Computer-Based Evaluation of α-Synuclein Pathology in Multiple System Atrophy as a Novel Tool to Recognize Disease Subtypes.

Multiple system atrophy (MSA) is a neurodegenerative disorder with variable disease course and distinct constellations of clinical (cerebellar [MSA-C] or parkinsonism [MSA-P]) and pathological phenotypes, suggestive of distinct α-synuclein (αSyn) strains. Neuropathologically, MSA is characterized by the accumulation of αSyn in oligodendrocytic glial cytoplasmic inclusions (GCI). Using a novel computer-based method, this study quantified the size of GCIs, density of all αSyn pathology, density of only the GCIs, and number of GCIs in MSA cases (n = 20). The putamen and cerebellar white matter were immunostained with the disease-associated 5G4 anti-αSyn antibody. Following digital scanning and image processing, total 5G4-immunoreactive pathology (ie, neuronal, neuritic, and glial) and GCIs were optically dissected for inclusion size and density measurement and then evaluated applying a novel computer-based method using ImageJ. GCI size varied between cases and brain regions (P < .0001), and heterogeneity in the density of all αSyn pathology including the density and number of GCIs were observed between regions and across cases, where MSA-C cases had a significantly higher density of all αSyn pathology in the cerebellar white matter (P = .049). Some region-specific morphologic variables inversely correlated with the age of onset and death, suggestive of an underlying aging-related cellular mechanism. Unsupervised K-means cluster analysis classified MSA cases into 3 distinct groups based on region-specific morphologic variables. In conclusion, we developed a novel computer-based method that is easily accessible, providing a first step to developing artificial intelligence-based evaluation strategies for large scale comparative studies. Our observations on the variability of morphologic variables between brain regions and cases highlight (1) the importance of computer-based approaches to detect features not considered in the routine diagnostic practice, and (2) novel aspects for the identification of previously unrecognized MSA subtypes that do not necessarily reflect the current clinical classification of MSA-C or MSA-P.

Revisiting the relevance of Hirano bodies in neurodegenerative diseases.

AIMS: Hirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases. METHODS: This cross-sectional study systematically evaluated HBs in a cohort of 193 cases with major neurodegenerative diseases, including AD (n = 91), Lewy body disease (LBD, n = 87), progressive supranuclear palsy (PSP, n = 36), multiple system atrophy (MSA, n = 14) and controls (n = 26). The prevalence, number and morphology of HBs in the stratum lacunosum (HBL) and CA1 pyramidal cell layer were examined. In addition, we investigated the presence of HBs in five additional hippocampal subregions. RESULTS: The morphological types of HBs in CA1 were divided into three, including a newly discovered type, and were evaluated separately, with their morphology confirmed in three dimensions: (1) classic rod-shaped HB (CHB), (2) balloon-shaped HB (BHB) and the newly described (3) string-shaped HB (SHB). The prevalence of each HB type differed between disease groups: Compared with controls, for CHB in AD, AD + LBD, PSP and corticobasal degeneration, for BHB in AD + LBD and PSP, and SHB in AD + LBD and PSP were significantly increased. Regression analysis showed that CHBs were independently associated with higher Braak NFT stage, BHBs with LBD and TDP-43 pathology, SHBs with higher Braak NFT stage, PSP and argyrophilic grain disease and HBLs with MSA. CONCLUSIONS: This study demonstrates that HBs are associated with diverse neurodegenerative diseases and shows that morphological types appear distinctively in various conditions.

Associations between readmission and patient-reported measures in acute psychiatric inpatients: a multicenter prospective longitudinal study.

PURPOSE: This study examined whether patient-reported measures (PRMs) addressing quality of life, personal agency, functional impairment, and treatment satisfaction at hospital discharge were associated with future readmission during a 12-month follow-up period. The study also examined whether readmission influenced changes in the same measures. METHODS: A multicenter prospective cohort study was conducted at 21 psychiatric hospitals in Japan. Participants completed the EuroQol-five-dimensions-five-level (EQ-5D), the Five-item Subjective Personal Agency Scale, and the Sheehan Disability Scale (SDS) at the time of index admission (T1), discharge from index admission (T2), and 6 months (T3) and 12 months (T4) after discharge. Inpatient treatment satisfaction was assessed at T2. Readmission and variables potentially associated with hospitalization and PRMs were evaluated using mixed-effects logistic regression models and mixed models for repeated measures. RESULTS: A total of 491 participants were followed for 12 months (attrition rate: 19.4%), and 480 were included in the EQ-5D analysis. The most common diagnoses were schizophrenia (59%), depression (14%), and bipolar disorder (13%). No patient-reported measures were significantly associated with readmission over the follow-up period. Interaction of readmission and time did not significantly affect changes in EQ-5D. Readmission did significantly influence SDS score changes between T2 and T3 (B = 1.78, 95% CI = 0.30-3.25, p = 0.018) and between T3 and T4 (B = 1.43, 95% CI = 0.14-2.72, p = 0.029). The same influence of readmission on SDS score changes was not observed in the model which adjusted for all potential covariates. CONCLUSION: Readmission was potentially associated with changes in self-reported functional impairment. Findings highlight the potential role of intensive post-discharge services in preventing readmission, rather than relying on time-of-discharge PRMs in order to predict readmission risk. TRIAL REGISTRATION: This study was registered in UMIN Clinical Trials Registry (UMIN000034220).

Prevalence and clinicopathological features of primary age-related tauopathy (PART): A large forensic autopsy study.

INTRODUCTION: Primary age-related tauopathy (PART), often regarded as a minimally symptomatic pathology of old age, lacks comprehensive cohorts across various age groups. METHODS: We examined PART prevalence and clinicopathologic features in 1589 forensic autopsy cases (≥40 years old, mean age ± SD 70.2 ± 14.2 years). RESULTS: PART cases meeting criteria for argyrophilic grain diseases (AGD) were AGD+PART (n = 181). The remaining PART cases (n = 719, 45.2%) were classified as comorbid conditions (PART-C, n = 90) or no comorbid conditions (pure PART, n = 629). Compared to controls (n = 208), Alzheimer's disease (n = 133), and AGD+PART, PART prevalence peaked in the individuals in their 60s (65.5%) and declined in the 80s (21.5%). No significant clinical background differences were found (excluding controls). However, PART-C in patients inclusive of age 80 had a higher suicide rate than pure PART (p < 0.05), and AGD+PART showed more dementia (p < 0.01) and suicide (p < 0.05) than pure PART. DISCUSSION: Our results advocate a reevaluation of the PART concept and its diagnostic criteria. HIGHLIGHTS: We investigated 1589 forensic autopsy cases to investigate the features of primary age-related tauopathy (PART). PART peaked in people in their 60s in our study. Many PART cases over 80s had comorbid pathologies in addition to neurofibrillary tangles pathology. Argyrophilic grain disease and Lewy pathology significantly affected dementia and suicide rates in PART. Our results suggest that the diagnostic criteria of PART need to be reconsidered.

Neuropathology of patients with preclinical or early clinical Alzheimer's disease with pathogenic PSEN1_p. L392V: Comparison of advanced siblings.

INTRODUCTION: Neuropathological investigation of presymptomatic or early symptomatic presenilin-1 (PSEN1) mutation carriers in familial Alzheimer's disease (AD) is extremely scarce. METHODS: We report the autopsy findings of brothers with familial AD. Case 1 is a 45-year-old man without obvious cognitive impairment, who committed suicide. Case 2 is a 57-year-old older brother of Case 1 with advanced AD symptoms, who died of hypothermia during wondering. RESULTS: In both cases, abundant amyloid plaques positive for amyloid ß (Aß) were found throughout the brain. Progression of neuronal loss and increasing amount and extension of neurofibrillary tangle pathology were evident in Case 2. Genetic investigation revealed a PSEN1_p. L392V mutation in both cases. DISCUSSION: The present study shows a possible neuropathological boundary between symptomatic and preclinical AD with pathogenic PSEN1 mutation. Additional clinicopathological investigation for familial AD-related mutation carriers may be significant to explore the association between familial AD and suicide.

Clinicopathological Appearance of Epidermal Growth-Factor-Containing Fibulin-like Extracellular Matrix Protein 1 Deposition in the Lower Gastrointestinal Tract: An Autopsy-Based Study.

This study examined the patterns of epidermal growth-factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) deposition in the small intestine and colon to evaluate the association between the histopathological severity of EFEMP1 deposition and constipation and determine the colocalization of amyloid transthyretin (ATTR) and EFEMP1 deposits. In 40 older cases (≥80 years of age), EFEMP1 deposition in the small intestine initiated in the submucosal and subserous vessels, subserous interstitium, and serosa (early stage), progressing to the muscularis propria and peri-Auerbach plexus area (intermediate stage), and finally spreading diffusely to other areas, excluding the mucosa and muscularis mucosa (advanced stage). The colon had a similar pattern of progression. During the middle-to-advanced stages, amyloid formation was observed in some vascular and serous deposits. A subgroup of cases was identified in which EFEMP1 deposition was the only presumed cause of constipation. Additionally, we demonstrated the colocalization of ATTR and EFEMP1 deposition. Apple-green birefringence was detected under polarized light only in approximately one-half of the cases in the small intestine and one-third of the cases in the colon. These findings strongly suggest that EFEMP1 deposits are correlated with pathological conditions of the lower gastrointestinal tract. As the histopathological diagnosis using Congo red-stained specimens is challenging, the combined use of elastic fiber staining and EFEMP1 immunohistochemistry is recommended to identify EFEMP1 deposition.

Distinctive Deposition Patterns of Sporadic Transthyretin-Derived Amyloidosis in the Atria: A Forensic Autopsy-Based Study.

Left-to-right differences in the histopathologic patterns of transthyretin-derived amyloid (ATTR) deposition in the atria of older adults have not yet been investigated. Hence, this study evaluated heart specimens from 325 serial autopsy subjects. The amount of ATTR deposits in the seven cardiac regions, including both sides of atria and atrial appendages, was evaluated semiquantitatively. Using digital pathology, we quantitatively evaluated the immunohistochemical deposition burden of ATTR in the myocardium. We identified 20 sporadic ATTR cardiac amyloidosis cases (nine males). All patients had ATTR deposition in the left atrial regions of the myocardium. In the semiquantitative analysis, 14 of the 20 cases showed more severe ATTR deposition on the left atrial regions than on the right side, with statistically significant differences in the pathology grading (p < 0.01 for both the atrium and atrial appendage). Quantitative analysis further supported the difference. Moreover, six had ATTR deposition in the epineurium and/or neural fibers of the atria. Cluster analysis revealed that ATTR deposition in the myocardium was significantly more severe in males than in females. The heterogeneous distribution of amyloid deposits between atria revealed in this study may impair the orderly transmission of the cardiac conduction system and induce arrhythmias, which may be further aggravated by additional neuropathy in the advanced phase. This impairment could be more severe among males. These findings emphasize that atrial evaluation is important for individuals with sporadic ATTR cardiac amyloidosis, particularly for early detection.

Molecular Behavior of α-Synuclein Is Associated with Membrane Transport, Lipid Metabolism, and Ubiquitin-Proteasome Pathways in Lewy Body Disease.

Lewy body diseases (LBDs) feature α-synuclein (α-syn)-containing Lewy bodies, with misfolded α-syn potentially propagating as seeds. Using a seeding amplification assay, we previously reported distinct α-syn seeding in LBD cases based on the area under seeding curves. This study revealed that LBD cases showing different α-syn seeding kinetics have distinct proteomics profiles, emphasizing disruptions in mitochondria and lipid metabolism in high-seeder cases. Though the mechanisms underlying LBD development are intricate, the factors influencing α-syn seeding activity remain elusive. To address this and complement our previous findings, we conducted targeted transcriptome analyses in the substantia nigra using the nanoString nCounter assay together with histopathological evaluations in high (n = 4) and low (n = 3) nigral α-syn seeders. Neuropathological findings (particularly the substantia nigra) were consistent between these groups and were characterized by neocortical LBD associated with Alzheimer's disease neuropathologic change. Among the 1811 genes assessed, we identified the top 20 upregulated and downregulated genes and pathways in α-syn high seeders compared with low seeders. Notably, alterations were observed in genes and pathways related to transmembrane transporters, lipid metabolism, and the ubiquitin-proteasome system in the high α-syn seeders. In conclusion, our findings suggest that the molecular behavior of α-syn is the driving force in the neurodegenerative process affecting the substantia nigra through these identified pathways. These insights highlight their potential as therapeutic targets for attenuating LBD progression.

Acute large-vessel occlusion due to an infected thrombus formation induced by invasive sphenoid sinus aspergillosis: illustrative case.

BACKGROUND: The authors describe a rare case of acute large-vessel occlusion due to an infected thrombus formation that was induced by invasive sphenoid sinus aspergillosis. OBSERVATIONS: An 82-year-old man with a history of immunoglobulin G4-related disease and long-term use of steroids and immunosuppressants was admitted to the authors' hospital with severe right hemiparesis. Cerebral angiography revealed occlusion of the left internal carotid artery (ICA). He underwent thrombectomy, resulting in successful recanalization. However, severe stenosis was evident in the left ICA cavernous segment. Pathological analysis of the retrieved thrombus identified Aspergillus. Postoperative magnetic resonance imaging revealed sinusitis in the left sphenoid sinus as a possible source of the infection. The patient's general condition deteriorated during the course of hospitalization due to refractory aspiration pneumonia, and he died 46 days after thrombectomy. Pathological autopsy and histopathological investigation of the left ICA and the left sphenoid sinus showed that Aspergillus had invaded the wall of the left ICA from the adjacent sphenoid sinus. These findings indicate a diagnosis of acute large-vessel occlusion due to infected thrombus formation induced by invasive sphenoid sinus aspergillosis. LESSONS: Pathological analysis of a retrieved thrombus appears useful for identifying rare stroke etiologies such as fungal infection.

The molecular spectrum of amyloid-beta (Aß) in neurodegenerative diseases beyond Alzheimer's disease.

This study investigated the molecular spectrum of amyloid-beta (Aß) in neurodegenerative diseases beyond Alzheimer's disease (AD). We analyzed Aß deposition in the temporal cortex and striatum in 116 autopsies, including Lewy body disease (LBD; N = 51), multiple system atrophy (MSA; N = 10), frontotemporal lobar degeneration-TDP-43 (FTLD-TDP; N = 16), and progressive supranuclear palsy (PSP; N = 39). The LBD group exhibited the most Aß deposition in the temporal cortex and striatum (90/76%, respectively), followed by PSP (69/28%), FTLD-TDP (50/25%), and the MSA group (50/10%). We conducted immunohistochemical analysis using antibodies targeting eight Aß epitopes in the LBD and PSP groups. Immunohistochemical findings were evaluated semi-quantitatively and quantitatively using digital pathology. Females with LBD exhibited significantly more severe Aß deposition, particularly Aß42 and Aß43 , along with significantly more severe tau pathology. Furthermore, a quantitative analysis of all Aß peptides in the LBD group revealed an association with the APOE-ε4 genotypes. No significant differences were observed between males and females in the PSP group. Finally, we compared striatal Aß deposition in cases with LBD (N = 15), AD without α-synuclein pathology (N = 6), and PSP (N = 5). There were no differences in the pan-Aß antibody (6F/3D)-immunolabeled deposition burden among the three groups, but the deposition burden of peptides with high aggregation capacity, especially Aß43 , was significantly higher in the AD and LBD groups than in the PSP group. Furthermore, considerable heterogeneity was observed in the composition of Aß peptides on a case-by-case basis in the AD and LBD groups, whereas it was relatively uniform in the PSP group. Cluster analysis further supported these findings. Our data suggest that the type of concomitant proteinopathies influences the spectrum of Aß deposition, impacted also by sex and APOE genotypes.

Successful carotid stenting of a carotid arterial dissection after straightening the tortuosity using an inflated balloon guiding catheter and the delivery wire of an anchored stent retriever.

The authors present a patient with carotid dissection in a tortuous arterial segment who successfully underwent carotid artery stenting (CAS) by straightening the tortuosity using an inflated balloon guiding catheter (BGC) and a stent retriever (SR). A 56-year-old man was transferred to our institute with right hemiparesis and a National Institutes of Health Stroke Scale score of 9. Magnetic resonance imaging showed left internal carotid artery (ICA) occlusion and ischemic change in the parietal lobe. Emergent angiography revealed tapered extracranial ICA occlusion sugg carotid artery dissection (CAD). CAS was attempted for CAD due to a mismatch of the motor area on clinical imaging. However, several attempts to navigate the stent delivery system over a guidewire failed. Therefore, we deployed a Trevo NXT ProVue SR (3 × 32 mm) in the middle cerebral artery, inflated a BGC, and then pulled on both to straighten the tortuous carotid artery, which resulted in successful navigation of the stent delivery system. The patient's symptoms improved after the recanalization. This case demonstrates the utility of a technique for navigation of a stent delivery system through a tortuous carotid artery in which the tortuosity is straightened by pulling on an inflated BGC and the delivery wire of the SR.

Short repetition time diffusion-weighted imaging improves visualization of prostate cancer.

PURPOSE: This study aimed to assess whether short repetition time (TR) diffusion-weighted imaging (DWI) could improve diffusion contrast in patients with prostate cancer (PCa) compared with long TR (conventional) reference standard DWI. MATERIALS AND METHODS: Our Institutional Review Board approved this retrospective study and waived the need for informed consent. Twenty-five patients with suspected PCa underwent multiparametric magnetic resonance imaging (mp-MRI) using a 3.0-T system. DWI was performed with TR of 1850 ms (short) and 6000 ms (long) with b-values of 0, 1000, and 2000s/mm2. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), visual score, apparent diffusion coefficient (ADC), and diagnostic performance were compared between short and long TR DWI for both b-values. The statistical tests included paired t-test for SNR and CNR; Wilcoxon signed-rank test for VA; Pearson's correlation and Bland-Altman plot analysis for ADC; and McNemar test and receiver operating characteristic analysis and Delong test for diagnostic performance. RESULTS: Regarding b1000, CNR and visual score were significantly higher in short TR compared with long TR (P = .003 and P = .002, respectively), without significant difference in SNR (P = .21). Considering b2000, there was no significant difference in visual score between short and long TR (P = .07). However, SNR and CNR in long TR were higher (P = .01 and P = .04, respectively). ADC showed significant correlations, without apparent bias for ADC between short and long TR for both b-values. For diagnostic performance of DWI between short and long TR for both b-values, one out of five readers noted a significant difference, with the short TR for both b-values demonstrating superior performance. CONCLUSIONS: Our data showed that the short TR DWI1000 may provide better image quality than did the long TR DWI1000 and may improve visualization and diagnostic performance of PCa for readers.

Multiple system atrophy with amyloid-ß-predominant Alzheimer's disease neuropathologic change.

Multiple system atrophy is a neurodegenerative disease with α-synuclein pathology predominating in the striatonigral and olivopontocerebellar systems. Mixed pathologies are considered to be of low frequency and mostly comprise primary age-related tauopathy or low levels of Alzheimer's disease-related neuropathologic change. Therefore, the concomitant presence of different misfolded proteins in the same brain region is less likely in multiple system atrophy. During the neuropathological evaluation of 21 consecutive multiple system atrophy cases, we identified four cases exhibiting an unusual discrepancy between high Thal amyloid-ß phase and low transentorhinal Braak neurofibrillary tangle stage. We mapped α-synuclein pathology, measured the size and number of glial cytoplasmic inclusions and compared the amyloid-ß peptides between multiple system atrophy and Alzheimer's disease. In addition, we performed α-synuclein seeding assay from the affected putamen samples. We performed genetic testing for APOE, MAPT, PSEN1, PSEN2 and APP. We refer to the four multiple system atrophy cases with discrepancy between amyloid-ß and tau pathology as 'amyloid-ß-predominant Alzheimer's disease neuropathologic change-multiple system atrophy' to distinguish these from multiple system atrophy with primary age-related tauopathy or multiple system atrophy with typical Alzheimer's disease neuropathologic change. As most multiple system atrophy cases with mixed pathologies reported in the literature, these cases did not show a peculiar clinical or MRI profile. Three amyloid-ß-predominant Alzheimer's disease neuropathologic change-multiple system atrophy cases were available for genetic testing, and all carried the APOE ɛ4 allele. The extent and severity of neuronal loss and α-synuclein pathology were not different compared with typical multiple system atrophy cases. Analysis of amyloid-ß peptides revealed more premature amyloid-ß plaques in amyloid-ß-predominant Alzheimer's disease neuropathologic change-multiple system atrophy compared with Alzheimer's disease. α-Synuclein seeding amplification assay showed differences in the kinetics in two cases. This study highlights a rare mixed pathology variant of multiple system atrophy in which there is an anatomical meeting point of amyloid-ß and α-synuclein, i.e. the striatum or cerebellum. Since biomarkers are entering clinical practice, these cases will be recognized, and the clinicians have to be informed that the prognosis is not necessarily different than in pure multiple system atrophy cases but that the effect of potential α-synuclein-based therapies might be influenced by the co-presence of amyloid-ß in regions where α-synuclein also aggregates. We propose that mixed pathologies should be interpreted not only based on differences in the clinical phenotype but also on whether protein depositions regionally overlap, potentially leading to a different response to α-synuclein-targeted therapies.