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Patients with neuronal intranuclear inclusion disease (NIID) can present with encephalitis‐like symptoms such as recurrent paroxysmal fever and unconsciousness. To date, no specific triggers for these symptoms have been reported. In our case, an 78‐year‐old woman became unconscious and developed fever after cerebral angiography. The patient had experienced four episodes of unconsciousness and fever in the past 7 years. Postangiography, she immediately became unconscious and developed fever. No vascular abnormalities were found and magnetic resonance imaging of the brain revealed expanding white matter lesions and hyperintense lesions along the corticomedullary junction. Genetic analysis revealed an abnormal GGC repeat expansion in NOTCH2NLC. Thus, we diagnosed the patient with NIID. We suggest that cerebral angiography is a possible trigger for encephalitis‐like symptoms in NIID. [ABSTRACT FROM AUTHOR]

Highlights: Progressive Supranuclear Palsy (PSP) presents with various clinical phenotypes, making accurate diagnosis difficult. No biomarker systems, such as the AT(N) system for Alzheimer's Disease (AD), have been established yet. In PSP, core AD cerebrospinal fluid biomarkers show a unique pattern, where Aβ42, Aβ40, p-tau, and t-tau levels are decreased while NfL levels are remarkably increased. Progressive Supranuclear Palsy (PSP) is the most common four-repeat tauopathy. PSP cases are typically characterized by vertical gaze palsy and postural instability; however, various phenotypes have been reported, making antemortem diagnosis based on clinical symptoms challenging. The development of biomarkers reflecting brain pathology and the ability to diagnose patients based on these biomarkers are essential for developing future intervention strategies, including disease-modifying therapies. However, despite many dedicated efforts, no highly specific fluid biomarker for PSP has yet been established. Conversely, several cerebrospinal fluid (CSF) biomarkers of Alzheimer's Disease (AD) have been established, and an AT(N) classification system has been proposed. Typically, among patients with AD, CSF amyloid β42 (Aβ42), but not Aβ40, is decreased, resulting in a reduction in the Aβ42/Aβ40 ratio, while tau phosphorylated at threonine 181 (p-tau181) and total tau (t-tau) are increased. Interestingly, the core CSF AD biomarkers show unique patterns in patients with PSP. Furthermore, reports have indicated that the CSF levels of both Aβ42 and Aβ40 are decreased independently of Aβ accumulation in PSP. Therefore, the Aβ42/Aβ40 ratio could potentially be used to differentiate PSP from AD. Additionally, studies have reported that CSF p-tau and t-tau are reduced in PSP, and that the neurofilament light chain is remarkably increased compared to healthy controls and patients with AD, even though PSP is a neurodegenerative disease associated with tau accumulation. These PSP-specific changes in AD-related core biomarkers may reflect the pathology of PSP and contribute to its diagnosis. As such, elucidating the mechanisms underlying the observed decreases in Aβ and tau levels could facilitate a better understanding of the pathogenesis of PSP. [ABSTRACT FROM AUTHOR]

Background and purpose: Colony‐stimulating factor 1 receptor (CSF1R)‐related leukoencephalopathy is an adult‐onset leukoencephalopathy caused by mutations in CSF1R. The present study aimed to explore the broader genetic spectrum of CSF1R‐related leukoencephalopathy in association with clinical and imaging features. Methods: Mutational analysis of CSF1R was performed for 100 consecutive patients with adult‐onset leukoencephalopathy. Sequence and copy number variation (CNV) analyses of CSF1R were performed. The genomic ranges of the deletions were determined by long‐read sequencing. Ligand‐dependent autophosphorylation of CSF1R was examined in cells expressing the CSF1R mutants identified in this study. Results: CSF1R mutations were identified in 15 patients, accounting for 15% of the adult‐onset leukoencephalopathy cases. Seven novel and five previously reported CSF1R mutations were identified. The novel mutations, including three missense and one in‐frame 3 bp deletion, were located in the tyrosine kinase domain (TKD) of CSF1R. Functional assays revealed that none of the novel mutations in the TKD showed autophosphorylation of CSF1R. Two partial deletions of CSF1R were identified that resulted in lack of the C‐terminal region, including the distal TKD, in two patients. Various clinical features including cognitive impairment, psychiatric symptoms and gait disturbance were observed. Various degrees of the white matter lesions and corpus callosum abnormalities on magnetic resonance imaging and characteristic calcifications on computed tomography were observed as imaging features. Conclusions: Our results highlight the importance of examining the CNV of CSF1R even when Sanger or exome sequencing reveals no CSF1R mutations. Genetic examination of sequences and CNV analyses of CSF1R are recommended for an accurate diagnosis of CSF1R‐related leukoencephalopathy. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) biomarkers reflect the pathological process underlying Alzheimer's disease (AD) and improve the accuracy of AD diagnosis. AT(N) classification using these CSF biomarkers has been used within the research framework to identify points on AD continuum. However, there has been little research into the utility of AT(N) classification in clinical practice. Methods: We measured the CSF levels of amyloid‐β (Aβ) 42, Aβ40, phosphorylated tau (Thr181), total tau (tTau), and neurofilament light chain (NfL) in samples from clinical cases, comprising 230 patients with Alzheimer's clinical syndrome (ACS) and 328 patients with non‐ACS. The concordance between two A‐markers (i.e., Aβ42 alone and the Aβ42/Aβ40 ratio) and the two N‐markers (i.e., tTau and NfL) were analyzed. We evaluated the prevalence of biological AD (i.e., A+T+) and the percentage of each AT(N) category identified using the CSF biomarkers in the ACS and non‐ACS samples. Results: The concordance of A‐markers was not significantly different between the ACS (87.4%) and non‐ACS (74.1%) groups. However, the frequency of discordant cases with AAβ42‐alone+/AAβ‐ratio− was significantly higher in the non‐ACS (23.8%) than in the ACS group (7.4%). The concordance of two N‐markers was 40.4% in the ACS group and 24.4% in the non‐ACS group. In the ACS samples, the frequency of biological AD in Ntau+ cases was 95% and that in NNfL+ cases was 65%. When the Aβ42/Aβ40 ratio was used as the A‐marker, the proportion of biological AD was 64.3% in ACS samples and 24.4% in non‐ACS samples. Notably, the proportion of AD continuum in the non‐ACS group was substantially different when the A‐marker was Aβ42 alone than when it was the Aβ42/Aβ40. Conclusions: Although the AT(N) classification system was intended for use in research, it may also be also useful for clinical diagnosis. As an A‐marker, the Aβ42/Aβ40 ratio reflects Aβ deposition more accurately than Aβ42 alone. As an N‐marker, NfL reflects neurodegeneration more accurately than tTau, particularly in non‐ACS patients. Thus, we recommend the use of AT(N) classification in clinical practice that is defined by CSF levels of AAβ‐ratioTNNfL. [ABSTRACT FROM AUTHOR]

Objective: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutations in CSF1R. Pathogenic mutations in exons 12-22 including coding sequence of the tyrosine kinase domain (TKD) of CSF1R were previously identified. We aimed to identify CSF1R mutations in patients who were clinically suspected of having ALSP and to determine the pathogenicity of novel CSF1R variants.Methods: Sixty-one patients who fulfilled the diagnostic criteria of ALSP were included in this study. Genetic analysis of CSF1R was performed for all the coding exons. The haploinsufficiency of CSF1R was examined for frameshift mutations by RT-PCR. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing CSF1R mutants.Results: We identified ten variants in CSF1R including two novel frameshift, five novel missense, and two known missense mutations as well as one known missense variant. Eight mutations were located in TKD. One frameshift mutation (p.Pro104LeufsTer8) and one missense variant (p.His362Arg) were located in the extracellular domain. RT-PCR analysis revealed that the frameshift mutation of p.Pro104LeufsTer8 caused nonsense-mediated mRNA decay. Functional assay revealed that none of the mutations within TKD showed autophosphorylation of CSF1R. The p.His362Arg variant located in the extracellular domain showed comparable autophosphorylation of CSF1R to the wild type, suggesting that this variant is not likely pathogenic.Conclusions: The detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of ALSP with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP. [ABSTRACT FROM AUTHOR]