Yiqun Chen

Neuronal intranuclear inclusion disease (NIID) is a highly clinically heterogeneous neurodegenerative disorder primarily attributed to abnormal GGC repeat expansions in the NOTCH2NLC gene. This study aims to comprehensively explore its phenotypic characteristics and genotype-phenotype correlation. A literature search was conducted in PubMed, Embase, and the Cochrane Library from September 1, 2019, to December 31, 2022, encompassing reported NIID cases confirmed by pathogenic NOTCH2NLC mutations. Linear regressions and trend analyses were performed. Analyzing 635 cases from 85 included studies revealed that familial cases exhibited significantly larger GGC repeat expansions than sporadic cases (p < 0.001), and this frequency significantly increased with expanding GGC repeats (p trend < 0.001). Age at onset (AAO) showed a negative correlation with GGC repeat expansions (p < 0.001). The predominant initial symptoms included tremor (31.70%), cognitive impairment (14.12%), and muscle weakness (10.66%). The decreased or absent tendon reflex (DTR/ATR) emerged as a notable clinical indicator of NIID due to its high prevalence. U-fiber was observed in 79.11% of patients, particularly prominent in paroxysmal disease-dominant (87.50%) and dementia-dominant cases (81.08%). Peripheral neuropathy-dominant cases exhibited larger GGC repeat expansions (median = 123.00) and an earlier AAO (median = 33.00) than other phenotypes. Moreover, a significant genetic anticipation of 3.5 years was observed (p = 0.039). This study provides a comprehensive and up-to-date compilation of genotypic and phenotypic information on NIID since the identification of the causative gene NOTCH2NLC. We contribute a novel diagnostic framework for NIID to support clinical practice.

Background and Purpose: The dynamic systemic inflammation level and stroke-associated infection (SAI) are related to the prognosis of acute ischemic stroke (AIS). We aimed to explore whether the systemic inflammatory response index (SIRI), systemic immune inflammation index (SII), and their dynamic changes possess predictability for SAI and long-term prognosis. Methods: A total of 1804 AIS patients without intravenous thrombolysis in two hospitals were included. We explored the relationship between SIRI, SII, and their dynamic changes and outcomes by constructing clusters. The mediating effects of SAI between prognosis and systemic inflammation were further evaluated. Results: Each SD increase in the concentration of SIRI exhibited a significant correlation with the risk of poor functional outcome, mortality, and functional dependency. Through K-means clustering analysis, patients with dramatically elevated or decreased systemic inflammation levels of SIRI (OR: 2.293, 95% CI: 1.279– 4.109) and SII (OR: 3.165, 95% CI: 1.627– 6.156) within 7 days had a higher risk of functional outcome. Through mediation analysis, SAI mediated the association between systemic inflammation and poor prognosis (SIRI: 33.73%, SII: 16.01%). Conclusion: Dramatically changing dynamics of SIRI and SII were significantly associated with a higher risk of poor prognosis in AIS patients. SAI mediated the association between systemic inflammation and prognosis at 1 year.

The unclear pathogenic mechanisms of neurodegenerative disorders stemming from NOTCH2NLC GGC repeat expansions drive focused research. Thus, a bibliometric and meta-analysis was conducted to uncover research trends and positivity rates in NOTCH2NLC. We conducted systematic searches in the Web of Science, PubMed, Embase, and Scopus databases for studies related to NOTCH2NLC up until August 2, 2023. Information regarding countries, institutions, authors, journals, and keywords of studies included in the Web of Science was analyzed and visualized. The positivity rates of NOTCH2NLC GGC repeat expansions across all screened patients and patients’ families were pooled under the random-effects model. Publication bias and its impact were examined using funnel plots, Egger’s linear regression, and trim-and-fill method. The bibliometric analysis, revealing pronounced publication growth, comprised 119 studies, which came from China and Japan particularly. “Neuronal intranuclear inclusion disease” emerged as a frequently used keyword. The meta-analysis comprised 36 studies, indicating global positivity rates of 1.79% (95% CI, 0.75–3.17) for all patients and 2.00% (95% CI, 0.26–4.78) for patients’ families. Subgroup analyses based on region and phenotype suggested the highest NOTCH2NLC positivity rates in Taiwan population (5.42%, 95% CI 0.08–16.89) and in leukoencephalopathy-dominant patients (8.25%, 95% CI, 3.01–15.60). Sensitivity analysis affirmed the robustness of results. In conclusion, NOTCH2NLC GGC repeat expansions exhibit rare globally, primarily in East Asia, and leukoencephalopathy-dominant patients, emphasizing regional and phenotypic distinctions. Emerging focal points in NOTCH2NLC researches underscore the need for collaborative exploration.