Research using brain tissue obtained through autopsies is essential for the development of treatments for several neurological disorders and for elucidating their pathophysiologies. However, owing to a decline in the number of autopsies, opportunities to examine central nervous system tissues are diminishing. It is therefore necessary to collaborate with brain banks and establish a system to ensure the proper storage, research utilization, and diagnostic analysis of nervous system tissues obtained through autopsies.

BACKGROUND:The purpose of this study was to clarify the usefulness of the 'hot cross bun' sign (HCBS) as a diagnostic imaging marker in a large cohort of patients with multiple system atrophy (MSA) and spinocerebellar ataxia (SCA). METHODS:This multicentre study included 97 patients with neuropathologically confirmed MSA, and 105 patients with genetically confirmed SCA. Neuroimaging features, including HCBS and middle cerebellar peduncle (MCP) hyperintensities, were assessed. HCBS was graded from 0 to 2: 0, none; 1, only a vertical hyperintense line; and 2, a cruciform hyperintense line. The neuropathological correlates of HCBS were evaluated in 15 patients with MSA with ≤3 months between MRI and autopsy. RESULTS:In patients with a disease duration <3 years, grade 1 or 2 HCBS was detected in 100% patients with MSA with predominant cerebellar ataxia (MSA-C) and 39.0% with SCA; whereas grade 2 HCBS was observed in 50% with MSA-C and 2.4% with SCA. Moreover, the coexistence of grade 2 HCBS and MCP hyperintensities exhibited a specificity of 100%. A neuropathological assessment revealed myelin loss, alpha-synuclein aggregates and astrocytic reaction in the MCP, transverse fibres, central zone between longitudinal fasciculi and raphe nucleus, with relative preservation in the longitudinal fasciculi and medial lemniscus in patients with MSA and grade 2 HCBS. CONCLUSIONS:Grade 1 or 2 HCBS is a highly sensitive finding in patients with MSA-C, and the observation of grade 2 HCBS within 3 years of motor symptom onset has excellent specificity for discriminating MSA-C from SCA, especially when accompanied by MCP hyperintensities.

Mean corpuscular volume (MCV) is routinely measured in patients with chronic kidney disease (CKD) and anemia; however, its prognostic significance, particularly in the context of erythropoiesis-stimulating agent (ESA) therapy, remains unclear. We conducted a post hoc analysis of the BRIGHTEN study, a multicenter, prospective trial that enrolled 1219 ESA-naïve patients with non-dialysis-dependent CKD who initiated darbepoetin alfa. Patients were categorized based on changes in MCV from baseline to week 16 as either increased or decreased. The primary outcome was renal function decline, defined as the initiation of dialysis, kidney transplantation, ≥ 50

Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Although C5 inhibitors, such as eculizumab and ravulizumab, have markedly improved outcomes, renal recovery remains limited in cases complicated by hypertensive emergency (HE) or malignant hypertension, likely due to complement-independent vascular injury. Angiotensin receptor–neprilysin inhibitor therapy exerts dual actions of renin–angiotensin system blockade and augmentation of natriuretic peptide signaling. Additionally, this therapy has recently demonstrated renal benefits in thrombotic microangiopathy with HE compared with conventional renin–angiotensin system inhibitors. However, the combined use of an angiotensin receptor–neprilysin inhibitor with a C5 inhibitor in aHUS with HE has not been reported. A 57-year-old Japanese man presented with marked anemia, severe renal dysfunction (serum creatinine concentration: 10.19 mg/dL; eGFR 5 mL/min/1.73 m2), and hypertensive emergency (blood pressure: 198/102 mmHg). Laboratory examinations showed hemolytic anemia and thrombocytopenia, leading to a diagnosis of thrombotic microangiopathy. Plasma exchange was performed, and intravenous antihypertensive therapy was initiated on day 1. Ravulizumab was started on day 2 after thrombotic thrombocytopenic purpura and Shiga toxin-associated HUS were excluded, and aHUS was clinically suspected on the basis of isolated C3 hypocomplementemia. Despite the requirement for initial hemodialysis, renal function gradually improved, allowing withdrawal of dialysis by day 14. A renal biopsy showed thrombotic microangiopathy with intravascular thrombi and concentric arteriolar wall thickening resembling onion-skin lesions. Consequently, sacubitril/valsartan was initiated on day 23, resulting in further renal recovery (creatinine concentration: 3.79 mg/dL on day 22 to 1.23 mg/dL at 1 year; eGFR 14 to 48 mL/min/1.73 m2 at 1 year) accompanied by improved blood pressure control. Genetic testing identified a heterozygous C3 c.493G > T (p.Val165Phe) variant, which confirmed C3 mutation-associated aHUS. We report the first case of C3 mutation-associated aHUS with HE, which was successfully treated with a combination of ravulizumab and sacubitril/valsartan. The renal improvement in this patient may suggest a potential, but unproven, contribution of angiotensin receptor–neprilysin inhibitor-based renin–angiotensin modulation to kidney recovery when added to complement inhibition in aHUS complicated by HE, although its independent effect remains unclear. Further cohort studies are warranted to clarify its potential therapeutic synergy.

The aberrant GGC repeat expansion in the 5'-untranslated region of the NOTCH2NLC gene causes neuronal intranuclear inclusion disease (NIID), a progressive neurodegenerative disorder. The clinical features of NIID are highly variable and include cognitive dysfunction, peripheral neuropathy, and episodic neurogenic symptoms. The pathogenesis of episodic symptoms in NIIDs remains unknown, and histopathological studies are limited. Here, we report an autopsy case of NIID in a 32-year-old Japanese female who developed severe episodic symptoms, including hemiplegic migraine, seizures, and impaired consciousness. Her major episodic symptoms appeared at the age of 16 years and were accompanied by alternating brain edema. She developed severe episodic symptoms with right brain edema at the age of 31. She became bedridden due to irreversible brain lesions and died 1 year later from a catheter-related bloodstream infection. Neuropathological analyses revealed numerous neuronal intranuclear inclusions and white matter lesions. In addition, bizarre astrocytes with eosinophilic cytoplasmic or intranuclear inclusions were observed. GFAP immunoreactivity in the bizarre astrocytes was diminished, AQP4 showed a disorganized distribution. The histological changes observed in this case suggest an association between non-neuronal cellular disturbances and episodic neurogenic symptoms in NIIDs.

Noncoding GGC repeat expansion of various genes leads to oculopharyngodistal myopathy (OPDM), an adult-onset progressive neuromuscular disorder characterized by ophthalmoplegia, pharyngeal dysfunction, and distal limb muscularweakness. Recently, clinical overlap among noncoding GGC repeat-associated neuromuscular diseases, including OPDM, fragile X-associated tremor/ataxia syndrome (FXTAS), and neuronal intranuclear inclusion disease (NIID), has been recognized. Here, we present an autopsy case of OPDM with GIPC1 mutation (OPDM2) in a 56-year-old man. Histopathological studies revealed loss of myelinated fibers in the cerebrum and the presence of neuronal and glial intranuclear inclusions, which are commonly observed in FXTAS and NIID. Numerous intranuclear inclusions in oligodendrocytes were a characteristic feature of our autopsied case. Although GGC repeat expansions in distinct genes produce similar neuropathological findings, such as neuronal and glial intranuclear inclusions, the affected cell populations differ.

AL amyloidosis is characterized by extracellular deposition of immunoglobulin light-chain fibrils, frequently leading to kidney involvement and progressive organ dysfunction. We report a case of kidney AL amyloidosis secondary to multiple myeloma in which daratumumab-based chemotherapy combined with autologous peripheral blood stem cell transplantation resulted in marked improvement, as confirmed by sequential kidney biopsy. The initial biopsy revealed vascular-dominant amyloid deposition, whereas the second biopsy obtained 2 years later demonstrated a marked reduction in amyloid burden, particularly within the vascular compartments. This histopathological improvement corresponded with hematologic remission and stabilization of kidney function. The observed reduction in tissue amyloid deposits was presumed to result from suppression of amyloidogenic light chains, leading to inhibition of new fibril formation and subsequent tissue remodeling. Our findings provide direct pathological evidence that daratumumab-based combination therapy, through immune-mediated plasma cell depletion, may indirectly promote the regression of amyloid deposits and contribute to functional recovery.

Prion disease is a general term for a disease that causes cognitive disorders due to the accumulation of abnormal prion protein in the brain. Creutzfeldt-Jakob disease (CJD) is the most common case of prion disease, and sporadic Creutzfeldt-Jakob disease (sCJD) accounts for more than 70% of CJD cases. Early and accurate diagnosis of sCJD remains challenging. The aim of this study is to classify 6 sCJD patients from 10 healthy older adults and 23 Alzheimer's disease (AD) patients using resting-state scalp-recorded electroencephalogram (EEG)-derived indices. Power spectrum, SL values by Synchronization Likelihood (SL), and graph metrics by SL values were calculated for 5 frequency bands as EEG-derived indices. In addition, power spectrum and SL values were standardized and exponentially transformed for each subject and each frequency band. Graph metrics were calculated by these SL values. These indices were used as features for classification. Classifiers were constructed by features selected by Recursive Feature Elimination (RFE). The highest classification accuracy was 97.44% using a 12-dimensional feature. This accuracy was confirmed by indices after standardization and exponential transformation. Additional validation analyses were performed to assess the reliability of the selected classifier. Accuracy of nested LOOCV was 84.62%, supporting meaningful classification ability under a leakage-controlled validation framework. An analysis of robustness removing a group of subjects with high similarity with many others showed that the selected classifier maintained a micro-F1 score of 90.32%. Permutation test indicated that the observed performance was significantly higher than chance level, and repeated stratified 10-fold cross-validation showed relatively stable performance across different data partitions. These findings suggest that resting-state EEG-derived indices may provide useful candidate features for classification of sCJD, AD, and healthy older adults. However, further validation using larger independent cohorts is required to establish the generalizability and clinical reliability of the proposed classifier.

Parkinson disease and pure autonomic failure are α-synucleinopathies that lead to peripheral autonomic neuropathy. These autonomic disturbances include well-known symptoms, such as orthostatic hypotension and constipation, and often overlooked symptoms, including supine hypertension and gastroparesis. This article describes the characteristics of diverse peripheral autonomic symptoms of α-synucleinopathies and discusses therapeutic interventions available in daily clinical practice and their impact on prognosis, in the absence of established disease-modifying drugs.

AIM:To establish and characterize neuropsychiatric manifestations of post-COVID-19 condition (PCC) through Japan's first nationwide registry integrating clinical assessments with patient-reported outcomes. METHODS:The Psychiatric Symptoms for COVID-19 Registry Japan collected data between December 2022 and September 2024, integrating electronic patient-reported outcomes (n = 806) with in-person clinical assessments (n = 136). Participants were classified as cases or tolerant controls following WHO criteria. The Composite Psychological Burden Score (CPBS) was constructed using principal component analysis of depression, anxiety, insomnia, cognitive dysfunction, and quality of life measures (accounting for 75.4% of variance). Sex-stratified multivariate analyses examined risk factors. RESULTS:Clinical evaluation revealed neurological symptoms (34.1%) as predominant manifestations, followed by pain-related symptoms (23.5%). PCC cases showed significantly higher rates of physical and psychiatric comorbidities, impaired quality of life, and work discontinuation (52.9%). Patient-reported perception of significant life changes due to PCC was most strongly associated with physician-diagnosed PCC (odds ratio [OR]: 11.2), followed by CPBS (OR: 6.25 per standard deviation, 95% CI: 2.48-15.7). Longer COVID-19 infection duration, unemployment, and reduced family communication were significant in both sexes. In sex-stratified analyses, psychiatric comorbidity (adjusted OR [aOR]: 5.68) and single status (aOR: 4.46) were significant in men and reduced outdoor activity in women (aOR up to 12.6); however, no interaction with sex reached significance, indicating that these sex differences were not statistically confirmed. CONCLUSION:Integrating subjective disease perception with psychological, cognitive, and quality of life measures may improve identification of neuropsychiatric burden in PCC. The sex-stratified patterns warrant confirmation in larger cohorts.

We report the first autopsy-proven case of colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy harboring the CSF1R mutation c.2320T>C (p.Cys774Arg). The patient, a man in his 40s, exhibited progressive neuropsychiatric symptoms with predominant frontal white matter lesions and corpus callosum atrophy. Neuropathological examination revealed frontal-predominant demyelination with a relatively low number of axonal spheroids compared with typical cases, as well as the absence of intracranial calcifications. In addition, prominent cerebral amyloid angiopathy was observed despite an APOE ε3/ε3 genotype. These findings expand the clinicopathological spectrum of CSF1R-related leukoencephalopathy and highlight variability in pathological features associated with different CSF1R mutations.

Autopsies have long been performed to determine the cause of death in the medical field. In fact, autopsies have significantly contributed to our understanding of neurological and psychiatric disorders. Patients and their families who wish to donate bodies for autopsy may have various expectations, such as contributing to the development of treatments for the diseases they experienced or facilitating the investigation of their causes. They may also hope that the removed and stored organs will be used effectively and appropriately by academic institutions and pharmaceutical companies, both in Japan and abroad. Accordingly, brain banks store samples that can be utilized for future medical research. The Japan Brain Bank Net (JBBN) was established to help fulfill this purpose. The network currently includes 19 institutions. In addition to storing and providing pathological tissue - functions traditionally associated with brain banks - JBBN also offers detailed and standardized neuropathological diagnoses. Currently, JBBN is working toward storing tissue suitable for emerging research methodologies, digitizing pathological images, applying artificial intelligence (AI) in neuropathological studies, and building a publicly accessible database. JBBN also aims to establish a permanent brain bank infrastructure to support the next generation of research.

Some patients with corticobasal degeneration (CBD) present with neuropsychiatric symptoms, including frontal lobe symptoms. However, stupor is rarely reported. Here, we report a case of acute restlessness at onset, which was clinically diagnosed as frontotemporal dementia (FTD) but was found to be CBD at autopsy. A 71-year-old woman with COVID-19 presented to our hospital. At the age of 62, she had suddenly become restless and confused without any preceding motor or psychiatric symptoms. She was treated with psychotropic drugs but subsequently entered stupor and was admitted to a psychiatric hospital. Magnetic resonance imaging showed mild atrophy of the frontal lobe. Single-photon emission computed tomography showed decreased blood flow in the frontal lobe, and the patient was clinically diagnosed with FTD. At the age of 71, she was transferred to our hospital from a psychiatric hospital for COVID-19 treatment. Upon transfer to our hospital, the patient presented with akinetic mutism. The patient died of respiratory failure 10 days after the onset of COVID-19. Immunostaining with AT8 and RD4 antibodies revealed astrocytic plaques, pretangles, coiled bodies, and threads, predominantly in the frontal lobes and basal ganglia. Other pathologies include accumulation of pTDP43 in the basal ganglia, thalamus, and frontal lobes. Argyrophilic grains were observed in the amygdala and the hippocampus, which corresponded to Saito stage 2. Other neurodegenerative proteins, such as amyloid β or α-synuclein, were not observed. The patient was pathologically diagnosed with CBD. We present a rare autopsy case involving a patient with CBD who presented with acute psychiatric symptoms and stupor. The psychiatric symptoms were characterized by agitation and fear-related behavior, which differ from the disinhibition and antisocial behavior typically associated with frontal lobe symptoms. Further autopsies are needed to examine the extent of tau pathology spread and accumulation to better understand the psychiatric symptoms of CBD.