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Objective: Triggering receptor expressed on myeloid cells‐2 (TREM2) and progranulin (PGRN) are critical regulators of microglia activation and can be detected in cerebrospinal fluid (CSF). However, whether microglial reactivity is detrimental or neuroprotective for Alzheimer disease (AD) is still debatable. Methods: We identified 663 participants with baseline β‐amyloid (Aβ) positron emission tomography (PET) and CSF biomarker data, including phosphorylated tau181 (p‐Tau181), soluble TREM2 (sTREM2), PGRN, and growth‐associated protein‐43 (GAP‐43). Among them, 254 participants had concurrent longitudinal CSF biomarkers. We used multivariate regression analysis to study the associations of CSF microglial biomarkers with Aβ PET, CSF p‐Tau181, and CSF GAP‐43 cross‐sectionally and longitudinally. A Chinese aging cohort's independent CSF samples (n = 65) were analyzed as a validation. Results: Higher baseline levels of CSF microglial biomarkers were related to faster rates of CSF sTREM2 increase and CSF PGRN decrease. Elevated CSF p‐Tau181 was associated with higher levels of CSF microglial biomarkers and faster rates of CSF sTREM2 increase and CSF PGRN decrease. In both cohorts, higher Aβ burden was associated with attenuated CSF p‐Tau181 effects on CSF microglial biomarker increases. Independent of Aβ PET and CSF p‐Tau181 pathologies, higher levels of CSF sTREM2 but not CSF PGRN were related to elevated CSF GAP‐43 levels and faster rates of CSF GAP‐43 increase. Interpretation: These findings suggest that higher Aβ burden may attenuate the p‐Tau‐associated microglial responses, and TREM2‐related microglial reactivity may independently correlate with GAP‐43‐related presynaptic loss. This study highlights the two‐edged role of microglial reactivity in AD and other neurodegenerative diseases. ANN NEUROL 2024;95:917–928 [ABSTRACT FROM AUTHOR]

Rationale: Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), share a distinct pathological feature, that is, a widespread accumulation of α‐synuclein (α‐syn) in the brain. There is a significant clinical unmet need for disease‐modifying treatments for synucleinopathies. Recently, a seaweed‐derived mixture of oligosaccharides sodium oligomannate, GV‐971, was approved for Phase 2 clinical trials for PD. This study aimed to further evaluate the therapeutic effects of GV‐971 on synucleinopathies using cellular and animal models and explore its associated molecular mechanisms. Methods: α‐Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp‐SNCAA53T mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV‐971 in ameliorating α‐syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp‐SNCAA53T mice 4 weeks after intragastric administration of GV‐971 (200 mg day−1 kg−1). Results: GV‐971 effectively prevented α‐syn aggregation and even disassembled pre‐aggregated α‐syn fibrils, in vitro and ex vivo. In addition, GV‐971 was able to rescue α‐syn‐induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp‐SNCAA53T mouse model, when treated at the age of 5 months, GV‐971 significantly decreased α‐syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions. Conclusions: Our results indicate that GV‐971, when administered at a relatively early stage of the disease process, significantly reduced α‐syn accumulation and aggregation in Prnp‐SNCAA53T mice. Furthermore, GV‐971 corrected α‐syn‐induced inhibition of EVs release in neurons, contributing to neuronal protection. Future studies are needed to further assess GV‐971 as a promising disease‐modifying therapy for PD and other synucleinopathies. [ABSTRACT FROM AUTHOR]

Background: Progressive spreading of α‐synuclein via gut‐brain axis has been hypothesized in the pathogenesis of Parkinson's disease (PD). However, the source of seeding‐capable α‐synuclein in the gastrointestinal tract (GIT) has not been fully investigated. Additionally, the mechanism by which the GIT microbiome contributes to PD pathogenesis remains to be characterized. Objectives: We aimed to investigate whether blood‐derived α‐synuclein might contribute to PD pathology via a gut‐driven pathway and involve GIT microbiota. Methods: The GIT expression of α‐synuclein and the transmission of extracellular vesicles (EVs) derived from erythrocytes/red blood cells (RBCs), with their cargo α‐synuclein, to the GIT were explored with various methods, including radioactive labeling of RBC‐EVs and direct analysis of the transfer of α‐synuclein protein. The potential role of microbiota on the EVs transmission was further investigated by administering butyrate, the short‐chain fatty acids produced by gut microbiota and studying mice with different α‐synuclein genotypes. Results: This study demonstrated that RBC‐EVs can effectively transport α‐synuclein to the GIT in a region‐dependent manner, along with variations closely associated with regional differences in the expression of gut‐vascular barrier markers. The investigation further revealed that the infiltration of α‐synuclein into the GIT was influenced significantly by butyrate and α‐synuclein genotypes, which may also affect the GIT microbiome directly. Conclusion: By demonstrating the transportation of α‐synuclein through RBC‐EVs to the GIT, and its potential association with gut‐vascular barrier markers and gut microbiome, this work highlights a potential mechanism by which RBC α‐synuclein may impact PD initiation and/or progression. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Plasma β‐amyloid (Aβ) Aβ42/Aβ40 measured by immunoprecipitation and liquid chromatography‐mass spectrometry assay has been demonstrated useful to identify Aβ PET positive individuals, but the concordance and discordance about the positivity of plasma Aβ42/Aβ40 (Plasma+/‐) and Aβ PET (PET+/‐) have not been fully characterized. Moreover, the association of Aβ deposition, cortical thickness (CTh), glucose metabolism, and microglial activation among different Plasma/PET profiles is poorly understood. Method: In this study, we classified 173 ADNI participants into Plasma‐/PET‐ (N = 48), Plasma+/PET‐ (N = 43), and Plasma+/PET+ (N = 73) group based on thresholds of composite Aβ PET (18F‐florbetapir, FBP) standardized uptake value ratio (SUVR) (≥1.11) and plasma Aβ42/Aβ40 (≤0.1218). Part of them had longitudinal 18F‐fluorodeoxyglucose (FDG) PET, structural MRI, and CSF soluble Triggering Receptor Expressed on Myeloid Cell 2 (sTREM2) data. Baseline and slopes of FBP SUVRs of 68 Freesurfer‐defined ROIs were compared between different Plasma/PET groups. The associations of regional FBP SUVRs, CSF sTREM2, regional glucose metabolism (reflected in FDG‐SUVR), and CTh (measured using structural MRI) were investigated in different Plasma/PET groups. Result: Plasma Aβ42/Aβ40 might become positive earlier than Aβ PET (Fig.1A, McNemar's test, p<0.001). Longitudinally, Plasma+/PET‐ participants showed faster rates of Aβ accumulation in bilateral BANKSSTS, supramarginal, and superior parietal cortices whereas demonstrated no difference in baseline FBP SUVRs than Plasma‐/PET‐ participants (Fig.1D‐E). Higher CSF sTREM2 level and faster rate of CSF sTREM2 increase were related to slower rates of Aβ accumulation in BANKSSTS (standardized β (βstd) = ‐0.418, p = 0.002) in Plasma+/PET+ but not in Plasma+/PET‐ individuals (Fig.2A and D). In contrast, thicker CTh (Fig. 4B‐C) and higher glucose metabolism (Fig. 4H‐I) in supramarginal and superior parietal cortices were coupled to faster rates of CSF sTREM2 increase in Plasma+/PET‐ rather than in Plasma+/PET+ individuals. Conclusion: These findings suggest that plasma Aβ42/Aβ40 might become abnormal earlier than Aβ PET, and plasma Aβ42/Aβ40 positive Aβ PET negative (Plasma+/PET‐) individuals accumulate Aβ plaques faster than Plasma‐/PET‐ individuals. Activated microglia may play a role in reducing fibrillar‐Aβ increasing rates in late amyloidosis stage, whereas it may be related to hypertrophy and hypermetabolism in early amyloidosis stages. [ABSTRACT FROM AUTHOR]

Background: Loss of function of triggering receptor expressed on myeloid cells 2 (TREM2) and progranulin (PGRN), predominantly expressed by microglia in the brain, contribute to the development of Alzheimer's disease (AD). Although animal studies suggest that the expressions of TREM2 and PGRN increase in activated microglia, their associations with AD‐related pathologies and subsequent outcomes are not well characterized. This study aimed to explore how cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) and PGRN relate to β‐amyloid (Aβ), tau, synaptic loss, neurodegeneration, and cognitive decline. Method: We identified 610 ADNI participants with Aβ PET and CSF biomarkers measurements at baseline and 250 individuals with longitudinal CSF biomarkers measurements. All participants had concurrent longitudinal structure MRI and Preclinical Alzheimer's Cognitive Composite (PACC) assessments. Using generalized linear models, we investigated the associations of CSF microglial biomarkers with Aβ PET, CSF p‐Tau181, CSF presynaptic biomarker growth‐associated protein‐43 (GAP‐43), hippocampal atrophy, and cognitive decline. Result: CSF p‐Tau181 levels rather than Aβ PET were positively associated with CSF microglial biomarkers, whereas higher Aβ PET SUVRs were related to attenuated effects of CSF p‐Tau181 on changes in CSF sTREM2 and CSF PGRN (Figure. 1). Mediation analyses further showed that Aβ PET and CSF p‐Tau181 had opposing effects on CSF microglial biomarkers (Figure. 2). In addition, CSF sTREM2 rather than CSF PGRN were positively associated with CSF GAP‐43 cross‐sectionally and longitudinally, independent of Aβ PET and CSF p‐Tau181 (Figure. 3). Furthermore, augmented microglial activation was associated with slower rates of hippocampal atrophy (sTREM2: standard β (βstd) = 0.11, p = 0.007; PGRN: βstd = 0.11, p = 0.003), but only CSF sTREM2 was related to reduced rates of cognitive decline (βstd = 0.11, p = 0.003). Conclusion: This study provides novel insights into the opposing microglial immune response to Aβ and tau pathologies, where elevated CSF p‐Tau181 rather than Aβ plaque is associated with microglial activation. TREM2‐dependent signaling may contribute to the microglia‐related presynaptic loss beyond Aβ and tau pathologies, and microglial activation is protective against hippocampal atrophy and cognitive decline. These findings are critical for understanding the roles of neuroinflammation in AD or other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) pre‐synaptic protein growth‐associated protein 43 (GAP43) appears to be closely linked to neurodegeneration and cognitive decline in Alzheimer's disease (AD). However, it is not well characterized about the associations of CSF GAP43 with β‐amyloid (Aβ), tau, neurodegeneration and cognitive decline. Method: We identified 790 Alzheimer's Disease Neuroimaging Initiative participants with concurrent CSF GAP43, Aβ PET, CSF p‐Tau181, residual hippocampal volume (rHCV), 18F‐fluorodeoxyglucose (FDG) PET and cognitive assessments within one year. Among of them, 340 individuals had longitudinal CSF GAP43 measurements. We compared baseline and longitudinal changes of CSF GAP43 among different biological stages defined by Aβ PET (A), CSF p‐Tau181 (T) and rHCV (N) in addition to their associations with Aβ PET, CSF p‐Tau181, rHCV, FDG PET and cognition cross‐sectionally and longitudinally, controlling for age, sex, APOE‐ε4 status and diagnosis. Result: Among different A/T and A/T/N profiles, we found all CSF p‐Tau181‐positive individuals had significant higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases regardless of Aβ deposition and hippocampal atrophy (Figure 1). Furthermore, increased CSF p‐Tau181 rather than Aβ PET was related to higher baseline CSF GAP43 and faster rates of CSF GAP43 increases regardless of A/T profiles (Figure 2). In the subgroups of individuals with longitudinal MRI, FDG PET and cognition data, we found that higher CSF GAP43 concentrations (n = 377) and faster rates of GAP43 increases (n = 240) were associated with faster hippocampal atrophy, hypometabolism and cognitive decline (Figure 3). Conclusion: These findings imply that tau aggregation rather than Aβ pathology is driving pre‐synaptic loss measured by CSF GAP43, which subsequently contributes to hippocampal atrophy and hypometabolism, resulting in cognitive decline in AD. Altogether, CSF GAP43 may be considered for an extra biomarker beyond A/T/N biomarkers, which can provide new insights into underlying AD pathogenesis prior to neurodegeneration. [ABSTRACT FROM AUTHOR]

Introduction: Although presynaptic loss measured by cerebrospinal fluid (CSF) growth‐associated protein‐43 (GAP‐43) is significantly involved in Alzheimer's disease (AD), the sequential association between CSF GAP‐43 and AD‐typical neurodegeneration is poorly understood. Methods: We compared baseline CSF GAP‐43 levels (n = 730) and longitudinal CSF GAP‐43 changes (n = 327) in various biological stages of AD, and investigated their relationships with cross‐sectional and longitudinal measures of residual hippocampal volume, 18F‐fluorodeoxyglucose PET, regional gray matter volume and cortical thickness, and cognition. Results: Elevated CSF GAP43 levels were significantly associated with faster rates of hippocampal atrophy, AD‐signature hypometabolism and cortical thinning, and middle temporal gray matter atrophy‐related and AD‐signature hypometabolism‐related cognitive decline. In contrast, baseline levels of all these neurodegeneration biomarkers did not predict longitudinal CSF GAP‐43 increases. Discussion: These findings suggest that presynaptic loss may occur prior to neurodegeneration, highlighting the importance of lowing tau aggregation and tau‐related synaptic dysfunction in elderly adults and AD patients. [ABSTRACT FROM AUTHOR]

Objective: Increased presynaptic dysfunction measured by cerebrospinal fluid (CSF) growth‐associated protein‐43 (GAP43) may be observed in Alzheimer's disease (AD), but how CSF GAP43 increases relate to AD‐core pathologies, neurodegeneration, and cognitive decline in AD requires further investigation. Methods: We analyzed 731 older adults with baseline β‐amyloid (Aβ) positron emission tomography (PET), CSF GAP43, CSF phosphorylated tau181 (p‐Tau181), and 18F‐fluorodeoxyglucose PET, and longitudinal residual hippocampal volume and cognitive assessments. Among them, 377 individuals had longitudinal 18F‐fluorodeoxyglucose PET, and 326 individuals had simultaneous longitudinal CSF GAP43, Aβ PET, and CSF p‐Tau181 data. We compared baseline and slopes of CSF GAP43 among different stages of AD, as well as their associations with Aβ PET, CSF p‐Tau181, residual hippocampal volume, 18F‐fluorodeoxyglucose PET, and cognition cross‐sectionally and longitudinally. Results: Regardless of Aβ positivity and clinical diagnosis, CSF p‐Tau181‐positive individuals showed higher CSF GAP43 concentrations (p < 0.001) and faster rates of CSF GAP43 increases (p < 0.001) compared with the CSF p‐Tau181‐negative individuals. Moreover, higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases were strongly related to CSF p‐Tau181 independent of Aβ PET. They were related to more rapid hippocampal atrophy, hypometabolism, and cognitive decline (p < 0.001), and predicted the progression from MCI to dementia (area under the curve for baseline 0.704; area under the curve for slope 0.717) over a median 4 years of follow up. Interpretation: Tau aggregations rather than Aβ plaques primarily drive presynaptic dysfunction measured by CSF GAP43, which may lead to sequential neurodegeneration and cognitive impairment in AD or neurodegenerative diseases. ANN NEUROL 2022;92:1001–1015 [ABSTRACT FROM AUTHOR]