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Intermediate filaments (IFs) are major constituents of the cytoskeleton and nuclear boundary in animal cells. They are of prime importance for the functional organization of structural elements. Depending on the cell type, morphologically similar but biochemically distinct proteins form highly viscoelastic filament networks with multiple nanomechanical functions. Besides their primary role in cell plasticity and their established function as cellular stress absorbers, recently discovered gene defects have elucidated that structural alterations of IFs can affect their involvement both in signaling and in controlling gene regulatory networks. Here, we highlight the basic structural and functional properties of IFs and derive a concept of how mutations may affect cellular architecture and thereby tissue construction and physiology.

INTRODUCTION We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer's disease (AD) stages. METHODS We performed path analysis on data from 384 cognitively unimpaired individuals from the ALzheimer and FAmilies (ALFA)+ study using structural equation modeling to quantify the relationships between biomarkers of reactive astrogliosis and the AD pathological cascade. RESULTS Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/40 was associated with Aβ aggregation on positron emission tomography (PET) and with CSF p‐tau181, which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF Aβ42/40 and Aβ‐PET, and CSF YKL‐40 partly explained the association between Aβ‐PET, p‐tau181, and NfL. DISCUSSION Our results suggest that reactive astrogliosis, as indicated by different fluid biomarkers, influences the pathogenic cascade during the preclinical stage of AD. While plasma GFAP mediates the early association between soluble and insoluble Aβ, CSF YKL‐40 mediates the latter association between Aβ and downstream Aβ‐induced tau pathology and tau‐induced neuronal injury. Highlights Lower CSF Aβ42/40 was directly linked to higher plasma GFAP concentrations. Plasma GFAP partially explained the relationship between soluble Aβ and insoluble Aβ. CSF YKL‐40 mediated Aβ‐induced tau phosphorylation and tau‐induced neuronal injury.

Background Total tau protein (T-Tau) and neurofilament light chain (NfL) have emerged as candidate plasma biomarkers of neurodegeneration, but studies have not compared how these biomarkers cross-sectionally or longitudinally associate with cognitive and neuroimaging measures. We therefore compared plasma T-Tau and NfL as cross-sectional and longitudinal markers of (1) global and domain-specific cognitive decline and (2) neuroimaging markers of cortical thickness, hippocampal volume, white matter integrity, and white matter hyperintensity volume. Methods We included 995 participants without dementia who were enrolled in the Mayo Clinic Study of Aging cohort. All had concurrent plasma NfL and T-tau, cognitive status, and neuroimaging data. Follow-up was repeated approximately every 15 months for a median of 6.2 years. Plasma NfL and T-tau were measured on the Simoa-HD1 Platform. Linear mixed effects models adjusted for age, sex, and education examined associations between baseline z -scored plasma NfL or T-tau and cognitive or neuroimaging outcomes. Analyses were replicated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) among 387 participants without dementia followed for a median of 3.0 years. Results At baseline, plasma NfL was more strongly associated with all cognitive and neuroimaging outcomes. The combination of having both elevated NfL and T-tau at baseline, compared to elevated levels of either alone, was more strongly associated at cross-section with worse global cognition and memory, and with neuroimaging measures including temporal cortex thickness and increased number of infarcts. In longitudinal analyses, baseline plasma T-tau did not add to the prognostic value of baseline plasma NfL. Results using ADNI data were similar. Conclusions Our results indicate plasma NfL had better utility as a prognostic marker of cognitive decline and neuroimaging changes. Plasma T-tau added cross-sectional value to NfL in specific contexts. Trial registration Not applicable

Introduction There is a tremendous need for identifying reliable blood-based biomarkers for Alzheimer’s disease (AD) that are tied to the biological ATN (amyloid, tau and neurodegeneration) framework as well as clinical assessment and progression. Methods One hundred forty-four elderly participants underwent 18F-AV45 positron emission tomography (PET) scan, structural magnetic resonance imaging (MRI) scan, and blood sample collection. The composite standardized uptake value ratio (SUVR) was derived from 18F-AV45 PET to assess brain amyloid burden, and the hippocampal volume was determined from structural MRI scans. Plasma glial fibrillary acidic protein (GFAP), phosphorylated tau-181 (ptau-181), and neurofilament light (NfL) measured by single molecular array (SIMOA) technology were assessed with respect to ATN framework, genetic risk factor, age, clinical assessment, and future functional decline among the participants. Results Among the three plasma markers, GFAP best discriminated participants stratified by clinical diagnosis and brain amyloid status. Age was strongly associated with NfL, followed by GFAP and ptau-181 at much weaker extent. Brain amyloid was strongly associated with plasma GFAP and ptau-181 and to a lesser extent with plasma NfL. Moderate association was observed between plasma markers. Hippocampal volume was weakly associated with all three markers. Elevated GFAP and ptau-181 were associated with worse cognition, and plasma GFAP was the most predictive of future functional decline. Combining GFAP and ptau-181 together was the best model to predict brain amyloid status across all participants (AUC = 0.86) or within cognitively impaired participants (AUC = 0.93); adding NfL as an additional predictor only had a marginal improvement. Conclusion Our findings indicate that GFAP is of potential clinical utility in screening amyloid pathology and predicting future cognitive decline. GFAP, NfL, and ptau-181 were moderately associated with each other, with discrepant relevance to age, sex, and AD genetic risk, suggesting their relevant but differential roles for AD assessment. The combination of GFAP with ptau-181 provides an accurate model to predict brain amyloid status, with the superior performance of GFAP over ptau-181 when the prediction is limited to cognitively impaired participants.

Stem cell therapy is a promising strategy to treat neurodegenerative diseases, traumatic brain injury, and stroke. For stem cells to progress towards clinical use, the risks associated with invasive intracranial surgery used to deliver the cells to the brain, needs to be reduced. Here, we show that MRI-guided focused ultrasound (MRIgFUS) is a novel method for non-invasive delivery of stem cells from the blood to the brain by opening the blood brain barrier (BBB) in specific brain regions. We used MRI guidance to target the ultrasound beam thereby delivering the iron-labeled, green fluorescent protein (GFP)-expressing neural stem cells specifically to the striatum and the hippocampus of the rat brain. Detection of cellular iron using MRI established that the cells crossed the BBB to enter the brain. After sacrifice, 24 hours later, immunohistochemical analysis confirmed the presence of GFP-positive cells in the targeted brain regions. We determined that the neural stem cells expressed common stem cell markers (nestin and polysialic acid) suggesting they survived after transplantation with MRIgFUS. Furthermore, delivered stem cells expressed doublecortin in vivo indicating the stem cells were capable of differentiating into neurons. Together, we demonstrate that transient opening of the BBB with MRIgFUS is sufficient for transplantation of stem cells from the blood to targeted brain structures. These results suggest that MRIgFUS may be an effective alternative to invasive intracranial surgery for stem cell transplantation.

Background Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) is considered as a prodromal stage of either multiple system atrophy (MSA) or Lewy body disease (LBD; Parkinson's disease and dementia with Lewy bodies). However, current knowledge is limited in predicting and differentiating the type of future phenoconversion in iRBD patients. We investigated the role of plasma neurofilament light chain (NfL) and cardiac metaiodobenzylguanidine (MIBG) uptake as predictors for phenoconversion. Methods Forty patients with iRBD were enrolled between April 2018 and October 2019 and prospectively followed every 3 months to determine phenoconversion to either MSA or LBD. Plasma NfL levels were measured at enrollment. Cardiac MIBG uptake and striatal dopamine transporter uptake were assessed at baseline. Results Patients were followed for a median of 2.92 years. Four patients converted to MSA and 7 to LBD. Plasma NfL level at baseline was significantly higher in future MSA-converters (median 23.2 pg/mL) when compared with the rest of the samples (median 14.1 pg/mL, p  = 0.003). NfL level above 21.3 pg/mL predicted phenoconversion to MSA with the sensitivity of 100% and specificity of 94.3%. Baseline MIBG heart-to-mediastinum ratio of LBD-converters (median 1.10) was significantly lower when compared with the rest (median 2.00, p  < 0.001). Heart-to-mediastinum ratio below 1.545 predicted phenoconversion to LBD with the sensitivity of 100% and specificity of 92.9%. Conclusions Plasma NfL and cardiac MIBG uptake may be useful biomarkers in predicting phenoconversion of iRBD. Elevated plasma NfL levels may suggest imminent phenoconversion to MSA, whereas low cardiac MIBG uptake suggests phenoconversion to LBD.

Sepsis-associated encephalopathy (SAE) contributes to mortality and neurocognitive impairment of sepsis patients. Neurofilament (Nf) light (NfL) and heavy (NfH) chain levels as biomarkers for neuroaxonal injury were not evaluated in cerebrospinal fluid (CSF) and plasma of patients with sepsis-associated encephalopathy (SAE) before. We conducted a prospective, pilot observational study including 20 patients with septic shock and five patients without sepsis serving as controls. The assessment of SAE comprised a neuropsychiatric examination, electroencephalography (EEG), magnetic resonance imaging (MRI) and delirium screening methods including the confusion assessment method for the ICU (CAM-ICU) and the intensive care delirium screening checklist (ICDSC). CSF Nf measurements in sepsis patients and longitudinal plasma Nf measurements in all participants were performed on days 1, 3 and 7 after study inclusion. Plasma NfL levels increased in sepsis patients over time (p = 0.0063) and remained stable in patients without sepsis. Plasma NfL values were significantly higher in patients with SAE (p = 0.011), significantly correlated with the severity of SAE represented by ICDSC values (R = 0.534, p = 0.022) and correlated with a poorer functional outcome after 100 days (R = -0.535, p = 0.0003). High levels of CSF Nf were measured in SAE patients. CSF NfL levels were higher in non-survivors (p = 0.012) compared with survivors and correlated with days until death (R = -0.932, p<0.0001) and functional outcome after 100 days (R = -0.749, p<0.0001). The present study showed for the first time that Nf levels provide complementary prognostic information in SAE patients indicating a higher chance of death and poorer functional/cognitive outcome in survivors.

Neurofilament light chain (NFL) measurement has been gaining strong support as a clinically useful neuronal injury biomarker for various neurodegenerative conditions. However, in Alzheimer’s disease (AD), its reflection on regional neuronal injury in the context of amyloid pathology remains unclear. This study included 83 cognitively normal (CN), 160 mild cognitive impairment (MCI), and 73 AD subjects who were further classified based on amyloid-beta (Aβ) status as positive or negative (Aβ+ vs Aβ−). In addition, 13 rats (5 wild type and 8 McGill-R-Thy1-APP transgenic (Tg)) were examined. In the clinical study, reduced precuneus/posterior cingulate cortex and hippocampal grey matter density were significantly associated with increased NFL concentrations in cerebrospinal fluid (CSF) or plasma in MCI Aβ+ and AD Aβ+. Moreover, AD Aβ+ showed a significant association between the reduced grey matter density in the AD-vulnerable regions and increased NFL concentrations in CSF or plasma. Congruently, Tg rats recapitulated and validated the association between CSF NFL and grey matter density in the parietotemporal cortex, entorhinal cortex, and hippocampus in the presence of amyloid pathology. In conclusion, reduced grey matter density and elevated NFL concentrations in CSF and plasma are associated in AD-vulnerable regions in the presence of amyloid positivity in the AD clinical spectrum and amyloid Tg rat model. These findings further support the NFL as a neuronal injury biomarker in the research framework of AD biomarker classification and for the evaluation of therapeutic efficacy in clinical trials.

Background Gray matter (GM) pathology is closely associated with physical and cognitive impairment in persons with multiple sclerosis (PwMS). Similarly, serum neurofilament light chain (sNfL) levels are related to MS disease activity and progression. Objectives To assess the cross–sectional and longitudinal associations between sNfL and MRI–derived lesion and brain volume outcomes in PwMS and age–matched healthy controls (HCs). Materials and Methods Forty‐seven HCs and 120 PwMS were followed over 5 years. All subjects underwent baseline and follow–up 3T MRI and sNfL examinations. Lesion volumes (LV) and global, tissue–specific and regional brain volumes were assessed. sNfL levels were analyzed using single molecule array (Simoa) assay and quantified in pg/mL. The associations between sNfL levels and MRI outcomes were investigated using regression analyses adjusted for age, sex, baseline disease modifying treatment (DMT) use and change in DMT over the follow‐up. False discovery rate (FDR)–adjusted q‐values <0.05 were considered significant. Results In PwMS, baseline sNfL was associated with baseline T1‐, T2‐ and gadolinium‐LV (q = 0.002, q = 0.001 and q < 0.001, respectively), but not with their longitudinal changes. Higher baseline sNfL levels were associated with lower baseline deep GM (β = −0.257, q = 0.017), thalamus (β = −0.216, q = 0.0017), caudate (β = −0.263, q = 0.014) and hippocampus (β = −0.267, q = 0.015) volumes. Baseline sNfL was associated with longitudinal decline of deep GM (β = −0.386, q < 0.001), putamen (β = −0.395, q < 0.001), whole brain (β = −0.356, q = 0.002), thalamus (β = −0.272, q = 0.049), globus pallidus (β = −0.284, q = 0.017), and GM (β = −0.264, q = 0.042) volumes. No associations between sNfL and MRI–derived measures were seen in the HCs. Conclusion Higher sNfL levels were associated with baseline LVs and greater development of GM atrophy in PwMS.

Background Cognitive impairment in people with MS (PwMS) has primarily been investigated using conventional imaging markers or fluid biomarkers of neurodegeneration separately. However, the single use of these markers do only partially explain the large heterogeneity found in PwMS. Objective To investigate the use of multimodal (bio)markers: i.e., serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and conventional imaging markers in predicting cognitive functioning in PwMS. Methods Eighty-two PwMS (56 females, disease duration = 14 ± 9 years) underwent neuropsychological and neurological examination, structural magnetic resonance imaging, blood sampling and lumbar puncture. PwMS were classified as cognitively impaired (CI) if scoring ≥ 1.5SD below normative scores on ≥ 20% of test scores. Otherwise, PwMS were defined as cognitively preserved (CP). Association between fluid and imaging (bio)markers were investigated, as well as binary logistics regression to predict cognitive status. Finally, a multimodal marker was calculated using statistically important predictors of cognitive status. Results Only higher NfL levels (in serum and CSF) correlated with worse processing speed ( r  = − 0.286, p  = 0.012 and r  = − 0.364, p  = 0.007, respectively). sNfL added unique variance in the prediction of cognitive status on top of grey matter volume (NGMV), p  = 0.002). A multimodal marker of NGMV and sNfL yielded most promising results in predicting cognitive status (sensitivity = 85%, specificity = 58%). Conclusion Fluid and imaging (bio)markers reflect different aspects of neurodegeneration and cannot be used interchangeably as markers for cognitive functioning in PwMS. The use of a multimodal marker, i.e., the combination of grey matter volume and sNfL, seems most promising for detecting cognitive deficits in MS.