Markers Of Neurodegeneration Research Articles

Brain metabolic resilience in Alzheimer's disease: A predictor of cognitive decline and conversion to dementia

BackgroundBrain atrophy measured by structural imaging has been used to quantify resilience against neurodegeneration in Alzheimer's disease. Considering glucose hypometabolism is another marker of neurodegeneration, we quantified metabolic resilience (MR) based on Fluorodeoxyglucose positron emission tomography (FDG PET) and investigated its clinical implications. MethodsWe quantified the MR and other resilience metrics, including brain resilience (BR) and cognitive resilience (CR), using partial least squares path modeling from the ADNI database. A linear mixed-effects model and a Cox proportional hazards model were used to identify the impact of each resilience on longitudinal cognitive function and conversion to dementia, respectively. ResultsA total of 848 participants were included in this study. All resilience metrics (CR, BR, and MR) were associated with slower cognitive decline. Results from the ANOVA test, AIC and BIC values showed that the additional inclusion of MR improved the performances of the linear mixed effect models. In survival analysis, all resilience variables were negatively associated with the risk of conversion to dementia. In line with the results of the linear mixed effects models, the additional inclusion of MR into the models with different resilience variables increased the C-index. ConclusionRelative preservation of brain glucose metabolism is a valuable predictor of future cognitive decline and conversion to dementia, adding value to existing resilience metrics. While the utility of FDG PET in clinical settings is limited by cost and accessibility, it might have potential usefulness as a prognostic marker, especially in a context of resilience.

Reactive retinal vasodilation may mask capillary loss in eyes without diabetic retinopathy and isolated neurodegeneration

Reactive retinal vasodilation occurs in healthy individuals when the demand for oxygen surpasses the supply that the vascular bed can provide. This phenomenon may also occur in individuals with diabetes who do not have diabetic retinopathy, potentially masking circulation deficiencies caused by early capillary closure. As a result, eyes with reactive retinal vasodilation may show a seemingly normal circulation area, while also displaying other diabetes-related changes such as neurodegeneration. Our hypothesis suggests that in eyes without overt ischemia, which is one of the phenotypes of diabetic retinal disease, neurodegeneration could be the result of undetected ischemia in the presence of reactive retinal vasodilation. We propose methodologies to investigate this hypothesis, including the assessment of retinal capillaries using optical coherence tomography angiography, as well as the measurement of neurodegeneration markers such as retinal sensitivity, electroretinogram amplitude reductions, and retinal layer thinning. Additionally, we outline an approach for estimating the contribution of large retinal vessels to the percentage of circulation within a measured retinal area, using variables such as vessel length density and vessel area density. If our hypothesis is confirmed, it could lead to the early identification of ischemia before the onset of diabetic retinopathy and offer an opportunity to assess interventions when endothelial and neural damage can still be mitigated.

Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses

Long-term symptoms such as pain, fatigue, and cognitive impairments are commonly observed in individuals affected by coronavirus disease 2019 (COVID-19). Metabolites of the kynurenine pathway have been proposed to account for cognitive impairment in COVID-19 patients.Here, cerebrospinal fluid (CSF) and plasma levels of kynurenine pathway metabolites in 53 COVID-19 patients and 12 non-inflammatory neurological disease controls in Sweden were measured with an ultra-performance liquid chromatography-tandem mass spectrometry system (UPLC-MS/MS) and correlated with immunological markers and neurological markers. Single cell transcriptomic data from a previous study of 130 COVID-19 patients was used to investigate the expression of key genes in the kynurenine pathway.The present study reveals that the neuroactive kynurenine pathway metabolites quinolinic acid (QUIN) and kynurenic acid (KYNA) are increased in CSF in patients with acute COVID-19. In addition, CSF levels of kynurenine, ratio of kynurenine/tryptophan (rKT) and QUIN correlate with neurodegenerative markers. Furthermore, tryptophan is significantly decreased in plasma but not in the CSF. In addition, the kynurenine pathway is strongly activated in the plasma and correlates with the peripheral immunological marker neopterin. Single-cell transcriptomics revealed upregulated gene expressions of the rate-limiting enzyme indoleamine 2,3- dioxygenase1 (IDO1) in CD14+ and CD16+ monocytes that correlated with type II-interferon response exclusively in COVID-19 patients.In summary, our study confirms significant activation of the peripheral kynurenine pathway in patients with acute COVID-19 and, notably, this is the first study to identify elevated levels of kynurenine metabolites in the central nervous system associated with the disease. Our findings suggest that peripheral inflammation, potentially linked to overexpression of IDO1 in monocytes, activates the kynurenine pathway. Increased plasma kynurenine, crossing the blood–brain barrier, serves as a source for elevated brain KYNA and neurotoxic QUIN. We conclude that blocking peripheral-to-central kynurenine transport could be a promising strategy to protect against neurotoxic effects of QUIN in COVID-19 patients.

Associations of neurocognitive and neuropsychiatric patterns with brain structural biomarkers and dementia risk: A latent class analysis.

Neurocognitive and neuropsychiatric symptoms are essential clinical manifestations of age-related cognitive impairment, yet their patterns of co-existence remain unclear through the cognitive continuum. To examine the associations of person-centered cluster-derived patterns, based on a comprehensive collection of domain-specific cognitive and neuropsychiatric assessments, with neuroimaging markers and dementia risk. 641 participants were included in the analysis from memory clinics in Singapore. Latent class analysis was applied to define clusters of individuals with different clinical patterns. The associations between identified clinical groups with neuroimaging markers of cerebrovascular diseases and neurodegeneration were analyzed using logistic regression models. Cox proportional hazard models were applied for incident dementia. Three latent classes differing in neurocognitive and neuropsychiatric impairment were identified (Class 1 "memory impairment only"; Class 2 "global cognitive impairment"; Class 3 "global cognitive and neuropsychiatric impairment"). Compared with Class 1, Class 2 and 3 were associated with smaller brain volumes, moderate-to-severe cortical atrophy and medial temporal lobe atrophy, and the presence of all cerebrovascular lesions. Moreover, compared with Class 2, Class 3 had smaller brain volumes, moderate-to-severe cortical atrophy and presence of intracranial stenosis. Additionally, compared to Class 1, Class 2 (hazard ratio [HR] = 3.84, 95%CI 2.11-7.00), and Class 3 (HR = 6.92, 95%CI 2.84-16.83) showed an increased risk of incident dementia. Participants characterized by multi-domain cognitive impairment and co-occurrence of cognitive and neuropsychiatric impairment showed the highest risk of incident dementia, which may be attributed to both neurodegenerative and cerebrovascular pathologies.

Divergent neurodegenerative patterns: comparison of fluorodeoxyglucose-PET and MRI-based Alzheimer’s disease subtypes

Abstract [18F] fluorodeoxyglucose (FDG)-PET and MRI are key imaging markers for neurodegeneration in Alzheimer's disease. It has been well established that parieto-temporal hypometabolism on FDG-PET is closely associated with medial temporal atrophy on MRI in Alzheimer's disease. Substantial biological heterogeneity, expressed as distinct subtypes of hypometabolism or atrophy patterns, has been previously described in Alzheimer's disease using data-driven and hypothesis-driven methods. However, the link between these two imaging modalities has not yet been explored in the context of Alzheimer's disease subtypes. To investigate this link, the current study utilised FDG-PET and MRI scans from 180 amyloid-beta positive Alzheimer's disease dementia patients, 339 amyloid-beta positive mild cognitive impairment and 176 amyloid-beta negative cognitively normal controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Random forest hierarchical clustering, a data-driven model for identifying subtypes, was implemented in the two modalities: one with standard uptake value ratios and the other with grey matter volumes. Five hypometabolism- and atrophy-based subtypes were identified, exhibiting both cortical-predominant and limbic-predominant patterns although with differing percentages and clinical presentations. Three cortical-predominant hypometabolism subtypes found were: Cortical Predominant (32%), Cortical Predominant+ (11%), Cortical Predominant posterior (8%); and two limbic-predominant hypometabolism subtypes: Limbic Predominant (36%) and Limbic Predominant frontal (13%). In addition, little atrophy (minimal) and widespread (diffuse) neurodegeneration subtypes were observed from the MRI data. The five atrophy subtypes were found: Cortical Predominant (19%), Limbic Predominant (27%), Diffuse (29%), Diffuse+ (6%) and Minimal (19%). Inter-modality comparisons showed that all FDG-PET subtypes displayed medial temporal atrophy, whereas the distinct MRI subtypes showed topographically similar hypometabolic patterns. Further, allocations of FDG-PET and MRI subtypes were not consistent when compared at an individual-level. Additional analysis comparing the data-driven clustering model with prior hypothesis-driven methods showed only partial agreement between these subtyping methods. FDG-PET subtypes had greater differences between limbic-predominant and cortical-predominant patterns and MRI subtypes had greater differences in severity of atrophy. In conclusion, this study highlighted that Alzheimer's disease subtypes identified using both FDG-PET and MRI capture distinct pathways showing cortical- versus limbic-predominance of neurodegeneration. However, the subtypes do not share a bidirectional relationship between modalities and are thus not interchangeable.

Features оf Changes in the Level of Neurotransmitters and Markers of Neurodegeneration in the Brain of Rats with Experimental Parkinson’s Disease Against the Background of Course Therapy with Steroid Glycoalkaloids

Parkinson’s disease is a chronic neurodegenerative disease, one of the pathobiochemical manifestations of which is an imbalance of neurotransmitters in the brain. The aim of this work is to study the effect of glycoalkaloids on changes in the level of neurotransmitters and markers of brain neurodegeneration in rats with experimental Parkinson’s disease. Parkinson’s disease was modeled in animals by intracerebral administration of rotenone. The studied glycoalkaloids were administered orally at a dose of 0.06 mg / kg, a course of 28 days after pathology modeling. The study found that the use of the analyzed glycoalkaloids did not affect the concentration of dopamine and serotonin, and also significantly (p 0.05) reduced the level of ACh by 35.9% and increased the level of GABA by 55.1%, reduced the concentration of S100β protein by 68.6% and increased the level of BDNF by 52.4%.

Cerebrovascular markers of WMH and infarcts in ADNI: A historical perspective and future directions.

White matter hyperintensities (WMH) and infarcts found on magnetic resonance imaging (MR infarcts) are common biomarkers of cerebrovascular disease. In this review, we summarize the methods, publications, and conclusions stemming from the Alzheimer's Disease Neuroimaging Initiative (ADNI) related to these measures. We combine analysis of WMH and MR infarct data from across the three main ADNI cohorts with a review of existing literature discussing new methodologies and scientific findings derived from these data. Although ADNI inclusion criteria were designed to minimize vascular risk factors and disease, data across all the ADNI cohorts found consistent trends of increasing WMH volumes associated with advancing age, female sex, and cognitive impairment. ADNI, initially proposed as a study to investigate biomarkers of AD pathology, has also helped elucidate the impact of asymptomatic cerebrovascular brain injury on cognition within a cohort relatively free of vascular disease. Future ADNI work will emphasize additional vascular biomarkers. HIGHLIGHTS: White matter hyperintensities (WMHs) are common to advancing age and likely reflect brain vascular injury among older individuals. WMH and to a lesser extent, magnetic resonance (MR) infarcts, affect risk for transition to cognitive impairment. WMHs and MR infarcts are present, even among Alzheimer's Disease Neuroimaging Initiative (ADNI) participants highly selected to have Alzheimer's disease (AD) as the primary pathology. WMH burden in ADNI is greater among individuals with cognitive impairment and has been associated with AD neurodegenerative markers and cerebral amyloidosis. The negative additive effects of cerebrovascular disease appear present, even in select populations, and future biomarker work needs to further explore this relationship.

NCOG-27. HIGHER LEVELS OF SERUM ICAM-1 AND IL-10 ARE ASSOCIATED WITH COGNITIVE DYSFUNCTION IN BOTH IDH-WILDTYPE AND IDH-MUTANT GLIOMA

Abstract BACKGROUND Cognitive dysfunction is common among glioma patients, but the contribution of specific mechanisms to the development of cognitive symptoms is unclear. Circulating levels of proteins linked to neurodegeneration, inflammation, and vascular damage have been associated with cognitive symptoms in neurological diseases and aging, but their prognostic value in glioma is unknown. Here, we examined associations between cognitive symptoms and serum levels of protein biomarkers in glioma patients. METHODS Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA, scores ≤ 25 = cognitive dysfunction). Cytokines (interleukin-1β [IL-1β], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-γ [IFN-γ], tumor necrosis factor-α [TNF-α]), and neurodegeneration (neurofilament light chain [NfL], tau, glial fibrillary acidic protein [GFAP]), and vascular damage markers (Serum amyloid A [SAA], C-reactive protein [CRP], vascular cell adhesion molecule 1 [VCAM-1], and intercellular adhesion molecule 1 [ICAM-1]) were measured using ultrasensitive assays (Meso Scale Discovery). RESULTS Patients (n=73) were predominantly male (58%), white (74%), with a median age of 44 (range=24,74). Cognitive dysfunction was found in 53% of the patients. Levels of NfL (p=0.035), IL-6 (p=0.006), IL-10 (p=0.007), TNF-α (p=0.035), IFN-γ (p=0.011), CRP (p=0.016), VCAM-1 (p=0.012), and ICAM-1 (p<0.001) were higher in patients with cognitive dysfunction when compared to those with normal cognition. After adjusting for isocitrate dehydrogenase (IDH) tumor mutation status, age, tumor grade, and number of surgeries, higher levels of ICAM-1 and IL-10, but not other markers, remained associated with cognitive dysfunction. MoCA scores were negatively correlated with GFAP (r=-0.24, p=0.038), IFN-γ (r=-0.31, p=0.008), IL-6 (r=-0.29, p=0.014), IL-10 (r=-0.24, p=0.039), and ICAM-1 (r=-0.39, p<0.001). CONCLUSIONS ICAM-1 and IL-10 levels were higher in patients with MOCA determined cognitive dysfunction, suggesting an association between cognitive symptoms and inflammation and vascular impairment in glioma patients. Future analyses in larger longitudinal cohorts are warranted to assess the predictive value of protein biomarkers.

NCOG-28. SERUM PROTEIN BIOMARKERS LINKED TO NEURODEGENERATIVE PROCESSES ARE ELEVATED IN GLIOMA PATIENTS AND ASSOCIATED WITH SEVERITY OF NEUROLOGIC SYMPTOMS

Abstract BACKGROUND Glioma patients frequently report neurologic symptoms, adding to the complexity of cancer management and negatively impacting quality of life. However, mechanisms associated with the development of neurologic symptoms in glioma patients remain unclear. Pathological changes in the brain of glioma patients might result in elevated peripheral blood levels of proteins previously linked to central nervous system (CNS) damage and neurodegeneration, including neurofilament light chain (NfL), tau, and glial fibrillary acidic protein (GFAP). Here, we tested the hypothesis that the circulating levels of these proteins in blood are elevated in glioma patients and associated with the severity of neurologic symptoms. METHODS Patients (n=73) were enrolled in a natural history study (NCT02851706, PI T. Armstrong). Healthy subjects (n=39) were recruited by the National Institutes of Health Clinical Center Blood Bank. Neurologic symptom severity and walking interference were assessed using MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Serum proteins were analyzed using ultrasensitive assays (Meso Scale Discovery). RESULTS Participants were predominantly white (patients 74%, healthy subjects 67%) and male (patients 58%, healthy subjects 54%). The median age was 44 (range=24,74) for patients and 49 (range=19,78) for healthy volunteers. No significant differences in age, sex, or race were observed between patients and healthy subjects. Serum levels of NfL (p<0.0001), GFAP (p<0.0001), and tau (p<0.0001) were higher in glioma patients when compared to healthy subjects. Patients with walking interference had higher levels of GFAP (p=0.003), NfL (p=0.003), and tau (p=0.004), and those who reported numbness had higher levels of GFAP (p=0.012). CONCLUSIONS These findings suggest that serum levels of protein markers of neurodegeneration are elevated in glioma patients and associated with the presence of neurologic symptoms. Blood-based biomarkers have the potential to shed light on the mechanisms underlying symptoms and offer a non-invasive alternative for monitoring CNS damage that impact patient outcomes.

Total retinal thickness is an important factor in evaluating diabetic retinal neurodegeneration

ObjectiveMacular retinal nerve fibre layer (mRNFL) and ganglion cell-inner plexiform layer thickness (GC-IPL) measurements are important markers of diabetic retinal neurodegeneration (DRN). In this cross-sectional study, we aimed to quantify...

Mitigating neuroinflammation in cognitive areas: exploring the impact of HMG-CoA reductase inhibitor.

Existing literature suggests that infection-specific mechanisms may play a significant role in the onset and progression of dementia, as opposed to the broader phenomenon of systemic inflammation. In addition, 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors have been proposed as a potential therapeutic approach for sepsis, given their anti-inflammatory and antioxidant properties. We investigated the neuroprotective effect of an HMG-CoA reductase inhibitor (simvastatin) by analyzing neurodegenerative markers, mitochondrial respiration, and neuronal tracing in the prefrontal cortex (PFC) and thalamic nucleus reuniens (RE) of sepsis survivor animals. Adult Wistar rats were subjected to sepsis by cecal ligation and puncture or left non-manipulated. The animals were treated with simvastatin or vehicle for 4 days before and 10 days after surgery. The treatment preserved the non-associative memory (P < 0.05), recovered expression of Smad-3 in the hippocampus (P < 0.05), and prevented increased expression of calpain-1 (hippocampus: P < 0.0001; PFC: P < 0.05) and GSKβ (hippocampus: P < 0.0001; PFC: P < 0.0001) in the brain structures of the sepsis survivor animals. These animals also showed mitochondrial dysfunction and decreased axon terminals in the RE. Simvastatin seems to restore energy metabolism by improving the electron transfer system (ETS) values in the hippocampus (P < 0.01) and the oxidative phosphorylation/ETS (P/E) ratio in the PFC (P < 0.05), in addition to preventing the reduction of axon terminals in survivor animals. These results suggest a potential neuroprotective effect and the importance of considering HMG-CoA reductase inhibitors as a possible adjuvant therapy in sepsis.

Retinal Function in Advanced Multiple Sclerosis.

People with multiple sclerosis (pwMS) experience autoimmunity-mediated inflammation and neurodegeneration throughout the central nervous system. There remains a need for clinically accessible, reliable functional markers of neurodegeneration in MS. Previous research has described changes to electroretinography (ERG)-derived measures of retinal bipolar cell function in pwMS early in the disease course. We, therefore, investigated ERG as a potential outcome measure in individuals with more advanced disease. This cross-sectional observational study included pwMS with Expanded Disability Status Scale (EDSS) scores of ≥3.0 and healthy control (HC) participants who underwent ERG, optical coherence tomography, high- and low-contrast visual acuity measurement, and an ophthalmological examination. ERG findings in MS eyes with and without previous optic neuritis (MS +ON; MS -ON) were compared with those in HC eyes. Effects of EDSS, disease duration, ON, and treatment status on selected ERG outcomes were measured. Additional exploratory analyses assessed potential influences of MS phenotype and disease status (clinically active, radiologically active, and disease progression). Delays to two ERG peak times (dark-adapted 3.0 b-wave; light-adapted flicker) were recorded in MS +ON and MS -ON eyes. No influences of EDSS score, disease duration, previous ON, or treatment status were observed. Exploratory analyses were consistent with no effects of MS phenotype or disease status. ERG findings are abnormal in individuals with moderate-severe disability caused by MS; however, these findings are not distinct from those observed earlier in the disease course. Although bipolar dysfunction appears to be common in pwMS throughout the disease course, ERG is likely not useful in monitoring or prognostication of MS.

Neurofilament light and cognition in community-dwelling non-Hispanic Blacks.

No large-scale characterizations of neurofilament light chain (NfL) and cognitive outcomes have been conducted in community-dwelling non-Hispanic Blacks. This study aims to enhance the application of blood biomarkers, in particular NfL, to ethno-racially diverse communities. We assess the association of NfL with cognitive outcomes, hypothesizing that NfL can identify cognitive changes regardless of diagnostic category. Baseline data were analyzed among n = 283 non-Hispanic Blacks (NHB) from the multi-ethnic Health and Aging Brain Study- Health Disparities (HABS-HD). Plasma NfL was measured on the Simoa platform. Linear regression models were conducted, covarying for age, gender, and education. The majority of study participants (72%) were cognitively unimpaired (CU), with 21% having mild cognitive impairment (MCI), and 6.7% with Alzheimer's disease (AD). In adjusted models among the entire sample, significant associations existed between NfL and Trails A (p < 0.0001), Trails B (p < 0.0001), phonemic (FAS) and semantic (Animals) fluency (p = 0.03), and Symbol Digit Substitution (p < 0.001). When separated by diagnostic classification, significant associations were removed for functions involving executive functions for all diagnostic groups. Higher levels of NfL were positively associated with cognitive diagnosis, older age, and less education. Plasma NfL levels are significantly associated with measures of executive functioning, which elucidate NfL as a non-specific marker of neurodegeneration associated with efficiency of brain functions involving attention, processing, and generativity. NfL may be a sensitive measure for the detection of alterations in cognitive processing before the onset of phenotypic functional changes of neurodegeneration.

Amyloid-Beta, Tau, and Microglial Activation in Aged Felid Brains.

Alzheimer's disease (AD) and its associated pathology have been primarily identified in humans, who have relatively large brains and long lifespans. To expand what is known about aging and neurodegeneration across mammalian species, we characterized amyloid-beta (Aβ) and tau lesions in five species of aged felids (n = 9; cheetah, clouded leopard, African lion, serval, Siberian tiger). We performed immunohistochemistry to detect Aβ40 and Aβ42 in plaques and vessels and hyperphosphorylated tau in the temporal lobe gyrus sylvius and in the CA1 and CA3 subfields of the hippocampus. We also quantified the densities and morphological types of microglia expressing IBA1. We found that diffuse Aβ42 plaques, but not dense-core plaques, were present more frequentlyin the temporal cortex and tended to be more common thanAβ40 plaques across species. Conversely, vascular Aβ was labeled more consistently with Aβ40 for each species on average. Although all individuals showed some degree of Aβ40 and/or Aβ42 immunoreactivity, only the cheetahs and clouded leopards exhibited intraneuronal hyperphosphorylated tau (i.e., pretangles), which was more common in the hippocampus. Reactive, intermediate microglia were significantly associated with total Aβ40 vessel area and pretangle load in the hippocampus. This study demonstrates the co-occurrence of Aβ and tau pathology in two felid species, cheetahs and clouded leopards. Overall, these results provide an initial view of the manifestation of Aβ and tau pathology in aged, large-brained felids, which can be compared with markers of neurodegeneration across different taxa, including domestic cats, nonhuman primates, and humans.

White matter integrity and motor function: a link between cerebral myelination and longitudinal changes in gait speed in aging.

Gait speed is a robust health biomarker in older adults, correlating with the risk of physical and cognitive impairments, including dementia. Myelination plays a crucial role in neurotransmission and consequently affects various functions, yet the connection between myelination and motor functions such as gait speed is not well understood. Understanding this link could offer insights into diagnosing and treating neurodegenerative diseases that impair mobility. This study analyzed 437 longitudinal observations from 138 cognitively unimpaired adults, aged 22 to 94years, to investigate the relationship between myelin content and changes in gait speed over an average of 6.42years. Myelin content was quantified using a novel multicomponent magnetic resonance relaxometry method, and both usual and rapid gait speeds (UGS, RGS) were measured following standard protocols. Adjusting for covariates, we found a significant fixed effect of myelin content on UGS and RGS. Longitudinally, lower myelin content was linked to a greater decline in UGS, particularly in brain regions associated with motor planning. These results suggest that changes in UGS may serve as a reliable marker of neurodegeneration, particularly in cognitively unimpaired adults. Interestingly, the relationship between myelin content and changes in RGS was only observed in a limited number of brain regions, although the reason for such local susceptibility remains unknown. These findings enhance our understanding of the critical role of myelination in gait performance in unimpaired adults and provide evidence of the interconnection between myelin content and motor functionimpairment.

Neurodegeneration is highly associated with comorbidity burden in HFrEF patients

Abstract Background Heart failure (HF) is associated with cognitive decline and risk for dementia. Blood levels of amyloid beta 40 and 42 (Aβ40, Aβ42), tau protein (tau), and neurofilament light chain (NfL) have been found to be altered in neurodegenerative disease. Previous research has established a clear association between these neuromarkers and the risk of developing cognitive dysfunction and mortality in the general population. Objective The aim of this study was to investigate the association between the respective neuromarkers and comorbidity burden, as well as to explore whether comorbidity burden impacts the relationship between neuromarkers and outcome in HF patients. Methods Plasma levels of Aβ40, Aβ42, tau, and NfL were quantified using a single-molecule array assay. The primary outcome parameter was all-cause mortality. Results A total of 470 HFrEF patients were enrolled in the study, with a median age of 62 years (IQR: 52–72); 77% were male. Median NT-proBNP concentration was 1812 pg/ml (IQR: 718–3881). Elevated levels of all biomarkers were closely associated with comorbidity burden (Figure 1). All neuromarkers showed increased levels in individuals with chronic kidney disease (CKD) and known carotid artery stenosis (CAS), except for Aβ40, which did not show significant elevation in CAS (NfL: p&amp;lt;0.001 for both; t-tau: p&amp;lt;0.001 and p=0.041; Aβ40: p&amp;lt;0.001 and p=0.050; Aβ42: p&amp;lt;0.001 and p=0.033, respectively). In patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), only NfL levels were significantly elevated (p&amp;lt;0.001 for both), whereas atrial fibrillation (AF) was associated with higher levels of NfL and t-tau (p&amp;lt;0.001 for both). In individuals with iron deficiency, only Aβ42 levels were significantly higher (p=0.025). All biomarkers showed significant associations with all-cause mortality [crude HR for an increase in 1-log unit (95%CI): NfL 4.44 (3.02-6.53), t-tau 5.04 (2.97-8.58), Aβ40 3.90 (2.27-6.72), Aβ42 5.14 (2.84-9.32); p&amp;lt;0.001 for all] (Figure 2). These associations remained statistically significant after adjusting for comorbidity burden including AF, T2DM, CAD, CKD, CAS and ID [adjusted HR for an increase in 1-log unit (95%CI): NfL 3.28 (1.93-5.57), t-tau 3.96 (2.07-7.57), Aβ40 2.42 (1.34-4.38), Aβ42 3.05 (1.56-5.97); p&amp;lt;0.01 for all]. Conclusion The findings suggest a close connection between elevated levels of markers of neurodegeneration and increased comorbidity burden in HFrEF patients. While this association may indicate the cumulative risk leading to neuronal injury and HFrEF progression, a causal relationship cannot be excluded. The observed accelerated neurodegeneration in HFrEF underscores the need for further investigation into this complex interplay.Figure 1Figure 2

Intrathecal IgG and IgM synthesis correlates with neurodegeneration markers and corresponds to meningeal B cell presence in MS

Intrathecal synthesis of immunoglobulins (Igs) is a key hallmark of multiple sclerosis (MS). B cells are known to accumulate in the leptomeninges of MS patients and associate with pathology in the underlying cortex and a more severe disease course. However, the role of locally produced antibodies in MS brain pathology is poorly understood. Here, we quantified the protein levels of IgA, IgM, IgG and albumin in serum and cerebrospinal fluid (CSF) samples of 80 MS patients and 28 neurological controls to calculate Ig indices. In addition, we quantified presence of meningeal IgA+, IgM+ and IgG+ B cells in post-mortem brain tissue of 20 MS patients and 6 controls using immunostainings. IgM and IgG, but not IgA, indices were increased in CSF of MS patients compared to controls, with no observed differences between MS disease types. Both IgM and IgG indices correlated significantly with neurofilament light (NfL) levels in CSF, but not with clinical or radiological parameters of disease. Similarly, IgG+ and IgM+ B cells were increased in MS meninges compared to controls, whereas IgA+ B cells were not. Neuronal loss did not differ between sections with low or high IgA+, IgM+ and IgG+ B cells, but was increased in sections with high numbers of all CD19+ meningeal B cells. Similarly, high presence of CD19+ meningeal B cells and IgG+ meningeal B cells associated with increased microglial density in the underlying cortex. Taken together, intrathecal synthesis of IgG and IgM is elevated in MS, which corresponds to an increased number of IgG+ and IgM+ B cells in MS meninges. The significant correlation between intrathecal IgG and IgM production and NfL levels, and increased microglial activation in cortical areas adjacent to meningeal infiltrates with high levels of IgG+ B cells indicate a role for intrathecal IgM- and IgG-producing B cells in neuroinflammatory and degenerative processes in MS.

Neurovascular unit, neuroinflammation and neurodegeneration markers in brain disorders.

Neurovascular unit (NVU) inflammation via activation of glial cells and neuronal damage plays a critical role in neurodegenerative diseases. Though the exact mechanism of disease pathogenesis is not understood, certain biomarkers provide valuable insight into the disease pathogenesis, severity, progression and therapeutic efficacy. These markers can be used to assess pathophysiological status of brain cells including neurons, astrocytes, microglia, oligodendrocytes, specialized microvascular endothelial cells, pericytes, NVU, and blood-brain barrier (BBB) disruption. Damage or derangements in tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased permeability and neuroinflammation in various brain disorders including neurodegenerative disorders. Thus, neuroinflammatory markers can be evaluated in blood, cerebrospinal fluid (CSF), or brain tissues to determine neurological disease severity, progression, and therapeutic responsiveness. Chronic inflammation is common in age-related neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and dementia. Neurotrauma/traumatic brain injury (TBI) also leads to acute and chronic neuroinflammatory responses. The expression of some markers may also be altered many years or even decades before the onset of neurodegenerative disorders. In this review, we discuss markers of neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders, especially those associated with neurovascular pathologies. These biomarkers can be evaluated in CSF, or brain tissues. Neurofilament light (NfL), ubiquitin C-terminal hydrolase-L1 (UCHL1), glial fibrillary acidic protein (GFAP), Ionized calcium-binding adaptor molecule 1 (Iba-1), transmembrane protein 119 (TMEM119), aquaporin, endothelin-1, and platelet-derived growth factor receptor beta (PDGFRβ) are some important neuroinflammatory markers. Recent BBB-on-a-chip modeling offers promising potential for providing an in-depth understanding of brain disorders and neurotherapeutics. Integration of these markers in clinical practice could potentially enhance early diagnosis, monitor disease progression, and improve therapeutic outcomes.

RNA Binding Protein Dysfunction Links Smoldering/Slowly Expanding Lesions to Neurodegeneration in Multiple Sclerosis.

Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS. Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration. We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1high) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1low), MS-A1high showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1high cases. hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2024.

Chemotherapy-induced cognitive impairment and its long-term development in patients with breast cancer: results from the observational CICARO study.

Chemotherapy-induced cognitive impairment (CICI) is a well-recognized side effect of breast cancer treatment. However, prospective long-term evaluations of CICI using standardized neuropsychological tests are scarce. This prospective longitudinal cohort study investigated cognitive dysfunction and its impact on quality of life and everyday functioning in patients with breast cancer receiving first-line chemotherapy compared to patients with breast cancer without chemotherapy. Assessment occurred prior to chemotherapy, postchemotherapy (median 6 months), and 2-3 years later. We used standardized neuropsychological tests, questionnaires, and scales to assess patients' quality of life and functioning. Additionally, serum analysis for neurodegenerative markers and autoantibodies was conducted. We included n = 53 patients. Overall cognitive function declined statistically significantly (P = .046) postchemotherapy compared to control patients, mostly driven by a reduced figural memory (P = .011). Patients who received chemotherapy showed a greater reduction in quality of life (increased fatigue symptoms, P = .023; reduced Karnofsky index, P<.001); however, without a statistically significant effect on cognitive decline. The neurodegenerative markers Neurofilament light chain (NfL) and phosphorylated Neurofilament heavy chain (pNfH) increased statistically significantly (P<.001) postchemotherapy and pNfH correlated with overall cognitive function. After 2-3 years, both cognitive performance and quality of life were comparable between chemotherapy-treated and control patients. Our findings suggest that chemotherapy statistically significantly contributes to overall cognitive dysfunction in patients with breast cancer, which disappears after 2-3 years, indicating a recovery in both objectively measurable cognitive function and subjective quality of life. Future research should examine larger sample sizes and explore screening indicators, particularly pNfH.