCT and CRP were aligned on the last day of dexamethasone treatment, and kinetics of these biomarkers were analyzed between 6 days prior to cessation of dexamethasone and 10 days afterwards. Furthermore, the D+T− and D+T+ groups were subdivided into secondary infection and no-secondary infection groups to analyze differences in PCT and CRP kinetics and calculate detection accuracy of these biomarkers for the occurrence of a secondary infection. Results Following cessation of dexamethasone, there was a rebound in PCT and CRP levels, most pronounced in the D+T− group. Upon occurrence of a secondary infection, no significant increase in PCT and CRP levels was observed in the D+T− group ( p  = 0.052 and p  = 0.08, respectively). Although PCT levels increased significantly in patients of the D+T+ group who developed a secondary infection ( p  = 0.0003), this rise was only apparent from day 2 post-infection onwards. CRP levels remained suppressed in the D+T+ group. Receiver operating curve analysis of PCT and CRP levels yielded area under the curves of 0.52 and 0.55, respectively, which are both markedly lower than those found in the group of COVID-19 patients not treated with immunomodulatory drugs (0.80 and 0.76, respectively, with p values for differences between groups of 0.001 and 0.02, respectively). Conclusions Cessation of dexamethasone in critically ill COVID-19 patients results in a rebound increase in PCT and CRP levels unrelated to the occurrence of secondary bacterial infections. Furthermore, immunomodulatory treatment with dexamethasone and tocilizumab considerably reduces the value of PCT and CRP for detection of secondary infections in COVID-19 patients.

Abstract Context During treatment, children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone, which induce acute side effects. Objective To determine the influence of a 5-day dexamethasone course on changes in leptin, fat mass, BMI, hunger, sleep, and fatigue and to explore associations between these changes. Methods Pediatric ALL patients were included during maintenance treatment. Data were collected before (T1) and after (T2) a 5-day dexamethasone course (6 mg/m2/day). At both time points, BMI, fat mass (bioelectrical impedance analysis), and leptin were assessed, as well as parent-reported questionnaires regarding hunger, fatigue, and sleep problems. Changes between T1 and T2 were assessed using paired tests. Correlation coefficients were calculated to assess associations between these changes (Delta scores: T2-T1). Univariable regression models were estimated to study associations between covariates and elevated leptin. Results We included 105 children, with median age 5.4 years (range, 3.0-18.8). Leptin and fat mass, as well as hunger scores, fatigue, and sleep deteriorated after 5 days of dexamethasone (P < .001), in contrast to BMI (P = .12). No correlations between delta leptin and delta fat mass, BMI, hunger, fatigue, or sleep were found. Elevated leptin on T1 was associated with older age (odds ratio [OR] 1.51; 95% CI, 1.28-1.77), higher fat mass (OR 1.19; 95% CI, 1.07-1.33), and earlier maintenance week (OR 0.96; 95% CI, 0.92-0.99). Conclusion Five days of high-dose dexamethasone treatment led to direct and significant changes in leptin, hunger scores, and fat mass. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and a dexamethasone-induced state of acute leptin resistance might play a role.

Cerebral organoids are 3D stem cell-derived models that can be utilized to study the human brain. The current consensus is that cerebral organoids consist of cells derived from the neuroectodermal lineage. This limits their value and applicability, as mesodermal-derived microglia are important players in neural development and disease. Remarkably, here we show that microglia can innately develop within a cerebral organoid model and display their characteristic ramified morphology. The transcriptome and response to inflammatory stimulation of these organoid-grown microglia closely mimic the transcriptome and response of adult microglia acutely isolated from post mortem human brain tissue. In addition, organoid-grown microglia mediate phagocytosis and synaptic material is detected inside them. In all, our study characterizes a microglia-containing organoid model that represents a valuable tool for studying the interplay between microglia, macroglia, and neurons in human brain development and disease. Brain organoid models reported to date lack cells of mesodermal origin, such as microglia. Here, the authors demonstrate that mature microglia-like cells are generated within their cerebral organoid model, providing new avenues for studying human microglia in a three-dimensional brain environment.

Background Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone (DEXA) treatment on the clinical course of PF in critically ill COVID-19 patients. Methods We performed a pre-post design study in 191 COVID-19 patients admitted to the Intensive Care Unit (ICU) spanning two treatment cohorts: the pre-DEXA - (n = 67) and the DEXA-cohort (n = 124). PF was identified based on radiological findings, worsening of ventilatory parameters and elevated circulating PIIINP levels. Longitudinal transcriptome profiles of 52 pre-DEXA patients were determined using RNA sequencing. Effects of prednisone treatment on clinical fibrosis parameters and outcomes were analyzed between PF- and no-PF-patients within both cohorts. Results Transcriptome analyses revealed upregulation of inflammatory, coagulation and neutrophil extracellular trap-related pathways in PF-patients compared to no-PF patients. Key genes involved included PADI4 , PDE4D , MMP8 , CRISP3 , and BCL2L15 . Enrichment of several identified pathways was associated with impaired survival in a external cohort of patients with idiopathic pulmonary fibrosis. Following prednisone treatment, PF-related profiles reverted towards those observed in the no-PF-group. Likewise, PIIINP levels decreased significantly following prednisone treatment. PF incidence was 28% and 25% in the pre-DEXA- and DEXA-cohort, respectively (p = 0.61). ICU length-of-stay ( pre-DEXA : 42 [29–49] vs. 18 [13–27] days, p < 0.001; DEXA : 42 [28–57] vs. 13 [7–24] days, p < 0.001) and mortality (pre-DEXA: 47% vs. 15%, p = 0.009; DEXA: 61% vs. 19%, p < 0.001) were higher in the PF-groups compared to the no-PF-groups within both cohorts. Early dexamethasone therapy did not influence these outcomes. Conclusions ICU patients with COVID-19 who develop PF exhibit upregulated coagulation, inflammation, and neutrophil extracellular trap-related pathways as well as prolonged ICU length-of-stay and mortality. This study indicates that early dexamethasone treatment neither influences the incidence or clinical course of PF, nor clinical outcomes.

The medial prefrontal cortex (mPFC) steers goal-directed actions and withholds inappropriate behavior. Dorsal and ventral mPFC (dmPFC/vmPFC) circuits have distinct roles in cognitive control, but underlying mechanisms are poorly understood. Here we use neuroanatomical tracing techniques, in vitro electrophysiology, chemogenetics and fiber photometry in rats engaged in a 5-choice serial reaction time task to characterize dmPFC and vmPFC outputs to distinct thalamic and striatal subdomains. We identify four spatially segregated projection neuron populations in the mPFC. Using fiber photometry we show that these projections distinctly encode behavior. Postsynaptic striatal and thalamic neurons differentially process synaptic inputs from dmPFC and vmPFC, highlighting mechanisms that potentially amplify distinct pathways underlying cognitive control of behavior. Chemogenetic silencing of dmPFC and vmPFC projections to lateral and medial mediodorsal thalamus subregions oppositely regulate cognitive control. In addition, dmPFC neurons projecting to striatum and thalamus divergently regulate cognitive control. Collectively, we show that mPFC output pathways targeting anatomically and functionally distinct striatal and thalamic subregions encode bi-directional command of cognitive control. This study presents an anatomical, neurophysiological and functional characterization of four distinct prefrontal populations that project to striatal and thalamic sub-regions. The authors show that each of these populations have a discrete role in the regulation of cognitive control.