Immune cell counts in cerebrospinal fluid predict cognitive function in aging and neurodegenerative disease

Snyder, Allison; Grant, Harli; Chou, Austin; Lindbergh, Cutter A.; Kramer, Joel H.; Miller, Bruce L.; Elahi, Fanny M

doi:10.1002/alz.12956

Cited by 7 publications

(4 citation statements)

References 73 publications

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“…There is growing recognition of the role of in ammation and immune dysregulation in neurodegeneration, including the development of a pro-in ammatory milieu in the central nervous system. 45 Genes implicated in both monogenic neurodegenerative disease as well as risk genes are related to microglia and immune pathways, such as APOE, TREM2, and TBK1, and many of which were also identi ed in our microglial transcriptomic and proteomic data. Like the observations seen in this family, clonal expansion of CD4 and CD8 positive T-cells have been described in amyotrophic lateral sclerosis type four and frontotemporal dementia patients, further supporting a link between immune dysregulation and disease.…”

Section: Discussionmentioning

confidence: 78%

An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome

Snyder,

Ryan,

Hawrot

et al. 2023

Preprint

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As genetic testing has become more accessible and affordable, variants of uncertain significance (VUS) are increasingly identified, and determining whether these variants play causal roles in disease is a major challenge. The known disease-associated Annexin A11 (ANXA11) mutations result in ANXA11 aggregation, alterations in lysosomal-RNA granule co-trafficking, and TDP-43 mis-localization and present as amyotrophic lateral sclerosis or frontotemporal dementia. We identified a novel VUS in ANXA11 (P93S) in a kindred with corticobasal syndrome and unique radiographic features that segregated with disease. We then queried neurodegenerative disorder clinic databases to identify the phenotypic spread of ANXA11 mutations. Multi-modal computational analysis of this variant was performed and the effect of this VUS on ANXA11 function and TDP-43 biology was characterized in iPSC-derived neurons. Single-cell sequencing and proteomic analysis of iPSC-derived neurons and microglia were used to determine the multiomic signature of this VUS. Mutations in ANXA11 were found in association with clinically diagnosed corticobasal syndrome, thereby establishing corticobasal syndrome as part of ANXA11 clinical spectrum. In iPSC-derived neurons expressing mutant ANXA11, we found decreased colocalization of lysosomes and decreased neuritic RNA as well as decreased nuclear TDP-43 and increased formation of cryptic exons compared to controls. Multiomic assessment of the P93S variant in iPSC-derived neurons and microglia indicates that the pathogenic omic signature in neurons is modest compared to microglia. Additionally, omic studies reveal that immune dysregulation and interferon signaling pathways in microglia are central to disease. Collectively, these findings identify a new pathogenic variant in ANXA11, expand the range of clinical syndromes caused by ANXA11 mutations, and implicate both neuronal and microglia dysfunction in ANXA11 pathophysiology. This work illustrates the potential for iPSC-derived cellular models to revolutionize the variant annotation process and provides a generalizable approach to determining causality of novel variants across genes.

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Section: Discussionmentioning

confidence: 78%

An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome

Snyder,

Ryan,

Hawrot

et al. 2023

Preprint

Self Cite

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“…This finding highlights the value of CSF inflammation indicators in identifying connections between innate immune dysfunction and neurodegenerative processes. 21 This immune dysfunction was previously thought to be restricted to the CNS, but accumulating data indicate pivotal contributions of the peripheral immune system as well.…”

Section: Discussionmentioning

confidence: 99%

Exploring the links among peripheral immunity, biomarkers, cognition, and neuroimaging in Alzheimer's disease

Li,

Zhang,

Wang

et al. 2023

Alz & Dem Diag Ass & Dis Mo

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INTRODUCTIONWe analyzed relationships among peripheral immunity markers, cognition, Alzheimer's disease (AD)‐related biomarkers, and neuroimaging to understand peripheral immunity involvement in AD.METHODSPeripheral immunity markers were assessed in AD, non‐AD neurodegenerative disorders, and controls, examining their connections with cognition, AD‐related biomarkers, and neuroimaging using multiple regression models.RESULTSThe study included 1579 participants. Higher levels of white blood cell, neutrophil, monocyte, neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), systemic immune‐inflammation index (SII), and lower lymphocyte‐to‐monocyte ratio (LMR) were associated with cognitive decline and more severe anxiety and depression. The impact of lower LMR, lymphocyte count, and higher NLR on cognitive decline is mediated through cerebrospinal fluid amyloid beta (Aβ) levels. Additionally, increased PLR, NLR, and SII were associated with brain atrophy and hippocampal Aβ deposition (amyloid positron emission tomography).DISCUSSIONPeripheral immunity markers offer a non‐invasive and cost‐effective means of studying AD‐related pathophysiological changes, providing valuable insights into its pathogenesis and treatment.Highlights Peripheral immunity markers linked to cognitive decline and anxiety/depression. Low LMR, LYM, and high NLR linked to reduced CSF Aβ, impacting cognition. High PLR, NLR, SII associated with brain atrophy and hippocampal Aβ deposition

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“…They suggested that the higher incidence of nosocomial pneumonia might contribute to the poor prognosis. Another study involving 199 patients found a negative correlation between MLR in cerebrospinal fluid and executive function in elderly patients with dementia, suggesting that inflammatory markers could predict neurodegenerative changes [ 32 ]. In our study, we divided patients into three subgroups based on MLR levels using a tertile method.…”

Section: Discussionmentioning

confidence: 99%

Association Between Monocyte-to-Lymphocyte Ratio and Hematoma Progression After Cerebral Contusion

Zhang,

Duan,

Zhang

et al. 2023

Neurocrit Care

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Background The objective of this research was to examine the impact of the monocyte-to-lymphocyte ratio (MLR) on the advancement of hematoma after cerebral contusion. Methods The clinical information and laboratory test findings of people with cerebral contusion were retrospectively analyzed. Using the tertiles of MLR, the study participants were categorized into three groups, enabling the evaluation of the correlation between MLR and the advancement of hematoma after cerebral contusion. Results Among the cohort of patients showing progression, MLR levels were significantly higher compared with the nonprogress group (P < 0.001). The high MLR group had a significantly higher proportion of patients with hematoma progression compared with the medium and low MLR groups. However, the medium MLR group had a lower proportion of patients with hematoma progression compared with the low MLR group. High MLR levels were independently linked to a higher risk of hematoma progression (Odds Ratio 3.546, 95% Confidence Interval 1.187–10.597, P = 0.024). By incorporating factors such as Glasgow Coma Scale score on admission, anticoagulant/antiplatelet therapy, white blood cell count, and MLR into the model, the predictive performance of the model significantly improved (area under the curve 0.754). Conclusions Our study suggests that MLR may serve as a potential indicator for predicting the progression of hematoma after cerebral contusion. Further research is necessary to investigate the underlying pathological and physiological mechanisms that contribute to the association between MLR and the progression of hematoma after cerebral contusion and to explore its clinical implications.

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Immune cell counts in cerebrospinal fluid predict cognitive function in aging and neurodegenerative disease

Cited by 7 publications

References 73 publications

An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome

An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome

Exploring the links among peripheral immunity, biomarkers, cognition, and neuroimaging in Alzheimer's disease

Association Between Monocyte-to-Lymphocyte Ratio and Hematoma Progression After Cerebral Contusion

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