Klotho: An emerging factor in neurodegenerative diseases

Olfactory proteotyping: towards the enlightenment of the neurodegeneration

<h3>Objective:</h3> Use biomarkers such as PET and CSF proteins to distinguishing multiple sclerosis-related cognitive impairment from co-existent progressive neurodegenerative diseases such as Alzheimer disease. <h3>Background:</h3> Among people with multiple sclerosis, cognitive impairment occurs commonly and is a potent predictor of disability. Some multiple sclerosis patients present with severe cognitive impairment, and distinguishing multiple sclerosis-related cognitive impairment from co-existent progressive neurodegenerative diseases such as Alzheimer disease poses a diagnostic challenge. <h3>Design/Methods:</h3> The study was a retrospective, descriptive study on convenience samples of separate cohorts, one of cognitively impaired multiple sclerosis patients evaluated on autopsy to demonstrate coincidence of both multiple sclerosis and neurodegenerative cognitive diseases. The second cohort were cognitively impaired multiple sclerosis patients evaluated by biomarker to investigate possible additional neurodegenerative cognitive disorders contributing to the cognitive impairment. <h3>Results:</h3> We investigated selected biomarkers among 31 severely impaired patients (biomarker cohort) and 12 severely impaired patients assessed at autopsy and selected 24 (23 biomarker cohort, 1 autopsy cohort) had comprehensive neurocognitive testing. Biomarker cohort investigations included 18F-Fluorodeoxyglucose PET and/or CSF amyloid Aβ1–42, phospho-tau and total tau levels. The autopsy cohort was evaluated with comprehensive neuropathological assessment for aetiology of cognitive impairment. The cohorts shared similar sex, age at multiple sclerosis onset and multiple sclerosis clinical course. The autopsy-cohort patients were older at diagnosis (69.5 versus 57 years, P=0.006), had longer disease duration [median (range) 20 years (3–59) versus 9 (1–32), P=0.001] and had more impaired bedside mental status scores at last follow-up [Kokmen median (range) 23 (1–38) versus 31 (9–34) P=0.01]. Autopsy-cohort patients confirmed, or excluded, coexistent neurogenerative disease by neuropathology gold standard. Most bio marker-cohort patients had informative results evaluating coexistent neurogenerative disease. <h3>Conclusions:</h3> Biomarkers may be useful in indicating a coexistent neurodegenerative disease earlier, and in life, in patients with multiple sclerosis and significant cognitive impairment. <b>Disclosure:</b> Dr. Londono has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Arumaithurai has nothing to disclose. Eleni Constantopoulos has nothing to disclose. Dr. Basso has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Taylor and Francis. The institution of Ross Reichard has received research support from NIH. An immediate family member of Ross Reichard has received publishing royalties from a publication relating to health care. The institution of Dr. Flanagan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Flanagan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Flanagan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon Therapeutics. Dr. Flanagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Pharmacy times. The institution of Dr. Flanagan has received research support from Viela Bio. Dr. Flanagan has received research support from UCB. Dr. Flanagan has received publishing royalties from a publication relating to health care. Dr. Flanagan has a non-compensated relationship as a Member of medical Advisory Board with The MOG Project that is relevant to AAN interests or activities. Dr. Flanagan has a non-compensated relationship as a Editorial board member with Journal of The Neurologic Sciences that is relevant to AAN interests or activities. Dr. Flanagan has a non-compensated relationship as a Editorial board member with Neuroimmunology Reports that is relevant to AAN interests or activities. Dr. Keegan has received publishing royalties from a publication relating to health care.

Optical coherence tomography (OCT) biomarkers are increasingly used by neurologists, psychiatrists, and ophthalmologists for the diagnosis, prognosis, and follow-up of neurodegenerative diseases. Long-term data on OCT biomarkers of selected primary and secondary neurodegenerative diseases of the central nervous system (CNS), such as multiple sclerosis (MS) or Parkinson's disease, are already available in part. In addition, there are rare neurodegenerative diseases with early disease onset that may show OCT abnormalities. Aliterature review on the association of OCT biomarkers with neurodegenerative diseases of the CNS beyond Alzheimer's disease is presented. Parkinson's disease, MS, Friedreich's ataxia, Huntington's disease, spinocerebellar ataxia, and lysosomal storage diseases are addressed. Relevant OCT biomarkers of neurodegenerative diseases are the macular ganglion cell inner plexiform layer (GCIPL) and the peripapillary retinal nerve fiber layer (pRNFL) thickness. Different sectors may be affected depending on the disease entity in addition to global pRFNL reduction. OCT‑angiography (OCT-A) is also increasingly used as abiomarker in neurodegenerative diseases. Optical coherence tomography biomarkers are used in an interdisciplinary context. Retinal pathologies should be excluded by an ophthalmologist. While OCT biomarkers are increasingly used clinically in MS, the benefit in other neurodegenerative diseases, especially the rare ones, is less well documented. Further longitudinal studies are required.

Role of hippocampal subfields in neurodegenerative disease progression analyzed with a multi-scale attention-based network

Possible association between PM2.5 and neurodegenerative diseases: A systematic review

The role of CXCL12/CXCR4/CXCR7 axis in cognitive impairment associated with neurodegenerative diseases.

Glutamate-induced excito-neurotoxicity likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases. Microglial clearance of dying neurons and associated debris is essential to maintain healthy neural networks in the central nervous system. In fact, the functions of microglia are regulated by various signaling molecules that are produced as neurons degenerate. Here, we show that the soluble CX3C chemokine fractalkine (sFKN), which is secreted from neurons that have been damaged by glutamate, promotes microglial phagocytosis of neuronal debris through release of milk fat globule-EGF factor 8, a mediator of apoptotic cell clearance. In addition, sFKN induces the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in microglia in the absence of neurotoxic molecule production, including NO, TNF, and glutamate. sFKN treatment of primary neuron-microglia co-cultures significantly attenuated glutamate-induced neuronal cell death. Using several specific MAPK inhibitors, we found that sFKN-induced heme oxygenase-1 expression was primarily mediated by activation of JNK and nuclear factor erythroid 2-related factor 2. These results suggest that sFKN secreted from glutamate-damaged neurons provides both phagocytotic and neuroprotective signals.

ALZHEIMER'S DISEASE BIOMARKERS AND COGNITION

BackgroundPreviously, we collected age-stratified incidence data of 404 epidemiological datasets of 10 neurodegenerative diseases (NDs), namely Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Fronto Temporal Dementia (FTD), Dementia with Lewy Bodies (DLB), Parkinsonism (PDM), Parkinson’s disease with Dementia (PDD), Creutzfeldt–Jakob disease (CJD), and Multiple Sclerosis (MS). We tested whether each ND follows a multistep model, found the number of steps necessary for the onset of each ND, found the number of common steps with other NDs and the number of specific steps of each ND, and built a parsimony tree of the genealogy of the NDs. The tree disclosed three groups of NDs: the stem NDs with less than 3 steps; the trunk NDs with 5–7 steps; and the crown NDs with more than 7 steps.MethodsWe made a multidimensional reduction of the previously collected age-stratified incidence epidemiological data of the 10 NDs. We studied the general range of incidence of the 10 NDs using the age- and sex-stratified incidence data. First, we calculated the log of the incidence versus the log of the age for each ND. Next, we calculated the age intervals of the spread of the incidence of each ND. We calculated the regression of the steps obtained with the multistep model versus the age of incidence of the NDs.ResultsWe found that the number of steps of the NDs is inversely correlated with the age of incidence of the NDs, and calculated the number of years required for a single step for each ND. Based on these results, we extended the genealogy tree model of the NDs to account for the time needed for a ND step to occur.ConclusionThe extended genealogy tree disclosed three groups of NDs according to the estimated time needed for a step to occur: the stem ND, HD, with 32.5 years/step, the trunk NDs ALS, FTD, PD and CJD, with 6.7–13.7 years/step; and the crown NDs PDM, PDD, AD and DLB, with 2.3–3.8 years/step. Thus, the NDs cluster into three groups according to both the number of steps and the number of years for a step to occur.

Neuronal and axonal destruction are hallmarks of neurodegenerative diseases, but it is difficult to estimate the extent and progress of the damage in the disease process. To investigate cerebrospinal fluid (CSF) levels of neurofilament light (NFL) protein, a marker of neuroaxonal degeneration, in control participants and patients with dementia, motor neuron disease, and parkinsonian disorders (determined by clinical criteria and autopsy), and determine its association with longitudinal cognitive decline. In this case-control study, we investigated NFL levels in CSF obtained from controls and patients with several neurodegenerative diseases. Collection of samples occurred between 1996 and 2014, patients were followed up longitudinally for cognitive testing, and a portion were autopsied in a single center (University of Pennsylvania). Data were analyzed throughout 2016. Concentrations of NFL in CSF. Levels of CSF NFL and correlations with cognition scores. A total of 913 participants (mean [SD] age, 68.7 [10.0] years; 456 [49.9%] women) were included: 75 control participants plus 114 patients with mild cognitive impairment (MCI), 397 with Alzheimer disease, 96 with frontotemporal dementia, 68 with amyotrophic lateral sclerosis, 41 with Parkinson disease (PD), 19 with PD with MCI, 29 with PD dementia, 33 with dementia with Lewy bodies, 21 with corticobasal syndrome, and 20 with progressive supranuclear palsy. Cognitive testing follow-up occurred for 1 to 18 years (mean [SD], 0.98 [2.25] years); autopsy-verified diagnoses were available for 120 of 845 participants with diseases (14.2%). There was a stepwise increase in CSF NFL levels between control participants (median [range] score, 536 [398-777] pg/mL), participants with MCI (831 [526-1075] pg/mL), and those with Alzheimer disease (951 [758-1261] pg/mL), indicating that NFL levels increase with increasing cognitive impairment. Levels of NFL correlated inversely with baseline Mini-Mental State Examination scores (ρ, -0.19; P < .001) in the full cohort (n = 822) and annual score decline in the full cohort (ρ, 0.36, P < .001), participants with AD (ρ, 0.25; P < .001), and participants with FTD (ρ, 0.46; P = .003). Concentrations of NFL were highest in participants with amyotrophic lateral sclerosis (median [range], 4185 [2207-7453] pg/mL) and frontotemporal dementia (2094 [230-7744] pg/mL). In individuals with parkinsonian disorders, NFL concentrations were highest in those with progressive supranuclear palsy (median [range], 1578 [1287-3104] pg/mL) and corticobasal degeneration (1281 [828-2713] pg/mL). The NFL concentrations in CSF correlated with TDP-43 load in 13 of 17 brain regions in the full cohort. Adding NFL to β-amyloid 42, total tau, and phosphorylated tau increased accuracy of discrimination of diseases. Levels of CSF NFL are associated with cognitive impairments in patients with Alzheimer disease and frontotemporal dementia. In other neurodegenerative disorders, NFL levels appear to reflect the intensity of the neurodegenerative processes.

Neurodegenerative disease refers to a group of disorders that predominantly damage the neurons in the brain. Despite significant progress in the knowledge of neurodegenerative diseases, there is currently no disease-modifying drug available. Vitamin K was first established for its involvement in blood clotting, but there is now compelling evidence indicating its role in the neurological system. In particular, the results of recent studies on the effects of vitamin K2 on preventing apoptosis, oxidative stress, and microglial activation in neuron cells through its role in electron transport are very promising against Alzheimer's disease. In addition to its protective effect on cognitive functions, its inhibitory effects on inflammation and α-synuclein fibrillization in Parkinson's disease, which has been revealed in recent years, are remarkable. Although there are many studies on the mechanism and possible treatment methods of neurodegenerative diseases, especially Parkinson's and Alzheimer's disease, studies on the relationship between vitamin K and neurodegenerative diseases are very limited, yet have promising findings. Vitamin K has also been proposed for therapeutic use in multiple sclerosis patients to lower the intensity or to slow down the progression of the disease. Accordingly, the aim of this study is to review the current evidence for the use of vitamin K supplementation in neurodegenerative diseases, in particular Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

PRM28 - What are indirect costs in neurodegenerative diseases? a methodological review

BackgroundWe leveraged digital deconvolution methods to determine cellular changes from brain transcriptomics of Alzheimer’s Disease(AD), and identified a change in cellular proportion between neuropathology, and severity of the disease as determined by Clinical Dementia Rating[5]. We expanded these approaches to Cerebral Spinal Fluid(CSF), to evaluate cellular changes associated with disease progresses.MethodWe used RNAseq data from published sources to test and refine a gene panel to deconvolve ambient RNA from CSF. Candidate marker genes were selected via literature search and verified using the brainseq [1] along with the human brain single‐cell gene expression [2]. We optimized gene panels using the leave‐one‐out cross‐validation method to predict proportions of neurons, astrocytes, microglia, oligodendrocytes, macrophages and endothelial cells, using bulk and ambient RNA sequenced in single‐cell transcriptomics.ResultWe leveraged our deconvolution to ascertain whether ambient RNA captured in single‐cell gene expression from the CSF captures the cellular population structure of the brain. Preliminary results show that cellular signatures for non‐immune cells are present in CSF in AD (Gate et al. (n = 9, Control = 3, MCI = 3, AD = 3)[3] and Multiple Sclerosis(MS)(Ramesh et al. (n = 15, Control = 3, MS = 12)[4]), and the proportions of those non‐immune cells change depending on the disease state. In MS, there is an increase in the proportion of Astrocytes (p = 3.4×10e‐2) in MS samples. Similar results were found for Neurons (p = 4.4×10e‐2) and Oligodendrocyte Precursor Cells (OPC) (p = 8.2×10e‐3). In AD, we identified significant differences between AD, MCI and controls (p = 0.01) in OPC.ConclusionThese results show that ambient RNA in the CSF can capture subtle differences in cellular population structure in AD and MS. These analyses were done on a small sample size, but show the potential to analyze larger cohorts and cell‐type specific transcriptional states. We also plan to expand the process to other neurologic diseases.

Small microscopic entities known as microbes, having a population of hundreds of billions or perhaps even in trillions, reside in our gastrointestinal tract. A healthy immune system, digestion, and creation of vitamins and enzymes are all thanks to these microbes. However, new research has shown a hitherto unrecognized connection between the microbiota of the intestines and the genesis of neurodegenerative diseases. Neurons in the CNS gradually deteriorate in neurodegenerative illnesses like multiple sclerosis and Parkinson's disease (PD). This deterioration impairs cognitive and physical function. Amyotrophic lateral sclerosis (ALS), PD, and Alzheimer's disease (AD) are just a few examples of neurodegenerative illnesses that pose a serious threat to world health and have few effective treatments. Recent research suggests that the gut microbiota, a diverse microbial population found in the gastrointestinal system, may substantially impact the cause and development of various diseases. The discovery of altered gut microbiota composition in people with these illnesses is one of the most critical lines of evidence connecting gut microbiota dysbiosis to neurodegenerative diseases. AD patients have a distinct characteristic of having a particular microbiota profile. In addition, an excess population of a specific microbe data profile is seen as compared to a healthy individual. Similar changes in the gut microbiota composition have been noted in people with multiple sclerosis and PD. The latest study indicates the potential that dysbiosis, a condition characterized by alteration in the intestinal microbiota's makeup and functioning, may have an effect on the onset and progression of neurodegenerative diseases, including PD and multiple sclerosis. In order to emphasize any potential underlying mechanisms and examine potential treatment repercussions, the review article's goal is to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders. The review article aims to summarize current knowledge about the connection between gut microbiota and neurodegenerative disorders, highlighting potential underlying mechanisms and examining potential treatment repercussions.

Resting-state functional magnetic resonance imaging (rsfMRI) is pivotal for mapping alterations in brain functional networks associated with neurodegenerative diseases, particularly Alzheimer's disease (AD). However, the causal mechanisms linking such network dysfunction to disease pathogenesis remain unresolved. This study aimed to elucidate bidirectional causal relationships between 191 resting-state fMRI phenotypes (derived from 34,691 individuals) and six neurodegenerative diseases, specifically AD, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), dementia with Lewy bodies (DLB), and Parkinson's disease (PD), using disease-specific GWAS data from European-ancestry cohorts. Bidirectional two-sample Mendelian randomization (MR) was performed using rsfMRI phenotypes from Zhao et al. (2022) and GWAS summary statistics (AD: ieu-b-5067/ebi-a-GCST90027158, ALS: ebi-a-GCST90027164, FTD: ieu-b-43, MS: ieu-b-18, DLB: ebi-a-GCST90001390, PD: ieu-b-7). Instrumental variables were filtered for significance (p < 5 × 10^-8), with sensitivity analyses (MR-PRESSO, Cochran's Q, MR-Egger) to ensure robustness. Forward MR identified 26 rsfMRI phenotypes causally linked to neurodegenerative diseases. AD risk was associated with reduced cerebellum-subcortical connectivity (OR = 0.957, p = 0.004), while heightened cerebellar activity increased DLB risk (OR = 2.58, p = 0.0063). Reverse MR revealed 64 disease-to-network effects: AD altered default mode network connectivity (OR = 0.965, p = 0.034), and PD disrupted salience-central executive network interactions (OR = 0.950, p = 0.00011). This study establishes robust bidirectional causal pathways between brain functional networks and neurodegenerative diseases, with AD showing unique vulnerability in cerebellar-subcortical and default mode circuits. These findings highlight network-specific therapeutic targets for AD and related disorders.