Combining plasma Aß and p-tau217 improves detection of brain amyloid in non-demented elderly.

BACKGROUND: Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer's disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-ß (Aß)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aß-positron emission tomography (PET) in the preclinical and prodromal AD. METHODS: We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study. J-TRC included 474 non-demented individuals (CDR 0: 331, CDR 0.5: 143). Participants underwent plasma Aß and p-tau217 assessments, and Aß-PET imaging. Findings in J-TRC were replicated in the BioFINDER cohort including 177 participants (cognitively unimpaired: 114, mild cognitive impairment: 63). In both cohorts, plasma Aß(1-42) (Aß42) and Aß(1-40) (Aß40) were measured using immunoprecipitation-MALDI TOF mass spectrometry (Shimadzu), and p-tau217 was measured with an immunoassay on the Meso Scale Discovery platform (Eli Lilly). RESULTS: Aß-PET was abnormal in 81 participants from J-TRC and 71 participants from BioFINDER. Plasma Aß42/Aß40 ratio and p-tau217 individually showed moderate to high accuracies when detecting abnormal Aß-PET scans, which were improved by combining plasma biomarkers and by including age, sex and APOE genotype in the models. In J-TRC, the highest AUCs were observed for the models combining p-tau217/Aß42 ratio, APOE, age, sex in the whole cohort (AUC = 0.936), combining p-tau217, Aß42/Aß40 ratio, APOE, age, sex in the CDR 0 group (AUC = 0.948), and combining p-tau217/Aß42 ratio, APOE, age, sex in the CDR 0.5 group (AUC = 0.955), respectively. Each subgroup results were replicated in BioFINDER, where the highest AUCs were seen for models combining p-tau217, Aß42/40 ratio, APOE, age, sex in cognitively unimpaired (AUC = 0.938), and p-tau217/Aß42 ratio, APOE, age, sex in mild cognitive impairment (AUC = 0.914). CONCLUSIONS: Combination of plasma Aß-related biomarkers and p-tau217 exhibits high performance when predicting Aß-PET positivity. Adding basic clinical information (i.e., age, sex, APOE Îµ genotype) improved the prediction in preclinical AD, but not in prodromal AD. Combination of Aß-related biomarkers and p-tau217 could be highly useful for pre-screening of participants in clinical trials of preclinical and prodromal AD.

Assessment of Gray Matter Microstructural Alterations in Alzheimer's Disease by Free Water Imaging.

Background: Cortical neurodegenerative processes may precede the emergence of disease symptoms in patients with Alzheimer's disease (AD) by many years. No study has evaluated the free water of patients with AD using gray matter-based spatial statistics. Objective: The aim of this study was to explore cortical microstructural changes within the gray matter in AD by using free water imaging with gray matter-based spatial statistics. Methods: Seventy-one participants underwent multi-shell diffusion magnetic resonance imaging, 11C-Pittsburgh compound B positron emission tomography, and neuropsychological evaluations. The patients were divided into two groups: healthy controls (n = 40) and the AD spectrum group (n = 31). Differences between the groups were analyzed using voxel-based morphometry, diffusion tensor imaging, and free water imaging with gray matter-based spatial statistics. Results: Voxel-based morphometry analysis revealed gray matter volume loss in the hippocampus of patients with AD spectrum compared to that in controls. Furthermore, patients with AD spectrum exhibited significantly greater free water, mean diffusivity, and radial diffusivity in the limbic areas, precuneus, frontal lobe, temporal lobe, right putamen, and cerebellum than did the healthy controls. Overall, the effect sizes of free water were greater than those of mean diffusivity and radial diffusivity, and the larger effect sizes of free water were thought to be strongly correlated with AD pathology. Conclusions: This study demonstrates the utility of applying voxel-based morphometry, gray matter-based spatial statistics, free water imaging and diffusion tensor imaging to assess AD pathology and detect changes in gray matter.

Ectopic Hepatocellular Carcinoma in the Gallbladder Wall With Choledocholithiasis: A Case Report.

An ectopic hepatocellular carcinoma (HCC) that originates from the ectopic liver is defined as a hepatic organ or tissue not conventionally linked to surrounding tissues. Ectopic HCC has a rare clinical incidence, and diagnosing it before surgery is challenging. Its characteristics and biological behavior have not been fully elucidated. This report presents a unique case of ectopic HCC in the gallbladder, discontinuous with the liver. A 74-year-old man was referred to our hospital after primarily complaining of fever and right hypochondrium pain. Plain computed tomography revealed a significantly thickened gallbladder wall containing fluid collection and incarceration of gallstone in the common bile duct. He was diagnosed with acute cholecystitis and obstructive cholangitis due to choledocholithiasis. After percutaneous transhepatic gallbladder drainage and endoscopic lithotomy for choledocholithiasis, a cholecystectomy was performed. Macroscopically, the resected gallbladder had a yellowish tumor (1 cm) within the significantly thickened gallbladder wall. Histopathological examination identified moderately differentiated HCC on the ectopic liver, discontinuous with the liver. Immunohistologically, the tumor was finally diagnosed as ectopic HCC with alpha-fetoprotein positive expression.

Relationship between the tau protein and choroid plexus volume in Alzheimer's disease.

Tau protein accumulation in the brain is thought to be one of the causes of Alzheimer's disease (AD). Recent studies found that the choroid plexus (CP) has a role in ß-amyloid and tau protein clearance in the brain. We evaluated the relationships between CP volume and the ß-amyloid and tau protein depositions. Participants were 20 patients with AD and 35 healthy subjects who underwent MRI and PET scanning using the ß-amyloid tracer 11C-PiB and the tau/inflammatory tracer 18F-THK5351. We computed the volume of the CP and estimated the relationships between the CP volume and ß-amyloid and tau protein/inflammatory deposition by Spearman's correlation test. The CP volume was significantly positively correlated with both the standardized uptake value ratio (SUVR) of 11C-PiB and the SUVR of 18F-THK5351 in all participants. The CP volume was also significantly positively correlated with the SUVR of 18F-THK5351in patients with AD. Our data suggested that the volume of the CP was a good biomarker for the evaluation of tau deposition and neuroinflammation.

Refractory Choledocholithiasis Causing Endogenous Endophthalmitis: A Case Report.

BACKGROUND Endogenous bacterial endophthalmitis is caused by a breach of the blood-ocular barrier by pathogens originating from distant infective foci. Here, we report a case of endogenous endophthalmitis due to cholangitis complicated by common bile duct stones, which is a rare source of infection. CASE REPORT A 73-year-old man with type II diabetes mellitus underwent endoscopic choledocholithotripsy 20 years ago and laparoscopic cholecystectomy 18 years ago. He had choledocholith-related cholangitis 6, 5, and 1 years previously and 4 times in the last year and underwent endoscopic choledocholithotripsy each time. Three days after the last surgery, the patient developed right endogenous endophthalmitis and vitrectomy was performed. Four months later, the patient relapsed with cholangitis and required surgery for recurrent endophthalmitis. Roux-en-Y choledochojejunostomy was performed with curative intent, and the patient was followed up for 5 years without recurrence of choledocholith, cholangitis, or endophthalmitis. CONCLUSIONS The recommended treatment strategy for patients diagnosed with common bile duct stones or choledocholithiasis is stone extraction. Endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic intervention is a widely accepted procedure. However, in cases of recurrent choledocholithiasis, the rate of recurrence increases and the interval between ERCP becomes shorter in proportion to the number of recurrences. In such intractable cases requiring numerous sessions of endoscopic stone removal, bypass Roux-en-Y choledochojejunostomy should be performed to prevent possible rare complications such as endogenous bacterial endophthalmitis.

BMP4-SMAD1/5/9-RUNX2 pathway activation inhibits neurogenesis and oligodendrogenesis in Alzheimer's patients' iPSCs in senescence-related conditions.

In addition to increasing ß-amyloid plaque deposition and tau tangle formation, inhibition of neurogenesis has recently been observed in Alzheimer's disease (AD). This study generated a cellular model that recapitulated neurogenesis defects observed in patients with AD, using induced pluripotent stem cell lines derived from sporadic and familial AD (AD iPSCs). AD iPSCs exhibited impaired neuron and oligodendrocyte generation when expression of several senescence markers was induced. Compound screening using these cellular models identified three drugs able to restore neurogenesis, and extensive morphological quantification revealed cell-line- and drug-type-dependent neuronal generation. We also found involvement of elevated Sma- and Mad-related protein 1/5/9 (SMAD1/5/9) phosphorylation and greater Runt-related transcription factor 2 (RUNX2) expression in neurogenesis defects in AD. Moreover, BMP4 was elevated in AD iPSC medium during neural differentiation and cerebrospinal fluid of patients with AD, suggesting a BMP4-SMAD1/5/9-RUNX2 signaling pathway contribution to neurogenesis defects in AD under senescence-related conditions.

[Laparoscopic Splenectomy for Metachronous Splenic Metastasis of Fallopian Tube Cancer with Synchronous Rectal Metastasis-A Case Report].

A 59-year-old woman underwent simple abdominal total hysterectomy with bilateral salpingo-oophorectomy, partial omentectomy, and extirpation of intrapelvic disseminated nodules for right fallopian tube cancer with rectal metastasis and peritoneal dissemination as primary debulking surgery(PDS). The histopathological diagnosis was high grade serous carcinoma( HGSC)of the right fallopian tube. After adjuvant chemotherapy with 4 courses of paclitaxel-carboplatin(TC), low anterior resection of the rectum for rectal metastasis and pelvic and para-aortic lymph node dissection were performed as interval debulking surgery(IDS). Histopathologically, lymph node metastasis was detected only in the right obturator lymph node. After adjuvant chemotherapy with 4 courses of TC, bevacizumab maintenance monotherapy was administered. Three years after PDS, laparoscopic splenectomy for splenic metastasis and extirpation of the solitary peritoneal metastases were performed as secondary debulking surgery(SDS). After adjuvant chemotherapy with 4 courses of TC, olaparib maintenance monotherapy was administered. The patient has remained alive without recurrence for 4 years after SDS and for 7 years after PDS. No case of metachronous splenic metastasis from fallopian tube cancer with synchronous rectal metastasis has been reported; however, long-term prognosis may be expected with PDS, IDS and SDS for platinum-sensitive HGSC.

[Neuroendocrine Carcinoma of the Non-Ampullary Duodenum-A Case Report].

A 69-year-old woman was admitted to a territory hospital because of severe right hypochondoralgia after 2 weeks of internal medicine for persistent epigastralgia. Gastroduodenal endoscopy revealed a large tumor with a fistula in the duodenal bulb that expanded to the stomach. Histopathologically, the biopsy specimen indicated a poorly differentiated adenocarcinoma and HER2 negative. Computed tomography revealed that the tumor invaded the left lobe of the liver. The patient was referred to our hospital for cancer treatment. After 1 course of chemotherapy with S-1 and CDDP, laparoscopic gastroenterostomy bypass was performed because of tumor hemorrhage and poor food intake. However, the tumor hemorrhage and poor food intake continued, and the tumor enlarged. Therefore, left hemihepatectomy and distal gastrectomy with resection of the duodenal bulb were performed 1 month after bypass surgery. Histological testing confirmed the diagnosis of duodenal large-cell neuroendocrine carcinoma invading the liver without lymph node metastasis. Adjuvant chemotherapy was not administered, and the patient has been alive without recurrence for 7 years and 3 months. Neuroendocrine carcinoma of the non-ampullary duodenum is very rare; however, a large cell type without lymph node metastasis may be a factor in the long-term prognosis.

Free water derived by multi-shell diffusion MRI reflects tau/neuroinflammatory pathology in Alzheimer's disease.

Introduction: Free-water (FW) imaging, a new analysis method for diffusion magnetic resonance imaging (MRI), can indicate neuroinflammation and degeneration. We evaluated FW in Alzheimer's disease (AD) using tau/inflammatory and amyloid positron emission tomography (PET). Methods: Seventy-one participants underwent multi-shell diffusion MRI, 18F-THK5351 PET, 11C-Pittsburgh compound B PET, and neuropsychological assessments. They were categorized into two groups: healthy controls (HCs) (n = 40) and AD-spectrum group (AD-S) (n = 31) using the Centiloid scale with amyloid PET and cognitive function. We analyzed group comparisons in FW and PET, correlations between FW and PET, and correlation analysis with neuropsychological scores. Results: In AD-S group, there was a significant positive correlation between FW and 18F-THK5351 in the temporal lobes. In addition, there were negative correlations between FW and cognitive function in the temporal lobe and cingulate gyrus, and negative correlations between 18F-THK5351 and cognitive function in the same regions. Discussion: FW imaging could be a biomarker for tau in AD alongside clinical correlations.

Relationships Between the Deposition of Amyloid-ß and Tau Protein and Glymphatic System Activity in Alzheimer's Disease: Diffusion Tensor Image Study.

BACKGROUND: Amyloid-ß (Aß) and tau protein accumulation in the brain is thought to be one of the causes of Alzheimer's disease (AD). Recent study found that the glymphatic system was waste drainage system in the brain and promoting the elimination of Aß and tau protein. OBJECTIVE: We evaluated the relationships between the glymphatic system activity and the Aß and tau protein deposition. METHODS: Subjects were 21 patients with AD and 36 healthy subjects who underwent diffusion tensor imaging (DTI) scan and the positron emission tomography (PET) using with the Aß tracer: 11C-PiB and the tau/inflammatory tracer: 18F-THK5351. We computed diffusion tensor image analysis along the perivascular space (DTI-ALPS) index as the proxy of glymphatic system activity, and estimated the relationships between the DTI-ALPS index and Aß and tau protein/inflammatory deposition. RESULTS: We found significant negative correlations between DTI-ALPS index and the standard uptake value ratio (SUVR) of 11C-PiB in the bilateral temporal and left parietal cortices and left posterior cingulate gyrus in all subjects. Further, we detected significant negative correlations between DTI-ALPS index and the SUVR of 18F-THK5351 in the bilateral temporal cortices and right parietal cortex in all participants, too. CONCLUSION: Our data suggested that DTI-ALPS index was a good biomarker for the evaluation of Aß and tau deposition and neuroinflammation, and this marker might be effective to estimate the glymphatic system activity.

Combination of Astrogliosis and Phosphorylated Tau for the Preclinical Diagnosis of Alzheimer Disease Using 3-Dimensional Stereotactic Surface Projection Images With 18 F-THK5351.

ABSTRACT: The Alzheimer disease (AD) brain is characterized microscopically by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles consisting of phosphorylated tau aggregations. 18 F-THK5351 is a first-generation PET tau tracer that also binds to monoamine oxidase B, which represents astrogliosis, and is useful to evaluate some non-AD neurodegenerative disorders. We examined the utility of 18 F-THK5351 in preclinical AD using 3-dimensional stereotactic surface projection images optimized for its pathological accumulation by comparison with a normal dataset. By using this 18 F-THK5351 3-dimensional stereotactic surface projection procedure, which can evaluate phosphorylated tau and neuroinflammation, we could diagnose preclinical AD effectively.

[Synchronous Double Primary Non-B, and Non-C Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma-A Case Report].

A 78-year-old man without hepatitis virus B or C underwent right hemi-hepatectomy and lymph node dissection for a tumor 5 cm in diameter located in the hepatic hilum of the posterior segment of the liver with portal vein thrombi extending into the main portal trunk and a tumor 1.5 cm in diameter in the peripheral side of segment 5 of the liver. Histopathologically, the former was diagnosed as intrahepatic cholangiocarcinoma and the latter as hepatocellular carcinoma(HCC). Five months after the surgery, intrahepatic and lymph node metastases were diagnosed based on computed tomography(CT); therefore, chemotherapy with S-1 for 3 months and gemcitabine and cisplatin(GC)for 5 months was administered, after which the metastatic lesions were not detected. Nineteen months after the surgery, partial resection of segment 2 of the liver was performed for a tumor 3 cm in diameter, which was diagnosed as HCC histopathologically. Two years after the second surgery, 2 recurrent nodules in the liver in segments 3 and 4 were detected on CT. Platinum-based hepatic arterial infusion chemotherapy(HAIC)and transcatheter arterial chemoembolization(TACE)were performed, and chemotherapy with GC was then administered for 7 months. For a new tumor detected in segment 1 in the liver, TACE was performed 17 months after initial HAIC. Seventy-four months after the initial surgery, 5 new nodules less than 1 cm in diameter were detected, and chemotherapy with sorafenib was administered for 5 months, after which the patient died of coronavirus disease 2019.

Methionine homozygosity for PRNP polymorphism and susceptibility to human prion diseases.

BACKGROUND: No studies have assessed the independent association of methionine homozygosity at codon 129 with the susceptibility to prion diseases, controlling for the effects of the codon 219 polymorphisms and other potential confounders, using a large-scale population-based dataset. METHODS: We conducted a case-control study using a Japanese nationwide surveillance database for prion diseases. The main exposure was methionine homozygosity at codon 129, and the outcome was development of prion diseases. Multivariable logistic regression models were employed for specific disease subtypes (sporadic Creutzfeldt-Jakob disease (CJD), genetic CJD and Gerstmann-Sträussler-Scheinker disease (GSS)). RESULTS: Of 5461 patients registered in the database, 2440 cases and 796 controls remained for the analysis. The cases comprised 1676 patients with sporadic CJD (69%), 649 with genetic CJD (27%) and 115 with GSS (5%). For patients with methionine homozygosity, potential risk for occurring prion diseases: adjusted OR (95% CI) was 2.21 (1.46 to 3.34) in sporadic CJD, 0.47 (0.32 to 0.68) in genetic CJD and 0.3 (0.17 to 0.55) in GSS. Among patients with specific prion protein abnormalities, the potential risk was 0.27 (0.17 to 0.41) in genetic CJD with 180 Val/Ile, 1.66 (0.65 to 5.58) in genetic CJD with 200 Glu/Lys, 3.97 (1.2 to 24.62) in genetic CJD with 232 Met/Arg and 0.71 (0.34 to 1.67) in GSS with 102 Pro/Leu. CONCLUSIONS: Methionine homozygosity at codon 129 was predisposing to sporadic CJD, but protective against genetic CJD and GSS, after adjustment for codon 219 polymorphism effect. However, the impacts differed completely among patients with specific prion protein abnormalities.

Laparoscopic lithotripsy and lithotomy of impacted stone at the terminal end of the common bile duct using a laparotomy biliary lithotomy spoon: A case report.

INTRODUCTION AND IMPORTANCE: Endoscopic intervention is considered first-line therapy for common bile duct (CBD) stones, in recent times. However, surgically altered anatomy and consequent inaccessibility of the duodenal papilla necessitate surgery in some patients. CASE PRESENTATION: A 61-year-old woman presented with fever and right subcostal pain. She underwent total gastrectomy and Roux-en-Y reconstruction for gastric ulcer, 4 years prior to presentation. Based on the clinical findings, she was diagnosed with acute obstructive cholangitis secondary to a CBD stone. Endoscopic retrograde biliary drainage was attempted; however, the duodenal papilla was endoscopically inaccessible owing to the previous Roux-en-Y reconstruction, and we performed percutaneous transhepatic gallbladder drainage (PTGBD). She underwent laparoscopic cholecystectomy and choledocholithotomy, 6 days after the PTGBD. Choledocholithotomy was attempted using basket forceps under choledochoscopic guidance; however, this procedure was unsuccessful, and we performed laparoscopic choledocholithotomy using a laparotomy biliary lithotomy spoon. CLINICAL DISCUSSION: Usually, laparoscopic cholecystectomy concomitant with CBD exploration is performed in patients with an endoscopically inaccessible duodenal papilla. However, an inadequately opened basket may not capture large impacted stones at the duodenal end of the CBD. Intraductal shock wave lithotripsy (electrohydraulic or laser lithotripsy) is considered in such cases; however, the specialized instruments required for this procedure are unavailable at all centers. Laparoscopic choledocholithotomy using a laparotomy biliary lithotomy spoon may be useful to overcome this surgically challenging situation. CONCLUSION: A laparotomy biliary lithotomy spoon is a simple, user-friendly, and economical device that may be useful for laparoscopic lithotripsy and lithotomy of impacted stones.

[Surgical Resection of Pulmonary Oligometastases of Ampullary Cancer-A Case Report and Review of Seven Cases].

A 62-year-old woman underwent a subtotal stomach-preserving pancreatoduodenectomy for ampullary carcinoma (T3bN0M0, Stage Ⅱb). Histopathologically, the tumor was a tubular adenocarcinoma with mixed features, predominantly the intestinal type, following which adjuvant chemotherapy was not performed. Computed tomography performed 32 months after surgery showed a tumor measuring 6.7 mm in diameter at the apex of the right lung. The tumor had gradually increased in size and measured 10 mm in diameter, 47 months postoperatively. Since other metastatic lesions were absent, partial resection of the right lung under video-assisted thoracic surgery was performed 48 months postoperatively. Histopathological testing confirmed a diagnosis of lung metastasis from the resected specimen of ampullary carcinoma without mediastinal lymph node metastasis. Adjuvant chemotherapy was not performed, and recurrence was not observed even after 53 months following the partial lung resection. Previously, 7 resected cases of solitary lung metastasis from ampullary cancer have been reported. The histopathological sub-type of these 7 cases were intestinal type in 5 and pancreatobiliary type in 2 cases, respectively. No mortality or recurrence was observed for 8-119 months in any of the 7 cases(median, 19 months). In conclusion, owing to the good prognosis, solitary lung metastasis from an ampullary cancer can be classified as an oligometastatic disease, based on the concept proposed by Hellman and Weichselbaum.

Soluble APP-α and APP-ß in cerebrospinal fluid as potential biomarkers for differential diagnosis of mild cognitive impairment.

OBJECTIVES: Concentrations of soluble amyloid precursor proteins-α (sAPPα) and -ß (sAPPß) in cerebrospinal fluid (CSF) may reflect the neuropathology of Alzheimer's disease (AD). We previously reported that the concentrations of both sAPPα and sAPPß were significantly higher in patients with mild cognitive impairment (MCI) due to AD (MCI-AD) than in control subjects without cognitive impairment. The present study analyzed whether these sAPPs are useful in the differential diagnosis of MCI. METHODS: A modified and sensitive method was used to analyze concentrations of sAPPα and sAPPß in CSF of patients with MCI-AD (n = 30) and MCI due to other causes (MCI-others) (n = 24). Phosphorylated tau (p-tau) and amyloid ß-protein 42 (Aß42) were also analyzed using standard methods. RESULTS: CSF concentrations of sAPPα and sAPPß were significantly higher in the MCI-AD than in the MCI-others group (p < 0.001). Furthermore, concentrations of both sAPPα and sAPPß were highly correlated with the concentration of p-tau, consistent with our previous report. CONCLUSIONS: Measurement of both sAPPs in CSF using sensitive methods can be helpful in the precise differential diagnosis of patients with MCI.