Pathological Changes In Brain Research Articles

High beta-amyloid(1–40) cerebrospinal fluid concentrations precede increase of serum biomarkers in a case with severe HELLP syndrome

Beta-amyloid peptides and tau protein concentrations were analysed at second and third trimester pregnancy in cerebrospinal fluid in a 27-year old woman who developed severe HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome. Contrary to a healthy pregnant control the beta-amyloid(1–40) load was much higher and the ratios beta-amyloid peptides(1–42/1-40) and phospho-tau/tau had increased before delivery. We observed that in early HELLP syndrome increased beta-amyloid levels preceded vascular biomarker changes. We conclude that high levels of beta-amyloid(1–40) in the second trimester of pregnancy might reflect pathologic maternal brain changes that go along with pathological changes in the materno-feto-placental unit.

Heparin-enriched plasma proteome is significantly altered in Alzheimer’s disease

IntroductionHeparin binding proteins (HBPs) with roles in extracellular matrix assembly are strongly correlated to β-amyloid (Aβ) and tau pathology in Alzheimer’s disease (AD) brain and cerebrospinal fluid (CSF). However, it remains challenging to detect these proteins in plasma using standard mass spectrometry-based proteomic approaches.MethodsWe employed heparin-affinity chromatography, followed by off-line fractionation and tandem mass tag mass spectrometry (TMT-MS), to enrich HBPs from plasma obtained from AD (n = 62) and control (n = 47) samples. These profiles were then correlated to Aβ, tau and phosphorylated tau (pTau) CSF biomarkers and plasma pTau181 from the same individuals, as well as a consensus brain proteome network to assess the overlap with AD brain pathophysiology.ResultsHeparin enrichment from plasma was highly reproducible, enriched well-known HBPs like APOE and thrombin, and depleted high-abundant proteins such as albumin. A total of 2865 proteins, spanning 10 orders of magnitude in abundance, were measured across 109 samples. Compared to the consensus AD brain protein co-expression network, we observed that specific plasma proteins exhibited consistent direction of change in both brain and plasma, whereas others displayed divergent changes, highlighting the complex interplay between the two compartments. Elevated proteins in AD plasma, when compared to controls, included members of the matrisome module in brain that accumulate with Aβ deposits, such as SMOC1, SMOC2, SPON1, MDK, OLFML3, FRZB, GPNMB, and the APOE4 proteoform. Additionally, heparin-enriched proteins in plasma demonstrated significant correlations with conventional AD CSF biomarkers, including Aβ, total tau, pTau, and plasma pTau181. A panel of five plasma proteins classified AD from control individuals with an area under the curve (AUC) of 0.85. When combined with plasma pTau181, the panel significantly improved the classification performance of pTau181 alone, increasing the AUC from 0.93 to 0.98. This suggests that the heparin-enriched plasma proteome captures additional variance in cognitive dementia beyond what is explained by pTau181.ConclusionThese findings support the utility of a heparin-affinity approach coupled with TMT-MS for enriching amyloid-associated proteins, as well as a wide spectrum of plasma biomarkers that reflect pathological changes in the AD brain.

Continuous theta burst stimulation ameliorates cognitive deficits in microinfarcts mice via inhibiting glial activation and promoting paravascular CSF-ISF exchange

Microinfarcts are widespread in the elderly, accompanied by varying degrees of cognitive decline. Continuous theta burst stimulation (cTBS) has been demonstrated to be neuroprotective on cognitive dysfunction, but the underlying cellular mechanism has been still not clear. In the present study, we evaluated the effects of cTBS on cognitive function and brain pathological changes in mice model of microinfarcts. The spatial learning and memory was assessed by Morris water maze (MWM), Glymphatic clearance efficiency was evaluated using in vivo two-photon imaging. The loss of neurons, activation of astrocytes and microglia, the expression and polarity distribution of the astrocytic aquaporin-4 (AQP4) were assessed by immunofluorescence staining. Our results showed that cTBS treatment significantly improved the spatial learning and memory, accelerated the efficiency of glymphatic clearance, up-regulated the AQP4 expression and improved the polarity distribution of AQP4 in microinfarcts mice. Besides, cTBS treatment increased the number of surviving neurons, whereas decreased the activated astrocytes and microglia. Our study suggested that cTBS accelerated glymphatic clearance and inhibited the excessive gliogenesis, which ultimately exerted neuroprotective effects on microinfarcts mice.

Analysis of miRNA Expression Profiles in Traumatic Brain Injury (TBI) and Their Correlation with Survival and Severity of Injury.

Traumatic brain injury (TBI) is the leading cause of traumatic death worldwide and is a public health problem associated with high mortality and morbidity rates, with a significant socioeconomic burden. The diagnosis of brain injury may be difficult in some cases or may leave diagnostic doubts, especially in mild trauma with insignificant pathological brain changes or in cases where instrumental tests are negative. Therefore, in recent years, an important area of research has been directed towards the study of new biomarkers, such as micro-RNAs (miRNAs), which can assist clinicians in the diagnosis, staging, and prognostic evaluation of TBI, as well as forensic pathologists in the assessment of TBI and in the estimation of additional relevant data, such as survival time. The aim of this study is to investigate the expression profiles (down- and upregulation) of a panel of miRNAs in subjects deceased with TBI in order to assess, verify, and define the role played by non-coding RNA molecules in the different pathophysiological mechanisms of brain damage. This study also aims to correlate the detected expression profiles with survival time, defined as the time elapsed between the traumatic event and death, and with the severity of the trauma. This study was conducted on 40 cases of subjects deceased with TBI (study group) and 10 cases of subjects deceased suddenly from non-traumatic causes (control group). The study group was stratified according to the survival time and the severity of the trauma. The selection of miRNAs to be examined was based on a thorough literature review. Analyses were performed on formalin-fixed, paraffin-embedded (FFPE) brain tissue samples, with a first step of total RNA extraction and a second step of quantification of the selected miRNAs of interest. This study showed higher expression levels in cases compared to controls for miR-16, miR-21, miR-130a, and miR-155. In contrast, lower expression levels were found in cases compared to controls for miR-23a-3p. There were no statistically significant differences in the expression levels between cases and controls for miR-19a. In cases with short survival, the expression levels of miR-16-5p and miR-21-5p were significantly higher. In cases with long survival, miR-21-5p was significantly lower. The expression levels of miR-130a were significantly higher in TBI cases with short and middle survival. In relation to TBI severity, miR-16-5p and miR-21-5p expression levels were significantly higher in the critical-fatal TBI subgroup. Conclusions: This study provides evidence for the potential of the investigated miRNAs as predictive biomarkers to discriminate between TBI cases and controls. These miRNAs could improve the postmortem diagnosis of TBI and also offer the possibility to define the survival time and the severity of the trauma. The analysis of miRNAs could become a key tool in forensic investigations, providing more precise and detailed information on the nature and extent of TBI and helping to define the circumstances of death.

Visual and Auditory Sensory Impairments Differentially Relate with Alzheimer's Pathology.

We intended to investigate the relationships between visual sensory impairment (VSI) or auditory sensory impairment (ASI) and brain pathological changes associated with cognitive decline in older adults. We primarily tried to examine whether each sensory impairment is related to Alzheimer's disease (AD) pathology, specifically beta-amyloid (Aβ) deposition, through both cross-sectional and longitudinal approaches in cognitively unimpaired older adults. Self-report questionnaires on vision and hearing status were administered at the baseline. Neuroimaging scans including brain [11C] Pittsburgh Compound B PET and MRI, as well as clinical assessments, were performed at baseline and 2-year follow-up. Cross-sectional analyses showed that the VSI-positive group had significantly higher Aβ deposition than the VSI-negative group, whereas there was no significant association between ASI positivity and Aβ deposition. Longitudinal analyses revealed that VSI positivity at baseline was significantly associated with increased Aβ deposition over 2 years (β = 0.153, p = 0.025), although ASI positivity was not (β = 0.045, p = 0.518). VSI positivity at baseline was also significantly associated with greater atrophic changes in AD-related brain regions over the 2-year follow-up period (β = -0.207, p = 0.005), whereas ASI positivity was not (β = 0.024, p = 0.753). Neither VSI nor ASI positivity was related to cerebrovascular injury, as measured based on the white matter hyperintensity volume. The findings suggest that VSI is probably related to AD-specific pathological changes, which possibly mediate the reported relationship between VSI and cognitive decline. In contrast, ASI appears not associated with AD pathologies but may contribute to cognitive decline via other mechanisms.

Huanglian Jiedu decoction alleviates ischemia-induced cerebral injury in rats by mitigating NET formation and activiting GABAergic synapses.

Huanglian Jiedu decoction (HLJD) has been used to treat ischemic stroke in clinic. However, the detailed protective mechanisms of HLJD on ischemic stroke have yet to be elucidated. The aim of this study is to elucidate the underlying pharmacological mechanisms of HLJD based on the inhibition of neuroinflammation and the amelioration of nerve cell damage. A middle cerebral artery occlusion reperfusion (MCAO/R) model was established in rats and received HLJD treatment. Effects of HLJD on neurological function was assessed based on Bederson's score, postural reflex test and asymmetry score. 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining, Hematein and eosin (HE) and Nissl staining were used to observe the pathological changes in brain. Then, transcriptomics was used to screen the differential genes in brain tissue in MCAO/R model rats following HLJD intervention. Subsequently, the effects of HLJD on neutrophil extracellular trap (NET) formation-related neuroinflammation, gamma-aminobutyric acid (GABA)ergic synapse activation, nerve cell damage and proliferation were validated using immunofluorescence, western blot and enzyme-linked immunosorbent assay (ELISA). Our results showed that HLJD intervention reduced the Bederson's score, postural reflex test score and asymmetry score in MCAO/R model rats. Pathological staining indicated that HLJD treatment decreased the cerebral infarction area, mitigated neuronal damage and increased the numbers of Nissl bodies. Transcriptomics suggested that HLJD affected 435 genes in MCAO/R rats. Among them, several genes involving in NET formation and GABAergic synapses pathways were dysregulated. Subsequent experimental validation showed that HLJD reduced the MPO+CitH3+ positive expression area, reduced the protein expression of PAD4, p-P38/P38, p-ERK/ERK and decreased the levels of IL-1β, IL-6 and TNF-α, reversed the increase of Iba1+TLR4+, Iba1+p65+ and Iba1+NLRP3+ positive expression area in brain. Moreover, HLJD increased GABA levels, elevated the protein expression of GABRG1 and GAT3, decreased the TUNEL positive expression area and increased the Ki67 positive expression area in brain. HLJD intervention exerts a multifaceted positive impact on ischemia-induced cerebral injury in MCAO/R rats. This intervention effectively inhibits neuroinflammation by mitigating NET formation, and concurrently improves nerve cell damage and fosters nerve cell proliferation through activating GABAergic synapses.

Exploration of the pharmacological components and therapeutic mechanisms in treatment of Alzheimer's disease with Polygonati Rhizoma and its processed product using combined analysis of metabolomics, network pharmacology, and gut microbiota

Polygonati Rhizoma (PR, Huangjing in Chinese) and its processed product (PRP), which are used in Traditional Chinese medicine (TCM) for cognitive enhancement and treatment of Alzheimer's disease (AD), have not been fully explored in terms of the different mechanisms underlying their anti-AD effects. Therefore, we used APP/PS1 mice as an AD model to assess the effects of PR and PRP on anxiety-like behaviors, cognitive function, memory performance, and pathological changes in the murine brain. UPLC-HRMS was applied to identify the components of PR and PRP that entered into the blood and brain. Network pharmacology was used to elucidate potential mechanisms underlying the improvement of AD. Differences in the intestinal flora composition between mice treated with PR and PRP were investigated using 16S rRNA sequencing, establishing a correlation between pharmacological components and distinct flora profiles. The results revealed that both PR and PRP interventions ameliorated cognitive deficits and attenuated Amyloid β (Aβ) plaque deposition in the brains of AD mice. Seven specific blood-entering components, namely glutamic acid, Phe-Phe, and uridine, etc., were associated with PR intervention, whereas ten specific blood-entering components including (2R,3S)-3-isopropylmalate, 3-methylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione, and 3-methoxytyrosine were related to PRP intervention. Uridine was identified as a common brain-penetrating component in both PR and PRP interventions. Network pharmacology analysis suggested that the NOD-like receptor signaling pathway, Calcium signaling pathway and Alzheimer's disease were specific pathways targeted in AD treatment using PR intervention. Moreover, the apoptosis pathway was specifically linked to AD treatment during PRP intervention. Furthermore, the administration of both PR and PRP enhanced the abundance and diversity of the intestinal flora in APP/PS1 mice. Western blotting confirmed that PR excels in regulates inflammation, whereas PRP balances autophagy and apoptosis to alleviate the progression of AD. This study offers valuable insights and establishes a robust foundation for further comprehensive exploration of the intrinsic correlation between TCM and AD.

Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment.

Brain pathological changes impair cognition early in disease etiology. There is an urgent need to understand aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2 is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We previously reported that Tusc2-/- female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2-/- female mice demonstrated a pro-inflammatory increase in astrocytes, expression of IFN-γ in CD4+ T cells and Granzyme-B in CD8+T cells. We also found fewer FOXP3+ T-regulatory cells and Ly49G+ NK and Ly49G+ NKT cells in female Tusc2-/- brains, suggesting a dampened anti-inflammatory response. Moreover, Tusc2-/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2+ dynamics. Overall, the data suggest that dysregulation of Ca2+-dependent processes and a heightened pro-inflammatory brain microenvironment in Tusc2-/- mice could underlie cognitive impairment. Thus, strategies to modulate the mitochondrial Tusc2- and Ca2+- signaling pathways in the brain should be explored to improve cognitive health.

Subcortical tau is linked to hypoperfusion in connected cortical regions in 4-repeat tauopathies.

Four-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R tauopathies are progressive supranuclear palsy (PSP) and corticobasal degeneration characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aβ-negative patients with clinically diagnosed PSP variants (n = 26) or corticobasal syndrome (n = 25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol to determine an early 0.5-2.5 min post tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlases. We determined tau epicentres as subcortical regions with the highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicentres to cortical regions of interest using a resting-state functional MRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether: (i) higher subcortical tau-PET was associated with reduced cortical perfusion; and (ii) cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicentres. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicentres aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicentre showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.

Analysis of the mechanism by which ketamine affects astrocytes in Parkinsonian rats through the PI3K/AKT axis.

Parkinson's disease (PD) remains the most common neurodegenerative disease worldwide, seriously affecting the normal life of patients. Currently, there is no effective clinical cure for PD. In this study, the research team explored the effect of ketamine (KET) on PD, which can lay a reliable foundation for future KET treatment of PD. First, the research team established a PD rat model with 6-hydroxydopamine (6-OHDA). The detection showed that the maximum angle of the inclined plate stay, the number oftimes of grid crossings andstanding, and the ATPaseactivity in brain tissue were significantly lower in PD rats than in control rats, while the positive rate of α-synuclein in brain tissue was increased, showing typical pathological manifestations of PD. After using KET to intervene in PD rats, the behavioral and brain pathological changes were significantly alleviated, and the inflammation and oxidative stress damage of brain tissue were effectively reduced, suggesting the potential therapeutic effects of KET on PD. Furthermore, the use of KET inhibited the PI3K/AKT axis in the brain tissue of PD rats and promoted autophagy. Moreover, the significant suppression of the PI3K/AKT axis by KET was also demonstrated in the PD cell model established through lipopolysaccharide (LPS) inducement of astrocyte cell line HA1800. It is suggested that the mechanismof KET on PD is related to the inhibition of the PI3K/AKT axis.

Effects of angiopoietin (Ang) 1/endothelial-enriched Tunica interna endothelial cell kinase 2 (Tie2) signaling pathway on autophagy-based neuroprotection and expression of aquaporin 4

We investigated Ang-1/Tie2 signaling’s role in cellular autophagy-based neuroprotection and aquaporins expression. 40 mice were randomized into sham surgery group, model group, Tie2-antagonist group, and Ang-1+Tie2 agonist group, followed by observing brain pathological changes, and mRNA levels of LC3-I, LC3-II and aquaporin 4 (AQP4), together with levels of TNF-α and IL-1β. A certain regularity of brain tissue structure was observed in sham surgery group but not in model group. In Ang-1+Tie2 agonist group, the brain tissue structure was more disordered, which was ameliorated in Tie2-antagonist group, along with a proportion of intact cells. The neurological score of mice in Tie2 antagonist group was lower than Ang-1+Tie2 agonist and model groups. Levels of LC3-I and AQP4 in Tie2 antagonist group were also lower, along with higher levels of LC3-I and AQP4. LC3-II levels were higher in Tie2 antagonist group compared with those in Ang-1+Tie2 agonist and model groups. Whereas LC3-II and IL-1β/TNF-α levels in Ang-1+Tie2 agonist group were lower with higher levels of IL-1β and TNF-α. Inhibition of Ang-1/Tie2 signaling could have a restorative effect on neural function in stroke mice.

Tanreqing injection inhibits dengue virus encephalitis by suppressing the activation of NLRP3 inflammasome

BackgroundEncephalitis caused by dengue virus (DENV) is considered a manifestation of severe dengue. Tanreqing injection (TRQ) is a well-known Chinese patented medicine, which has been used to treat brain-related disorders by inhibiting inflammation. Nevertheless, the effects of TRQ on DENV encephalitis have not been studied. The aim of this study was to evaluate the effects of TRQ on DENV encephalitis and to explore its potential mechanisms.MethodsThe cytotoxicity of TRQ was examined by MTT assay, and the anti-DENV activities of TRQ in BHK-21 baby hamster kidney fibroblast were evaluated through CCK-8 and plaque assays. The expression levels of NO, IL1B/IL-1β, TNFα and IL6 were measured by qRT‒PCR and ELISA in the BV2 murine microglial cell line. The inhibitory effects of TRQ on NLRP3 inflammasome activation in BV2 cells were examined by Western blotting, qRT‒PCR and ELISA. The effects of TRQ on HT22 mouse hippocampal neuronal cells were examined by CCK-8 assay, morphology observation and flow cytometry. Moreover, a DENV-infected ICR suckling mouse model was developed to investigate the protective role of TRQ in vivo.ResultsTRQ decreased the release of NO, IL6, TNFα and IL1B from BV2 cells and inhibited the activation of NLRP3. The presence of the NLRP3 agonist nigericin reversed the anti-inflammatory activities of TRQ. Furthermore, TRQ inhibited the death of HT22 cells by decreasing IL1B in DENV-infected BV2 cells. In addition, TRQ significantly attenuated weight loss, reduced clinical scores and extended the survival in DENV-infected ICR suckling mice. Critically, TRQ ameliorated pathological changes in ICR suckling mice brain by inhibiting microglia and NLRP3 activation and decreasing the production of inflammatory factors and the number of dead neurons.ConclusionTRQ exerts potent inhibitory effects on dengue encephalitis in vitro and in vivo by reducing DENV-2-induced microglial activation and subsequently decreasing the inflammatory response, thereby protecting neurons. These findings demonstrate the potential of TRQ in the treatment of dengue encephalitis.

Interaction Between a High-Fat Diet and Tau Pathology in Mice: Implications for Alzheimer's Disease.

Obesity is a modifiable risk factor for Alzheimer's disease (AD). However, its relation with tau pathology (i.e., aberrant tau protein behavior in tauopathies such as AD) has been inconclusive. This study investigated the interaction between a high-fat diet (HFD) and tau pathology in adult male mice. Transgenic mice overexpressing human P301S Tau (those with the pathology) and wild-type (WT) littermates were subjected to behavioral tests, functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and western blotting analysis to investigate the effects of prolonged HFD versus regular diet during adulthood. HFD increased body weight in both WT and P301S mice but had minimal effect on blood glucose levels. The brain response to HFD was tau genotype-specific. WT mice exhibited decreased recognition memory and enhanced network connectivity in fMRI, while P301S mice exhibited white matter tract disorganization in DTI as the sole significant finding. The reduction of insulin receptor β, insulin downstream signaling, neuronal nuclear protein, CD68-positive phagocytic activity, and myelin basic protein level were confined to the cortex of WT mice. In contrast to P301S mice, WT mice showed significant changes in the tau protein and its phosphorylation levels along with increased soluble neurofilament light levels in the hippocampus. HFD-induced brain dysfunction and pathological changes were blunted in mice with the pathology and more profound in healthy mice. Our findings highlight the need to consider this interaction between obesity and tau pathology when tailoring treatment strategies for AD and other tauopathies.

Association of Neurofilament Light Chain, [18F]PI-2620 Tau-PET, TSPO-PET, and Clinical Progression in Patients With β-Amyloid-Negative CBS.

Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in β-amyloid (Aβ)-negative CBS. We included patients with clinically diagnosed Aβ-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [18F]PI-2620-PET for assessing tau pathology, [18F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction). Overall, 21 patients with Aβ-negative CBS with ∼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, p = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [18F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = -0.056/0.023, p = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, p < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model. [18F]PI-2620 tau-PET, [18F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aβ-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.

Prognostic value of Neurofilament light chain, [18F]‐PI2620 PET and [18F]GE‐180‐PET in amyloid‐negative Corticobasal Syndrome

AbstractBackgroundCorticobasal syndrome (CBS) with underlying 4‐repeat tauopathy is a progressive neurodegenerative disorder characterized by declining cognitive and motor functions. Biomarkers for assessing pathological brain changes in CBS including tau‐ and microglia‐PET or neurofilament light chain (NfL) have recently been evaluated for differential diagnosis and disease staging, yet the prognostic accuracy of these biomarkers for predicting disease trajectories remains unclear. To address this, we performed a head‐to‐head comparison of neuroimaging (tau‐PET, microglia‐PET) and plasma biomarker NfL as prognostic tools for future clinical trajectories in 21 CBS patients with longitudinal clinical data.MethodWe included 21 clinically diagnosed CBS patients with ∼2‐year clinical follow‐up data who underwent baseline [18F]PI‐2620‐PET for assessing tau pathology, [18F]GE‐180‐PET for microglia activation and plasma‐NfL for neurodegeneration. All patients were negative on amyloid biomarkers. To quantify tau and microglia load we assessed summary scores of whole‐brain, cortical and subcortical tracer signal. NfL was assessed using immunoassays on the Simoa platform. Symptom progression was determined using a battery of cognitive and motor tests. Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster progression of symptoms over time (i.e. time x biomarker interaction).ResultOverall, there was on average a rapid decline over time on the assessed clinical scores. For tau‐PET, CBS patients with higher global tau load showed faster clinical progression. This time x tau‐PET interaction was driven by cortical rather than subcortical tau‐PET load. Patients with higher [18F]GE‐180‐PET whole‐brain load showed slower clinical progression. Concerning plasma biomarker NfL, higher plasma‐NfL was prognostic of faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau‐PET, microglia‐PET as well as plasma‐NfL showed significant (i.e. p&lt;0.05) interaction effects with time on clinical trajectories when tested in the same model, suggesting that these biomarkers explain unique variability in future disease trajectories.Conclusion[18F]PI‐2620 tau‐PET, [18F]GE‐180 microglia‐PET and plasma‐NfL show prognostic potential for clinical progression in CBS patients with probable 4‐repeat tauopathy, which can be useful for clinical decision making as well as stratifying patients in clinical trials.

Identify Alzheimer’s disease subtypes and markers from multi‐omic data of human brain and blood with a subspace merging algorithm

AbstractBackgroundAlzheimer’s disease (AD) is a highly heterogeneous disease with different disease trajectory, brain pathological changes, and risk factors. Identifying subtypes of AD can have greatly impact AD diagnosis, treatment, and disease management. Our goal is to identify subtypes of AD by integrating multiple types of omics data from AD patients’ brain samples and blood samples.MethodWe applied a subspace merging algorithm on AD patient brain samples with matched transcriptomic, DNA methylation, and proteomics data collected from the ROSMAP study. This algorithm merges patient graphs generated from these three datasets on a Grassmann manifold followed by spectral clustering. Differential gene expression and pathway analysis were applied to establish the gene signatures between the subtypes (patient clusters) and to the transcriptomic data of the peripheral blood monocyte (PBMC) from the matching patients to identify possible blood markers.ResultOur analysis identified two patient clusters between which the cognitive test scores or the degree of AD pathology are significantly different. Differentially expressed genes between the two groups were identified from both brain and blood samples. Gene set enrichment analysis identified a group of genes significantly enriched with synaptic functions in the brain samples. The Ingenuity Pathway Analysis was used to examine any connections between the significantly differentially expressed genes in the brain samples with the ones identified from the PBMC samples. The low density lipoprotein receptor (LDLR) gene, which was an APOE receptor observed from the blood sample is connected with 12 genes from the brain sample. The results suggested that LDLR could be a novel blood biomarker for AD subtyping.ConclusionThe subspace merging algorithm integrated multimodal omics data from the patients and successfully identified two clusters with distinct clinical progression. Differential expression analysis identified 388 significant genes from the brain samples and 18 from the PBMC samples. The pathway analysis indicated that LDLR could be a novel blood biomarker for AD subtyping. Future work will focus on validating LDLR as a candidate blood marker for AD subtyping using other public datasets with similar study design. The clinical relevance and molecular mechanism basis for the findings will also be investigated.

Reports of responses to coconut oil and medium‐chain triglyceride oil in 288 persons with Alzheimer’s and other cognitive impairment

AbstractBackgroundGlucose hypometabolism is an early key feature of AD. Ketones provide alternative fuel to glucose during fasting, ketogenic diet (KD), and ketogenic oil consumption, and are taken up normally in the AD brain (Croteau J Alz Dis 2018). RCTs of KD ± MCT oil or CO (in program recipes) report improvement in people with cognitive impairment (reviewed in Cunnane NRDD 2020; Phillips Alz Res Therapy 2021), usually attributed to generation of ATP by circulating ketones. Ketones are also anti‐inflammatory (Kim Frontiers Immunol 2022) and reduced beta‐amyloid plaques and tau tangles in animal models (Kashiwaya PNAS 2000; Wu FASEB 2020). While blood ketones from CO are lower than from MCT oil, lauric acid (50% of CO) potently stimulated ketone production in cultured KT‐5 astrocytes (Nonaka J Oleo Science 2016), suggesting a more direct effect. Virgin CO also contains antioxidants and substances that inhibit amyloid plaque formation (Chatterjee Mech Ageing Devel 2020).MethodResponse/non‐response to CO ± MCT oil from all communications about persons with AD and other memory impairment collected by the author from 2008 to mid‐2014 were analyzed. Respondents were not prompted regarding expected improvements. Verbatim phrases allowed further categorization of improvements.Result288 reports were tabulated (33‐94yo; 48% male/52% female; 55% AD, 25% other dementia, 6% Parkinson’s, 2.4% MCI, 12% other memory complaints). 72% consumed only CO, 26% CO+MCT, and 2% MCT only. 89.2% reported improvements overall, further categorized as Memory/Cognition (72.6%), Social/Behavior/Mood/Personality (37.4%), Speech/Conversation (37.7%), Resumption of Self‐Care/Other Activities (28.4%), Physical Symptoms (20.7%), and Sleep (3.9%).ConclusionJust a few targeted FDA‐approved drug therapies claim slowing of cognitive decline. However, nutritional ketosis broadly addresses important pathological changes in the AD brain, including insulin resistance, glucose hypometabolism, and inflammation. A growing number of RCTs of KD ± MCTs/CO with positive cognitive outcomes and improvement in biomarkers add weight to this large collection of communications reporting meaningful improvements while consuming CO and/or MCT oil in cognition, social interaction, self‐care, and other areas important to daily life. Nutritional ketosis deserves more attention from funding organizations and greater public awareness for the potential to improve the lives of people with AD and other neurological impairments.

HIV-1 gp120-Induced Cognitive Disorder Is Concomitant with Altered Gut Microbiota

Background HIV-associated neurocognitive disorders (HAND) is an essential factor affecting the quality of life of people living with HIV (PLWH), and the prevalence of HAND in PLWH can reach 19% to 64%. More than 50% of HAND patients treated with highly active antiretroviral therapy (HAART) did not show improvement in symptoms of cognitive impairment. HIV-1 envelope protein gp120 may be a major contributor to HAND pathology. HIV-1 gp120 enters neurons by binding CXCR4 and CCR5 and can also bind neuronal tubulin to cause direct neurotoxicity and neuronal death. HIV-1 gp120 transgenic mice (Tgm) are commonly used as HAND animal models, and Tgm brain pathological changes and differential gene expression are highly consistent with HAND patients. Intestinal flora affects the progression of diseases by regulatory the intestinal barrier, and several studies have confirmed that the normalization of abnormal intestinal flora reduces the damage to the nervous system in a variety of neurodegenerative diseases. Studies reported that Akkermansia muciniphila has a downward trend in PLWH, which may cause intestinal barrier damage. There is still a lack of relevant evidence to confirm the association between abnormal changes in gut microbiota and HAND induced by HIV-1 gp120. Therefore, in this study, we examined the gut microbiota changes in 6, 9, and 12 months Tgm to explore the relationship between age-dependent significantly different bacterial genera, intestinal barrier and neuronal damage. Methods The fresh feces were collected from HIV-1 gp120 transgenic mice (Tgm) and C57BL/6J mice (wild type, WT) at ages 6, 9, and 12 months using perianal stimulation at the same time (n=5). Total bacterial DNA was extracted from each fecal sample and the V3-V4 region of 16S rRNA was sequenced by the Illumina MiSeq platform. 12 months Tg and WT mice were sacrificed, and serum was collected to detect lipopolysaccharide (LPS) concentration by ELISA, and brain tissue of mice in each group was collected for Map2 immunohistochemical staining (n=5). SPSS 20.0 software was used for statistical analysis. P &amp;lt;0.05 were considered statistically significant. Results 16S rRNA analysis showed that increased age was significantly associated with increased abundance of Blautia ( P &amp;lt;0.01) and Prevotellaceae_NK3B31_group ( P &amp;lt;0.0001) genus and decreased abundance of Akkermansia genus ( P &amp;lt;0.05) in Tgm. Notably, the increasing age of WT was associated with the opposite trend of Blautia, Prevotellaceae_NK3B31_group and Akkermansia genus abundance, indicating those genus changes with age and gp120 induced. To further explore the effect of gut microbiota on the gut barrier, serum LPS concentrations were detected for 12 months Tgm and WT. The results showed that serum LPS level was significantly higher in Tgm than in WT ( P &amp;lt;0.01), indicating that the intestinal barrier may be impaired in Tgm. Finally, we collected 12 months Tgm and WT brain tissues for Map2 immunohistochemical staining to evaluate neuronal synaptic length and integrity. Compared with WT, the expression of map2 in the hippocampus and cerebral cortex was significantly decreased ( P &amp;lt;0.05), indicating neuronal damage in Tgm. Conclusion At the genus level, the abundance of Akkermansia was negatively correlated and the Blautia and Prevotellaceae_NK3B31_group abundance was positively correlated with increasing age in Tgm but showed an opposite trend in WT. The serum LPS level increased dramatically in the 12 months Tgm, indicating Tgm with intestinal barrier damage. Map2 expression was reduced considerably hippocampus and cortex in Tgm brain, which means neuronal synaptic integrity was impaired. ( Acknowledgements: National Natural Science Foundation of China, No. 82172259 to H.C.; Corresponding author: Hong Cao, gzhcao@smu.edu.cn.)

Effects of Fmr1 Gene Mutations on Sex Differences in Autism-Like Behavior and Dendritic Spine Development in Mice and Transcriptomic Studies

Fragile X syndrome (FXS) is the most common single gene disorder contributing to autism spectrum disorder (ASD). Although significant sex differences are observed in FXS, few studies have focused on the phenotypic characteristics as well as the differences in brain pathological changes and gene expression in FXS by sex. Therefore, we analyzed sex differences in autism-like behavior and dendritic spine development in two-month-old male and female Fmr1 KO and C57 mice and evaluated the mechanisms at transcriptome level. Results suggest that Fmr1 KO mice display sex differences in autism-like behavior and dendritic spine density. Compared to females, male had more severe effects on anxiety, repetitive stereotype-like behaviors, and socializing, with higher dendritic spine density. Furthermore, two male-biased and five female-biased expressed genes were screened based on KEGG pathway enrichment and protein–protein interaction (PPI) analyses. In conclusion, our findings show mutations in the Fmr1 gene lead to aberrant expression of related genes and affect the sex-differentiated behavioral phenotypes of Fmr1 KO mice by affecting brain development and functional architecture, and suggest future studies should focus on including female subjects to comprehensively reflect the differentiation of FXS in both sexes and develop more precise and effective therapeutic strategies.

Brain Status Transferring Generative Adversarial Network for Decoding Individualized Atrophy in Alzheimer's Disease.

Deep learning has been widely investigated in brain image computational analysis for diagnosing brain diseases such as Alzheimer's disease (AD). Most of the existing methods built end-to-end models to learn discriminative features by group-wise analysis. However, these methods cannot detect pathological changes in each subject, which is essential for the individualized interpretation of disease variances and precision medicine. In this article, we propose a brain status transferring generative adversarial network (BrainStatTrans-GAN) to generate corresponding healthy images of patients, which are further used to decode individualized brain atrophy. The BrainStatTrans-GAN consists of generator, discriminator, and status discriminator. First, a normative GAN is built to generate healthy brain images from normal controls. However, it cannot generate healthy images from diseased ones due to the lack of paired healthy and diseased images. To address this problem, a status discriminator with adversarial learning is designed in the training process to produce healthy brain images for patients. Then, the residual between the generated and input images can be computed to quantify pathological brain changes. Finally, a residual-based multi-level fusion network (RMFN) is built for more accurate disease diagnosis. Compared to the existing methods, our method can model individualized brain atrophy for facilitating disease diagnosis and interpretation. Experimental results on T1-weighted magnetic resonance imaging (MRI) data of 1,739 subjects from three datasets demonstrate the effectiveness of our method.