Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

Acute respiratory failure caused by brainstem demyelinating lesions in an older patient with an atypical relapsing autoimmune disorder.

An 84-year-old man presented with somnolence, dysphagia, and right hemiplegia, all occurring within a month, approximately one year after initial admission due to subacute, transient cognitive decline suggestive of acute disseminated encephalomyelitis involving the cerebral white matter. Serial magnetic resonance imaging (MRI) studies over that period revealed three high-intensity signal lesions on fluid-attenuated inversion recovery images, appearing in chronological order in the left upper and left lower medulla oblongata and left pontine base. Despite some clinical improvement following methylprednisolone pulse therapy, the patient died of respiratory failure. Autopsy revealed four fresh, well-defined lesions in the brainstem, three of which corresponded to the lesions detected radiologically. The remaining lesion was located in the dorsal medulla oblongata and involved the right solitary nucleus. This might have appeared at a later disease stage, eventually causing respiratory failure. Histologically, all four lesions showed loss of myelin, preservation of axons, and infiltration of lymphocytes, predominantly CD8-positive T cells, consistent with the histological features of autoimmune demyelinating diseases, particularly the confluent demyelination observed in the early and acute phases of multiple sclerosis (MS). In the cerebral white matter, autoimmune demyelination appeared superimposed on ischemic changes, consistent with the cerebrospinal fluid (CSF) and MRI findings on initial admission. No anti-AQP4 or MOG antibodies or those potentially causing autoimmune encephalitis/demyelination were detected in either the serum or CSF. Despite several similarities to MS, such as the relapsing-remitting disease course and lesion histology, the entire clinicopathological picture in the present patient, especially the advanced age at onset and development of brainstem lesions in close proximity within a short time frame, did not fit those of MS or other autoimmune diseases that are currently established. The present results suggest that exceptionally older individuals can be affected by an as yet unknown inflammatory demyelinating disease of the CNS.

Missense Variants in COL4A1/2 Are Associated with Cerebral Aneurysms: A Case Report and Literature Review.

BACKGROUND: Although cerebral aneurysm (CA) is a defining complication of COL4A1/2-related vasculopathy, the specific factors influencing its onset remain uncertain. This study aimed to identify and analyze these factors. METHODS: We described a family presenting with a novel variant of the COL4A1 gene complicated with CA. Concurrently, an exhaustive review of previously documented patients with COL4A1/2-related vasculopathy was conducted by sourcing data from PubMed, Web of Science, Google Scholar, and Ichushi databases. We compared the variant types and locations between patients with CA (positive group) and those without CA (negative group). RESULTS: This study included 53 COL4A1/2 variants from 76 patients. Except for one start codon variant, all the identified variants in CA were missense variants. Otherwise, CA was not associated with other clinical manifestations, such as small-vessel disease or other large-vessel abnormalities. A higher frequency of missense variants (95.5% vs. 58.1%, p = 0.0035) was identified in the CA-positive group. CONCLUSIONS: CA development appears to necessitate qualitative alterations in COL4A1/2, and the underlying mechanism seems independent of small-vessel disease or other large-vessel anomalies. Our findings suggest that a meticulous evaluation of CA is necessary when missense variants in COL4A1/2 are identified.

Corrigendum: Regeneration of the cerebral cortex by direct chemical reprogramming of macrophages into neuronal cells in acute ischemic stroke.

[This corrects the article DOI: 10.3389/fncel.2023.1225504.].

Indications for a brain biopsy in neurological diseases of unknown etiology: The role of magnetic resonance imaging findings and liquid biopsy in yielding definitive pathological diagnoses.

Brain biopsies are often considered for patients who cannot be diagnosed with various laboratory test results. However, physicians tend to be hesitant regarding their application in possibly non-neoplastic brain diseases, due to the invasiveness and risks. The aim was to determine the indications for brain biopsies in cases of neurological diseases of unknown etiology. We retrospectively evaluated diagnostic accuracy, laboratory findings (including a liquid biopsy for malignant lymphoma), magnetic resonance imaging (MRI) characteristics and the post-treatment outcomes of patients undergoing brain biopsies for neurological diseases of unknown etiology. The data of patients who had undergone a brain biopsy during their admission to Niigata University Hospital, between 2011 and 2024, were reviewed. Moreover, the laboratory data and MRI findings between patients with definitive and nonspecific biopsy diagnoses were compared. Twenty-six patients underwent a brain biopsy, and a definitive diagnosis was obtained in 14 patients (53.8%). Even in cases where a nonspecific diagnosis was made, biopsy findings helped rule out malignancy and guide clinical diagnosis and treatment decisions. The liquid biopsy for malignant lymphoma was performed in eight patients, with one yielding a positive result, consistent with primary central nervous system lymphoma. The sensitivity and specificity of liquid biopsy were 0.5 and 1, respectively. Diffusely contrasted cortical lesions and the presence of mass effects on MRI, were significantly associated with a definitive diagnosis, compared to a nonspecific diagnosis. In conclusion, brain MRI and liquid biopsies can assist in determining the appropriate indications for brain biopsies in neurological diseases of unknown etiology.

UCP2 polymorphisms, daily step count, and number of teeth associated with all-cause mortality risk in Sado City: A hospital-based cohort study.

Objective: Uncoupling protein 2 (UCP2) is an ion/anion transporter in the mitochondrial inner membrane that plays a crucial role in immune response, regulation of oxidative stress, and cellular metabolism. UCP2 polymorphisms are linked to chronic inflammation, obesity, diabetes, heart disease, exercise efficiency, and longevity. Daily step count and number of teeth are modifiable factors that reduce mortality risk, although the role of UCP2 in this mechanism is unknown. This study aimed to assess the possible effects of UCP2 polymorphisms on the association between daily step count and number of teeth with all-cause mortality. Methods: This study was conducted as a cohort project involving adult Japanese outpatients at Sado General Hospital (PROST). The final number of participants was 875 (mean age: 69 y). All-cause mortality during thirteen years (from June 2008 to August 2021) was recorded. The functional UCP2 genotypes rs659366 and rs660339 were identified using the Japonica Array®. Survival analyses were performed using multivariate Cox proportional hazard models. Results: There were 161 deaths (mean observation period: 113 months). Age, sex, daily step count, and the number of teeth were significantly associated with mortality. In females, UCP2 polymorphisms were associated with mortality independent of other factors (rs659366 GA compared to GG + AA; HR = 2.033, p = 0.019, rs660339 C T compared to CC + TT; HR = 1.911, p = 0.029). Multivariate models, with and without UCP2 genotypes, yielded similar results. The interaction terms between UCP2 genotype and daily step count or number of teeth were not significantly associated with mortality. Conclusion: The effects of UCP2 polymorphisms on the association between daily step count or the number of teeth and all-cause mortality were not statistically significant. In females, UCP2 polymorphisms were significantly associated with all-cause mortality. Our findings confirmed the importance of physical activity and oral health and suggested a role of UCP2 in mortality risk independently with those factors.

Validation study of the Japanese version of the King's Parkinson's Disease Pain Scale and the King's Parkinson's Disease Pain Questionnaire.

INTRODUCTION: The King's Parkinson's Disease Pain Scale (KPPS)/King's Parkinson's Disease Pain Questionnaire (KPPQ) was developed as a tool to quantitatively assess pain in patients with Parkinson's disease (PwPD). Here, we conducted a Japanese multicenter validation study to verify the reliability of KPPS/KPPQ in Japanese PwPD. METHODS: PwPD, ≥20 years, with unexplained pain were included; those with a definitive primary cause of pain other than PD were excluded. A total of 151 patients who fulfilled the criteria were analyzed, and test-retest reliability was investigated in 25 individuals. RESULTS: The 151 patients included 101 women (66.9 %); mean age 68.3 ± 9.9 years, mean disease duration 9.2 ± 5.2 years. The most frequent pain type in the KPPS classification was musculoskeletal pain (82.8 %). There was a positive correlation between KPPS total score and the Non-Motor Symptoms Scale (NMSS) total score, NMSS item 27, the Parkinson's disease sleep scale-version 2 (PDSS-2) total score, PDSS-2 item 10, the Parkinson's Disease Questionnaire-8 (PDQ-8) summary index and PDQ-8 item 7. Cronbach's alpha of KPPS was 0.626 (0.562-0.658) and the intraclass correlation coefficient of test-retest reliability was 0.740. Cronbach's alpha of KPPQ was 0.660 (0.617-0.705) and a test-retest reliability of kappa coefficient was 0.593 (0.0-1.0). CONCLUSIONS: KPPS correlated well with other scales for assessing pain. KPPS correlated well with patients' quality of life, non-motor symptoms, and sleep disturbances. The reproducibility of KPPS/KPPQ makes it suitable for continuous evaluation of the same patient. On the other hand, the internal consistency of KPPS/KPPQ is rather low.

Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD.

The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is aberrantly accumulated in the neurons of most patients with sporadic ALS/FTD and other TDP-43 proteinopathies, how TDP-43 forms cytoplasmic aggregates remains unknown. In this study, we show that a deficiency in DCTN1, a subunit of the microtubule-associated motor protein complex dynactin, perturbs the dynamics of stress granules and drives the formation of TDP-43 cytoplasmic aggregation in cultured cells, leading to the exacerbation of TDP-43 pathology and neurodegeneration in vivo. We demonstrated using a Drosophila model of ALS/FTD that genetic knockdown of DCTN1 accelerates the formation of ubiquitin-positive cytoplasmic inclusions of TDP-43. Knockdown of components of other microtubule-associated motor protein complexes, including dynein and kinesin, also increased the formation of TDP-43 inclusions, indicating that intracellular transport along microtubules plays a key role in TDP-43 pathology. Notably, DCTN1 knockdown delayed the disassembly of stress granules in stressed cells, leading to an increase in the formation of pathological cytoplasmic inclusions of TDP-43. Our results indicate that a deficiency in DCTN1, as well as disruption of intracellular transport along microtubules, is a modifier that drives the formation of TDP-43 pathology through the dysregulation of stress granule dynamics.

Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans.

Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3'-5' DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause DNA damage. Here, we show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.