Differentiating multiple system atrophy (MSA) from Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) remains challenging. Retinal optical coherence tomography (OCT) offers noninvasive insights into neurodegeneration but remains underexplored in MSA. To compare OCT-derived retinal parameters in MSA, PD, PSP, and healthy controls (HCs), evaluate associations with clinical features and dopaminergic degeneration. We enrolled 21 MSA, 22 PD, and 23 PSP patients, plus 23 HCs. OCT measured macular and retinal nerve fiber layer thicknesses. Clinical assessments and 11C-CFT PET evaluated motor/non-motor symptoms and presynaptic dopaminergic integrity. MSA exhibited significant retinal differences compared to HCs and PSP, with subtler distinctions observed when compared to PD. Retinal thickness correlated with axial motor impairments, dysphagia, and dopaminergic uptake in the caudate nucleus. OCT parameters may aid in differentiating MSA from other parkinsonian syndromes and serve as a indicator linked to disease severity and dopaminergic dysfunction.

Neuro-immune crosstalk is increasingly recognized in Parkinson's disease (PD), and ATP13A2 is well known for its neuroprotective role. However, it remains unclear whether ATP13A2 mutations carried by PD patients contribute to immune dysfunction that exacerbates disease progression. Here, we systematically demonstrate that many ATP13A2 mutations result in a loss-of-expression phenotype. ATP13A2 is highly expressed in macrophages. Myeloid ATP13A2 deficiency causes uncontrolled NLRP3 inflammasome activation driven by lysosomal alkalization and subsequent disrupted mitochondrial homeostasis, rendering mice susceptible to a PD-like phenotype. PD-linked ATP13A2 loss-of-expression mutants fail to restore the ATP13A2 levels required to suppress NLRP3 hyperactivation in ATP13A2-depleted human THP-1 monocytes. Macrophages from a PD patient carrying the ATP13A2 loss-of-expression L927P mutation exhibit excessive NLRP3 activation due to lysosomal-mitochondrial dysfunction. Our findings provide insight into PD pathogenesis, emphasizing genetic factor-driven dysregulated macrophage NLRP3 activation, particularly in ATP13A2 loss-of-expression mutation cases.

BACKGROUND:Recent studies have reported associations between expanded HSF1 intronic variable number tandem repeats (VNTRs) and essential tremor (ET), necessitating independent validation. METHODS:We analyzed HSF1 VNTR lengths in 720 ET patients and 507 controls using fluorescence amplicon length analysis. Sequence composition and interruption patterns were characterized using long-read sequencing (LRS) data from 26 ET patients and 29 controls harboring expanded VNTRs. RESULTS:Expanded VNTRs showed similar frequencies in ET patients and controls at both 700 base pairs (bp) (5.9% vs. 4.3%, P = 0.22) and 550 bp thresholds (13.7% vs. 10.8%, P = 0.14). LRS refined the motif pattern from (CCCCGCNCCGCCT)n/(CCNCGCCT)n to (CNCCGCNCCGCCT)n/(CNNCGCCT)n. Both patients and controls showed identical repeat configurations with predominantly CC interruptions accompanied by CCCCG interruptions (75% in patients, 41.4% in controls). Self-organizing map analysis revealed no clustering differences between groups. CONCLUSIONS:In our study, expanded HSF1 VNTRs are not enriched in ET patients, with no distinguishing sequence features between patients and controls. Further validation in additional large cohorts is warranted. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND AND OBJECTIVES:Multiple system atrophy (MSA) is a progressive neurodegenerative disorder presenting significant clinical heterogeneity, posing challenges in diagnosis and treatment. This study uses spatial independent component analysis (ICA) of 18F-fluorodeoxyglucose (FDG) PET to deconstruct disease heterogeneity and elucidate the large-scale brain network mechanisms of MSA. METHODS:This cross-sectional study included patients with MSA and healthy controls (HCs) from the Second Affiliated Hospital, Zhejiang University School of Medicine. MSA diagnosis was based on the 2022 Movement Disorder Society MSA criteria. All participants underwent FDG-PET imaging. Clinical assessments and dopamine transporter (DAT) PET were performed in patients with MSA. Spatial ICA was applied to identify metabolic covariance networks. Moderation analysis and structural equation modeling (SEM) were used to explore underlying pathway mechanisms. RESULTS:Ninety-five patients with MSA and 102 HCs were included (mean age: 62.25 vs 61.84 years; 51% vs 43% female). Five MSA-related ICs were identified: cerebellar network, salience network, compensatory network, default mode network (DMN), and basal ganglia network (all q < 0.05, false discovery rate-adjusted, vs controls). The combination of ICs aligns with the MSA metabolic abnormalities. The cerebellar network was associated with cognitive impairment (Mini-Mental State Examination: β = 13.87, 95% CI 5.86-21.88, p = 9.04 × 10-4; Montreal Cognitive Assessment: β = 14.63, 95% CI 7.45-21.81, p = 1.13 × 10-4), cerebellar symptoms (β = -38.58, 95% CI -73.37 to -3.78, p = 0.03), and posterior putamen DAT (β = -72.79, 95% CI -120.35 to -25.23, p = 0.0031). The compensatory network showed increased metabolism associated with more severe parkinsonian symptoms (β = 3.66, 95% CI 1.51-5.81, p = 1.08 × 10-3). The basal ganglia network was associated with parkinsonian symptoms (β = -2.56, 95% CI -4.03 to -1.09, p = 8.37 × 10-4) and posterior putamen DAT (β = 48.24, 95% CI 15.99-80.50, p = 0.0038). DMN moderated the relationship between the cerebellar network and cognitive function. SEM demonstrated that posterior putamen DAT and basal ganglia network contributed to motor symptoms while the compensatory network acted as a compensatory mechanism. DISCUSSION:This study demonstrated that the metabolic abnormalities in MSA can be decomposed into 5 large-scale brain networks, providing a comprehensive understanding of the disease's heterogeneous mechanisms.

Schwartz-Jampel Syndrome Type 1 (SJS1) is a rare autosomal recessive disorder characterized by myotonia and distinctive facial features, such as blepharospasm and pursed lips. The condition results from biallelic variants in HSPG2, which are usually inherited from both parents. So far, de novo or mosaic HSPG2 variants have not been reported. An 11-year-old boy with no family history presented with myotonia and gait instability. Laboratory tests showed elevated creatine kinase levels, and electromyography revealed neurogenic myotonic discharges. Whole-exome sequencing trio was performed, and identified three HSPG2 variants in the patient: c.7438 C > T (p.Arg2480Trp), c.9145del (p.Ala3049GlnfsTer56), and c.12899G > T (p.Arg4300Leu). Long-read sequencing of the patient confirmed that c.7438 C > T and c.12899G > T were in cis on one allele, while c.9145del was on the other allele, establishing a compound heterozygous genotype. Retrospective analysis detected low-level maternal mosaicism for c.9145del, which explained the initial segregation discrepancy. This case is the first documentation of a de novo and a potential mosaic variant in HSPG2. It highlights the limitations of conventional sequencing in detecting mosaic variants and the utility of long-read sequencing in resolving challenging inheritance patterns, underscoring the growing value of advanced sequencing technologies in rare disease diagnostics.

BACKGROUND:Familial cortical myoclonic tremor with epilepsy (FCMTE) is an autosomal dominant neurological disease characterized by cortical myoclonic tremor and epileptic seizures. The proposed pathogenic (TTTCA) pentanucleotide repeat expansion (exp) insertion, flanking the polymorphic (TTTTA)exp, has been reported in seven distinct FCMTE causative genes/loci, and a repeat motif-specific phenotype correlation is claimed. However, the pathogenic mechanism of FCMTE is still poorly understood. METHODS:We investigated how the (TTTCA)exp insertion causes the disease, mainly employing the FCMTE1 patients-induced pluripotent stem cell-derived neurons (iPSC-neurons), focusing on the formation of (UUUCA)exp RNA foci and their associated cellular toxicity. RESULTS:First, (TTTCA)exp insertion neither altered SAMD12 expression nor translates into repeat peptides. Second, (UUUCA)exp RNA foci were detected in both the constructed cell line and iPSC-neurons, and presented toxicity effects. Third, NOVA2, a neuron-specific splicing regulator, was identified as the key RNA-binding protein interacting with (UUUCA)exp RNA. The (UUUCA)exp RNA disrupted the nuclear distribution pattern of NOVA2, and reciprocally, knockdown of NOVA2 promoted the formation of (UUUCA)exp RNA foci. Shared synaptic-related pathways of alternative splicing events were observed in both FCMTE1-iPSC-neurons and NOVA target genes. CONCLUSIONS:These findings support a repeat motif-dependent mechanism involving (UUUCA)exp RNA foci and the functional disruption of the key RNA-binding protein NOVA2, providing valuable insights for future studies on FCMTE and other pentanucleotide repeat expansion diseases. © 2026 International Parkinson and Movement Disorder Society.

Abstract Cerebral oxygen extraction fraction (OEF) reflects the balance between cerebral oxygen delivery and metabolic demand, but its normative evolution across the human lifespan remains unknown. Here we used rapid, non-contrast TRUST MRI to establish a multisite normative model of global cerebral OEF in 2,025 healthy individuals aged 0-93 years from 17 imaging sites. OEF increased from the neonatal period to middle adulthood, followed by a slower rise and plateau in later life, with the fastest change occurring during early development and no significant sex differences. Individual OEF deviation scores were associated with vascular risk burden in healthy adults. Applying the model to 885 patients revealed disease-related OEF alterations, including positive deviations in pediatric obstructive sleep apnea, autoimmune disorders, brain tumors, mild cognitive impairment and dementia. OEF deviation further tracked tumor grade and Ki-67 proliferation. These findings establish lifespan OEF charting as a scalable framework for individualized physiological neuroimaging.

The clinical interpretation of Alzheimer’s disease (AD) is frequently complicated by the prevalence of missense variants designated as being of uncertain significance within associated genes. Conventional computational prediction tools often overlook disease-specific pathophysiological contexts and lack pertinence and interpretability. Therefore, the present study aimed to develop a novel, interpretable framework for predicting the pathogenicity of AD missense variants by integrating transcriptomic and proteomic data enrichment patterns with machine learning methods. A cross-sectional variant-level analysis was performed using publicly available databases. Missense variants in APOE, APP, PSEN1, PSEN2, SORL1, and TREM2 reported in AD patients were retrieved from Alzforum and compared with missense variants from individuals without neurological diseases, as cataloged in the gnomAD v2.1.1 non-neuro subset. Variants were annotated with tissue-specific expression, secondary structure, relative solvent accessibility, and other functional features using tools like AlphaFold. Enrichment of specific features was assessed with Fisher’s exact tests with Bonferroni correction for multiple comparisons. Given that PSEN1 showed the strongest enrichment signals, six machine-learning algorithms were trained on PSEN1 variants to distinguish AD-associated variants from gnomAD variants, using a 10 × 5 nested cross-validation scheme. External validation was conducted using PSEN1 missense variants from ClinVar annotated as pathogenic/likely pathogenic or benign/likely benign. Model performance was compared with SIFT and PolyPhen-2, and interpretability was evaluated by feature ablation and SHapley Additive exPlanations analyses. AD-associated variants exhibited statistically significant enrichment within some transcriptomic or proteomic features, with PSEN1 contributing significantly to the enrichment observed across these features. Random forest and gradient boosting models achieved high performance in the internal training dataset and maintained high recall in the external validation dataset, outperforming SIFT and approaching the performance of PolyPhen-2. Relative solvent accessibility was the most discriminative individual feature, while regional and topological features provided complementary discriminative power. This integrative, multi-omics framework links disease-specific enrichment patterns with interpretable gene-level machine learning for AD missense variants. The results highlight the importance of expression level, structural context, etc. for PSEN1 variant pathogenicity and may help prioritize variants for functional studies. Further validation in additional genes and independent cohorts is warranted prior to any clinical application.

BACKGROUND:Perry disease is a rare autosomal dominant inherited neurodegenerative disorder caused by cytoskeleton-associated protein glycine-rich (CAP-Gly) domain-related variants in the DCTN1 gene, with characteristic TDP-43 pathology. The typical manifestations are parkinsonism, psychiatric symptoms, weight loss, and central hypoventilation. OBJECTIVE:The aim of the study was to delineate the genotypic and phenotypic spectrum of Perry disease in a Chinese parkinsonism cohort. METHODS:We screened the DCTN1 CAP-Gly domain-related variants in 932 Chinese parkinsonism patients using next-generation sequencing, and functional studies of the identified variants were conducted. RESULTS:Three variants were detected (two novel: p.Arg32Cys, p.Gly67Ser; one reported: p.Gly71Arg), indicating a rate of 0.32% (3/932). Clinical presentations mimicked progressive supranuclear palsy or early-onset Parkinson's disease. Functional studies supported pathogenicity, revealing impaired localization of DCTN1-encoded p150Glued protein, TDP-43 pathology, and altered lysosomal positioning. CONCLUSIONS:Our study broadens the genetic and phenotypic spectrum of Perry disease. These findings support consideration of DCTN1 CAP-Gly domain-related variants in patients with parkinsonism to facilitate early recognition and management. © 2026 International Parkinson and Movement Disorder Society.

Primary brain calcification (PBC) is a neurodegenerative disorder characterized by bilateral brain calcification. JAM2 is a PBC causative gene, encoding the tight junction protein JAM2 and critical for blood-brain barrier (BBB) integrity, with an uncertain pathogenic mechanism. We analyzed two JAM2 missense mutations identified in PBC patients using plasmid constructs, immunoprecipitation, flow cytometry, and structural modeling. A Jam2 knockout (KO) mouse model was generated to assess behavioral deficits, brain calcification, and BBB integrity via histology, Evans blue assay, and in situ hybridization. JAM2-W108C mutants showed abnormal localization, while JAM2-R108H specifically disrupted JAM2-JAM3 interaction, mirroring the pathogenic JAM3-E116K mutation. Jam2 KO mice exhibited midbrain calcification (von Kossa staining) and motor impairments (rotarod/beam-walking tests) at 6-12 months. JAM2 and JAM3 co-localized in brain endothelial cells, and KO mice demonstrated BBB leakage (Evans blue extravasation). The main pathogenic mechanism of JAM2-PBC should be associated with the impaired JAM2-JAM3 heterodimer formation, compromising tight junctions and BBB integrity. Our study indicates JAM2-JAM3 interaction as a potential therapeutic target for PBC and related brain calcification disorders.

Abstract We identified biallelic loss-of-function BPNT1 mutations in 3 patients with recurrent vitamin B12–dependent megaloblastic anemia. Mechanistically, BPNT1 deficiency caused the accumulation of PAP (3′-phosphoadenosine 5′-phosphate), impaired ribosome biogenesis, and reduced ileal expression of the cubilin/amnionless receptor complex in Bpnt1-null mice.

Biallelic variants in SYNJ1 were initially identified in early-onset Parkinson’s disease, often accompanied by atypical neurological manifestations. However, their occurrence in patients with a multiple system atrophy-mimicking phenotype has not been well described. A 71-year-old Chinese woman with gradually worsening motor and autonomic symptoms was assessed. The evaluation included clinical examination, genetic testing, and functional studies. The patient exhibited gait instability, cerebellar ataxia, parkinsonism, urinary autonomic dysfunction, and poor levodopa responsiveness. Genetic analysis identified novel compound heterozygous SYNJ1 variants (c.1574 A > G and c.142G > T). Functional assays evaluating each variant individually showed reduced synaptojanin-1 abundance without altered localization. This case expands the clinical context in which biallelic SYNJ1 variants may be implicated and suggests that SYNJ1 analysis could be considered in atypical parkinsonism with cerebellar dysfunction.

Primary brain calcification(PBC)is a hereditary neurodegenerative disorder with symmetrical calcification in the bilateral basal ganglia and other brain regions as its core imaging feature,and presents diverse heterogeneous clinical manifestations such as movement disorders,cognitive impairment,and psychiatric disturbances.The identification of multiple causative genes has not only facilitated the exploration of PBC pathogenesis but also continuously expanded its phenotypic spectrum.The diagnosis,evaluation,and management of this disease are experiencing pivotal shifts,accompanied by new challenges.In 2025,the first international expert consensus on PBC was published,laying a foundation for the standardized diagnosis and treatment of PBC worldwide.Based on China's clinical practice and research status,and referring to the inter-national consensus,domestic experts in related fields conducted multiple rounds of discussions,supplemented and revised the contents covering clinical manifestations,auxiliary examinations,diagnostic criteria,differen-tial diagnosis,molecular classification and characteristics,genetic testing and counseling,disease management and treatment of PBC,and finally developed this consensus.This consensus aims to provide guidance for the standardized diagnosis,treatment,and research of PBC in China,help improve the quality of diagnosis and treatment,and drive the steady advancement of relevant research in this field.

BACKGROUND:Growing evidence links lysosomal dysfunction to parkinsonism. TRPML1, a lysosomal cation channel encoded by the MCOLN1 gene, is essential for lysosomal function. Biallelic loss-of-function variants in MCOLN1 cause mucolipidosis type IV. However, the role of heterozygous MCOLN1 variants remains unclear. METHODS:Two patients with α-synucleinopathies underwent clinical evaluation and whole-genome sequencing. The functional effects of TRPML1 variants were assessed using immunofluorescence, lysosomal patch-clamp recording, and autophagic flux assay. RESULTS:Two heterozygous MCOLN1 variants were identified: p.E376K in a patient with multiple system atrophy and p.L315del in a patient with early-onset Parkinson's disease. Functional analyses showed that p.L315del disrupted lysosomal localization, and both variants significantly reduced lysosomal currents upon TRPML1 agonist stimulation, with a trend toward impaired autophagic flux, indicating loss of function. CONCLUSIONS:These findings demonstrate that both variants impair TRPML1 function in vitro, identifying MCOLN1 as a candidate gene for α-synucleinopathies that warrants further investigation in larger cohorts. © 2026 International Parkinson and Movement Disorder Society.

Interictal epileptiform discharge (IED) detection is essential for clinical electroencephalography (EEG) analysis. Although deep learning approaches enable automated IED detection, they require extensive fine-grained channel-level annotations that are scarce in practice. To overcome this data bottleneck, this study introduces a Spatial Prior-injected IED Detection Network (SPID-Net), a weakly supervised model trained with coarse-grained epoch-level annotations to achieve fine-grained channel-level IED detection. Spatial priors are injected by two key components to address the lack of spatial guidance in weakly supervised training. First, the Graph-based Spatial Fusion Block (GSFB) with an auxiliary loss encourages spatial coherence among spatially adjacent channels. This enhances spatial continuity and enables single-channel IED inference under missing-channel scenarios. Second, the Pseudo-Label Supervision (PLS) strategy explicitly introduces spatial priors to improve the detection of subtle and spatially adjacent IED patterns. Experiments on two public datasets, TUEV and VEPI, show that SPID-Net achieves state-of-the-art performance, with an F1-score of 0.9154 and an AUPRC of 0.9714. Notably, cross-dataset experiments further confirm its robustness and transferability: the proposed SPID-Net pretrained on one dataset can be effectively adapted to another with a small amount of fine-tuning data. These results demonstrate its substantial cross-domain adaptation capability under few-shot transfer learning scheme, underscoring its potential for practical clinical applications.

The DCTN1 gene encodes the core subunit of the dynactin complex, which plays a pivotal role in retrograde axonal transport within neurons. Variants in this gene are not only responsible for Perry disease and distal hereditary motor neuropathy (dHMN), but also encompass a broad phenotypic spectrum including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP), highlighting its significant clinical heterogeneity. This review summarizes the clinical phenotypic spectrum, pathogenic molecular mechanisms, and advances in diagnosis and treatment of neurodegenerative disorders associated with DCTN1 variants, with the aim of providing a reference for precision diagnosis and management of these disorders.

Parkinson's disease (PD) care remains profoundly unequal across and within countries, despite major advances in understanding and treatment. Drawing on PD specialists’ personal stories of real-world experiences from diverse regions across Asia, Africa, and South America, this paper highlights the key barriers to equitable PD care and identifies pragmatic, scalable solutions. Across settings, several major barriers consistently emerge: a critical shortage and uneven distribution of trained specialists; geographic disparities limiting access to care; substantial financial barriers, particularly for comprehensive and advanced therapies; fragmented healthcare systems lacking integration and multidisciplinary support; and low public awareness and persistent stigma, leading to delayed diagnosis and treatment. Strategies to address these challenges include workforce development through training, mentorship, and international collaboration; bringing expertise and services closer to patients via outreach programs and the use of “simple” technologies such as telemedicine and mobile communication platforms; ensuring universal access to essential medications, particularly levodopa; integrating multidisciplinary care models; public awareness campaigns and support groups empowering patients and caregivers and reducing stigma; and embedding research into routine care. The experiences presented here illustrate that meaningful progress is achievable through pragmatic solutions, collaborative networks, and sustained commitment to patient-centered care.

BACKGROUND AND PURPOSE:MSA is a progressive neurodegenerative disorder with two main subtypes: MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P). The latest diagnostic criteria emphasize the importance of neuroimaging markers from MRI alongside clinical symptomatology assessment. This study investigates the relationship between visual MRI markers and multiple system atrophy (MSA) subtypes, clinical features, and cerebral glucose metabolism and striatal dopaminergic degeneration. MATERIALS AND METHODS:Eighty-nine patients with MSA, 67 with predominant parkinsonism (MSA-P) and 22 with predominant cerebellar ataxia (MSA-C), underwent extensive clinical and neuropsychiatric evaluations and routine MRI scans to assess markers like the hot-cross bun (HCB) sign, putaminal iron deposition, midbrain to pons (M/P) ratio, and cerebellar atrophy. PET imaging with 18F-fluorodeoxyglucose (18F-FDG) and 11C-2β-carbomethoxy-3β-(4-fluorophenyl) tropane (11C-CFT) was performed to evaluate brain metabolism and striatal dopaminergic uptake abnormalities. RESULTS:Canonical correlation analysis revealed significant associations between clinical symptoms and MRI markers, particularly the HCB sign, M/P ratio, and putaminal iron deposition. The HCB sign and M/P ratio correlated with cerebellar dysfunction, while putaminal iron deposition correlated with parkinsonism severity, particularly in MSA-P. Cerebellar and putaminal metabolism negatively correlated with their respective structural changes. However, putaminal iron deposition showed no significant correlation with striatal dopaminergic uptake. CONCLUSIONS:Visual MRI markers are crucial for diagnosing MSA and delineating disease subtype and symptom severity. Supratentorial and infratentorial MRI markers reflect the severity of parkinsonism and cerebellar dysfunction, respectively. Putaminal iron deposition reflects the severity of parkinsonism, suggesting that iron deposition plays an important role in the pathophysiological mechanisms contributing to parkinsonism in MSA.

BACKGROUND:Primary brain calcifications are observed in several inherited diseases due to different pathogenic mechanisms, including the disruption of the neurovascular unit, mitochondrial dysfunction, and impaired nucleic acid metabolism. OBJECTIVE:The aim of the study was to identify a novel genetic cause of brain calcifications in genetically unresolved cases. METHODS:Exome sequencing data from two unrelated Pakistani patients with generalized dystonia and primary brain calcifications were analyzed. The best candidate gene (ie, RRP12) was then investigated in two large cohorts of patients with brain calcifications from France (n = 111) and China (n = 543). RRP12 loss-of-function phenotype was explored through Western blot and immunocytofluorescence studies on patient-derived fibroblasts and in a knockdown zebrafish model. RESULTS:A combined approach of exome sequencing and homozygosity mapping allowed the prioritization of a rare homozygous variant in RRP12 (c.1558C>T, p.R520C) in two apparently unrelated Pakistani patients from consanguineous families, presenting with infantile-onset generalized dystonia, spasticity, and widespread brain calcifications. Screening of two large cohorts of patients with unresolved brain calcifications revealed two affected French siblings and one unrelated Chinese individual, each carrying rare, biallelic, missense variants in the RRP12 gene (c.1429G>A, p.E477K and c.2634T>G, p.F878L, respectively). Molecular studies revealed a significant reduction in RRP12 protein and abnormal nucleolar morphology in patient'derived fibroblasts. Consistent with its essential role in RNA metabolism, rrp12 knockdown in zebrafish caused severe developmental delay, crimping, and early lethality. CONCLUSIONS:RRP12 is a novel candidate gene for autosomal recessive brain calcifications, possibly associated with a wide clinical spectrum ranging from early-onset severe forms to adult-onset paucisymptomatic presentations. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.