Exacerbation of delirium and epileptic seizures in an older man with idiopathic Parkinson's disease due to multiple prescriptions: a case report.

Introduction: Parkinson's disease (PD) is a disorder characterized by motor symptoms, such as rigidity, akinesia, and resting tremor, as well as non-motor symptoms, including psychiatric manifestations and autonomic failure. The prevalence of PD increases with age, and the condition is more common in men than in women. Conversely, polypharmacy has emerged as a paramount medical concern, especially among older patients, correlating with medicines' adverse effects, interactions between medicines, frequent admissions to the hospital, and a high risk of morbidity and mortality. Case description: We encountered an older male patient with idiopathic PD and mild renal dysfunction. Originally prescribed 14 types of medicines, including anti-PD drugs, the patient developed delirium and epileptic seizures during hospitalization. After reducing the number of medications, including amantadine, the symptoms significantly improved. This clinical course suggests that polypharmacy, in addition to PD itself, poses a significant risk of delirium and epileptic seizures, even in patients with mild renal dysfunction. Conclusion: This report is indicative of the risk of polypharmacy and highlights the importance of citing drug interactions for a correct diagnosis in patients presenting with complex symptoms.

Case report: A case of piriformis pyomyositis and pyogenic sacroiliitis due to non-typhoidal Salmonella bacteremia in an immunocompetent healthy adult.

Non-typhoidal Salmonella (NTS) rarely causes bacteremia and subsequent focal infections as an extraintestinal complication, even in immunocompetent adults. A 25-year-old man was hospitalized for several days with difficulty moving due to fever, acute buttock pain, and shivering. He had no recent or current respiratory symptoms and no clear gastrointestinal symptoms. Physical examination revealed mild redness around the left buttock and difficulty raising the left lower extremity due to pain, in addition to which blood tests showed high levels of inflammatory markers. His clinical course and laboratory findings suggested sepsis, and magnetic resonance imaging revealed a high-intensity area in the left piriformis muscle on diffusion-weighted imaging; therefore, acute piriformis pyomyositis was strongly suggested. Cephazolin was started upon hospitalization; however, blood and stool cultures proved positive for NTS, and the antibiotics were changed to ceftriaxone. Follow-up MRI showed a signal in the left piriformis muscle and newly developed left pyogenic sacroiliitis. On the 25th hospital day, a colonoscopy was performed to identify the portal of entry for bacteremia, which revealed a longitudinal ulcer in the sigmoid colon in the healing process. His buttock pain gradually improved, and the antibiotics were switched to oral levofloxacin, which enabled him to continue treatment in an outpatient setting. Finally, the patient completed seven weeks of antimicrobial therapy and returned to daily life without leaving any residual disability. Invasive NTS infection due to bacteremia is rare among immunocompetent adults. Piriformis pyomyositis and subsequent pyogenic sacroiliitis should be added to the differential diagnosis of acute febrile buttock pain. In the case of NTS bacteremia, the entry site must be identified for source control. Additionally, the background of the host, especially in such an immunocompetent case, needs to be clarified; therefore, the patient should be closely examined.

Amyloid accumulation in cases of suspected comorbid cerebral amyloid angiopathy and isolated cortical venous thrombosis.

BACKGROUND AND AIM: The differentiation of isolated cortical venous thrombosis (ICVT) from cerebral amyloid angiopathy (CAA) can be difficult because both diseases share similar neurological symptoms and imaging findings. N-methyl-11C-2-(4'-methylaminophenyl)-6-hydroxybenzo-thiazole (11C-PiB) positron emission tomography (PET) functions as a diagnostic modality for CAA by detecting amyloid deposition. The present prospective study evaluated amyloid deposition using 11C-PiB-PET in consecutive patients with suspected ICVT. METHOD: This study was a prospective observational study. Patients who attended or were hospitalized between May 2019 and March 2020 were included in the analysis. Consecutive patients who met the criteria for suspicion of ICVT were enrolled in the study, and the clinical course, symptoms, imaging findings (including magnetic resonance imaging), and the 11C-PiB-PET findings of each case were analyzed. RESULTS: The study cohort included four patients (64-82 years of age, all women). In one younger patient, 11C-PiB-PET afforded no findings suggestive of CAA, whereas the remaining three patients exhibited 11C-PiB-PET findings suggestive of CAA. CONCLUSION: Although 11C-PiB-PET would be a reasonable modality for distinguishing ICVT from CAA, especially in younger patients, it might be difficult to differentiate ICVT from CAA in elderly patients because of the potential deposition of amyloid. CLINICAL TRIAL REGISTRATION: URL: https://www.umin.ac.jp/ctr/ Unique identifier: UMIN 000037101.

Case Report: A case of TAFRO syndrome with severe and prolonged thrombocytopenia: diagnostic pitfalls.

Thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome is a rare condition with diverse clinical and pathological characteristics related to multi-organ damage. We report a case of TAFRO syndrome complicated by immune thrombocytopenia with prolonged fever and thrombocytopenia for several weeks. A 61-year-old man was transferred with sepsis caused by Enterococcus faecalis, and developed disseminated intravascular coagulation. Antibiotics treatment was initiated: however, low-grade fever and thrombocytopenia persisted despite the adequate antimicrobial treatment. Systemic edema, pleural effusion, and ascites had developed before hospitalization, and renal and liver function had deteriorated, resulting in progressive multi-organ damage. Prednisolone 40 mg/day was initiated based on the assumption of a condition in which excessive production of inflammatory cytokines would lead to systemic deterioration and fatal organ damage. Subsequently, the fever resolved, and renal function began to normalize. However, thrombocytopenia did not show much recovery trend after Helicobacter pylori eradication therapy and initiation of thrombopoietin receptor agonists. Bone marrow biopsy results showed normal bone marrow with no malignant findings. Alternatively, significant clinical signs met the diagnostic criteria for TAFRO syndrome, and a renal biopsy revealed thrombotic microangiopathy, which is also reasonable for renal involvement in TAFRO syndrome. The use of cyclosporine remarkably corrected the thrombocytopenia. We considered this a case of TAFRO syndrome that developed after sepsis with disseminated intravascular coagulation and performed the differential diagnosis of prolonged thrombocytopenia and excluded it. Although TAFRO syndrome is a unique disease concept, diagnostic criteria may consist of nonspecific elements such as generalized edema, thrombocytopenia, persistent fever, and elevated inflammatory response, and there are many differential conditions to exclude, requiring caution in diagnosing TAFRO syndrome.

Correction: Hoshi et al. High Correlation among Brain-Derived Major Protein Levels in Cerebrospinal Fluid: Implication for Amyloid-Beta and Tau Protein Changes in Alzheimer's Disease. Metabolites 2022, 12, 355.

In the original publication [...].

Brain-Derived Major Glycoproteins Are Possible Biomarkers for Altered Metabolism of Cerebrospinal Fluid in Neurological Diseases.

Cerebrospinal fluid (CSF) plays an important role in the homeostasis of the brain. We previously reported that CSF major glycoproteins are biosynthesized in the brain, i.e., lipocalin-type prostaglandin D2 synthase (L-PGDS) and transferrin isoforms carrying unique glycans. Although these glycoproteins are secreted from distinct cell types, their CSF levels have been found to be highly correlated with each other in cases of neurodegenerative disorders. The aim of this study was to examine these marker levels and their correlations in other neurological diseases, such as depression and schizophrenia, and disorders featuring abnormal CSF metabolism, including spontaneous intracranial hypotension (SIH) and idiopathic normal pressure hydrocephalus (iNPH). Brain-derived marker levels were found to be highly correlated with each other in the CSF of depression and schizophrenia patients. SIH is caused by CSF leakage, which is suspected to induce hypovolemia and a compensatory increase in CSF production. In SIH, the brain-derived markers were 2-3-fold higher than in other diseases, and, regardless of their diverse levels, they were found to be correlated with each other. Another abnormality of the CSF metabolism, iNPH, is possibly caused by the reduced absorption of CSF, which secondarily induces CSF accumulation in the ventricle; the excess CSF compresses the brain's parenchyma to induce dementia. One potential treatment is a "shunt operation" to bypass excess CSF from the ventricles to the peritoneal cavity, leading to the attenuation of dementia. After the shunt operation, marker levels began to increase within a week and then further increased by 2-2.5-fold at three, six, and twelve months post-operation, at which point symptoms had gradually attenuated. Notably, the marker levels were found to be correlated with each other in the post-operative period. In conclusion, the brain-derived major glycoprotein markers were highly correlated in the CSF of patients with different neurological diseases, and their correlations were maintained even after surgical intervention. These results suggest that brain-derived proteins could be biomarkers of CSF production.

Reduced renal function is associated with prolonged hospitalization in frail older patients with non-severe pneumonia.

Objective: Pneumonia is a disease with high morbidity and mortality among older individuals in Japan. In practice, most older patients with pneumonia are not required ventilatory management and are not necessarily in critical respiratory condition. However, prolonged hospitalization itself is considered to be a serious problem even in these patients with non-critical pneumonia and have negative and critical consequences such as disuse syndrome in older patients. Therefore, it is essential to examine the factors involved in redundant hospital stays for older hospitalized patients with non-severe pneumonia, many of whom are discharged alive. Method: We examined hospitalized patients diagnosed with pneumonia who were 65 years and older in our facility between February 2017 and March 2020. A longer length of stay (LOS) was defined in cases in which exceeded the 80th percentile of the hospitalization period for all patients was exceeded, and all other cases with a shorter hospitalization were defined as a shorter LOS. In a multivariate logistic regression model, factors determining longer LOSs were analyzed using significant variables in univariate analysis and clinically relevant variables which could interfere with renal function, including fasting period, time to start rehabilitation, estimated glomerular filtration rate (eGFR), the Quick Sequential Organ Failure Assessment (qSOFA) score of 2 or higher, bed-ridden state. Results: We analyzed 104 eligible participants, and the median age was 86 (interquartile range, 82-91) years. Overall, 31 patients (30.7%) were bed-ridden, and 37 patients (35.6%) were nursing-home residents. Patients with a Clinical Frailty Scale score of 4 or higher, considered clinically frail, accounted for 93.2% of all patients. In multivariate analysis, for a decrease of 5 ml/min/1.73m2 in eGFR, the adjusted odds ratios for longer LOSs were 1.22 (95% confidence interval, 1.04-1.44) after adjusting for confounders. Conclusion: Reduced renal function at admission has a significant impact on prolonged hospital stay among older patients with non-severe pneumonia. Thoughtful consideration should be given to the frail older pneumonia patients with reduced renal function or with chronic kidney disease as a comorbidity at the time of hospitalization to prevent the progression of geriatric syndrome associated with prolonged hospitalization.

High Correlation among Brain-Derived Major Protein Levels in Cerebrospinal Fluid: Implication for Amyloid-Beta and Tau Protein Changes in Alzheimer's Disease.

The cerebrospinal fluid (CSF) plays an important role in homeostasis of the brain. We previously demonstrated that major CSF proteins such as lipocalin-type prostaglandin D2 synthase (L-PGDS) and transferrin (Tf) that are biosynthesized in the brain could be biomarkers of altered CSF production. Here we report that the levels of these brain-derived CSF proteins correlated well with each other across various neurodegenerative diseases, including Alzheimer's disease (AD). In addition, protein levels tended to be increased in the CSF samples of AD patients compared with the other diseases. Patients at memory clinics were classified into three categories, consisting of AD (n = 61), mild cognitive impairment (MCI) (n = 42), and cognitively normal (CN) (n = 23), with MMSE scores of 20.4 ± 4.2, 26.9 ± 1.7, and 29.0 ± 1.6, respectively. In each category, CSF protein levels were highly correlated with each other. In CN subjects, increased CSF protein levels correlated well with those of AD markers, including amyloid-ß and tau protein, whereas in MCI and AD subjects, correlations declined with AD markers except p-tau. Future follow-up on each clinical subject may provide a clue that the CSF proteins would be AD-related biomarkers.

[Undergraduate geriatric education in foreign countries].

In Japan, which has become a super-aged society, medical care for the elderly is more important than ever before. Geriatric education for medical students and young doctors is essential to ensure the best medical care possible for the elderly. In this paper, the Working Group for Education of the Japan Geriatrics Society collected and analyzed data and information on undergraduate education in the fields of geriatrics and gerontology at medical schools in various countries through the Internet, comparing the findings with those in Japan. Of the countries surveyed, 62% had undergraduate education in geriatrics and gerontology as mandatory subjects in medical school. Countries with advanced welfare programs, such as the United Kingdom, Germany, Austria, Denmark, Finland, Sweden, the Netherlands, Spain, Canada and New Zealand, performed substantial undergraduate education in geriatrics and gerontology. A lack of available staff and time for education was cited as a hurdle in many countries. The importance of education in geriatrics and gerontology is being emphasized in many countries, but few programs are satisfactory at present. The "struggle" to improve undergraduate education in geriatrics and gerontology therefore continues. We should endeavor to improve education in the fields of geriatrics and gerontology by working hand in hand with geriatricians and gerontologists around the world.

18F-THK5351 Positron Emission Tomography Imaging in Neurodegenerative Tauopathies.

Introduction: We aimed to determine whether in vivo tau deposits and monoamine oxidase B (MAO-B) detection using 18F-THK5351 positron emission tomography (PET) can assist in the differential distribution in patients with corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD) and whether 18F-THK5351 retention of lesion sites in CBS and PSP can correlate with clinical parameters. Methods: 18F-THK5351 PET was performed in 35 participants, including 7, 9, and 10 patients with CBS, PSP, and AD, respectively, and 9 age-matched normal controls. In CBS and PSP, cognitive and motor functions were assessed using the Montreal Cognitive Assessment, Addenbrooke's Cognitive Examination-Revised, and Frontal Assessment Battery, Unified Parkinson's Disease Rating Scale Motor Score, and PSP Rating Scale. Results: 18F-THK5351 retention was observed in sites susceptible to disease-related pathologies in CBS, PSP, and AD. 18F-THK5351 uptake in the precentral gyrus clearly differentiated patients with CBS from those with PSP and AD. Furthermore, 18F-THK5351 uptake in the inferior temporal gyrus clearly differentiated patients with AD from those with CBS and PSP. Regional 18F-THK5351 retention was associated with the cognitive function in CBS and PSP. Conclusion: Measurement of the tau deposits and MAO-B density in the brain using 18F-THK5351 may be helpful for the differential diagnosis of tauopathies and for understanding disease stages.

Transferrin Biosynthesized in the Brain Is a Novel Biomarker for Alzheimer's Disease.

Glycosylation is a cell type-specific post-translational modification that can be used for biomarker identification in various diseases. Aim of this study is to explore glycan-biomarkers on transferrin (Tf) for Alzheimer's disease (AD) in cerebrospinal fluid (CSF). Glycan structures of CSF Tf were analyzed by ultra-performance liquid chromatography followed by mass spectrometry. We found that a unique mannosylated-glycan is carried by a Tf isoform in CSF (Man-Tf). The cerebral cortex contained Man-Tf as a major isofom, suggesting that CSF Man-Tf is, at least partly, derived from the cortex. Man-Tf levels were analyzed in CSF of patients with neurological diseases. Concentrations of Man-Tf were significantly increased in AD and mild cognitive impairment (MCI) comparing with other neurological diseases, and the levels correlated well with those of phosphorylated-tau (p-tau), a representative AD marker. Consistent with the observation, p-tau and Tf were co-expressed in hippocampal neurons of AD, leading to the notion that a combined p-tau and Man-Tf measure could be a biomarker for AD. Indeed, levels of p-tau x Man-Tf showed high diagnostic accuracy for MCI and AD; 84% sensitivities and 90% specificities for MCI and 94% sensitivities and 89% specificities for AD. Thus Man-Tf could be a new biomarker for AD.

Behçet's Disease with Extremely High Levels of Urinary ß2-Microglobulin after Non-Steroidal Anti-Inflammatory Drug Treatment.

Behçet's disease is an inflammatory disease which manifests itself as various symptoms, such as uveitis, oral and genital aphthae, erythema nodosa, gastro-intestinal ulcerations and encephalopathy. Among the manifestations, renal dysfunction is reported in some percentage of the patients with this disorder. We experienced a middle-aged male with Behçet's disease who showed an extremely high level of urinary ß2-microglulin, which is one of the markers of renal dysfunction, despite normal serum creatinine levels. The patient was on non-steroidal anti-inflammatory drug (NSAID) therapy for 7 weeks, and this could have affected his renal dysfunction. The present report suggests that renal injury should not be underestimated in patients with Behçet's disease, especially in patients using NSAIDs.

DNA damage in embryonic neural stem cell determines FTLDs' fate via early-stage neuronal necrosis.

The early-stage pathologies of frontotemporal lobal degeneration (FTLD) remain largely unknown. In VCPT262A-KI mice carrying VCP gene mutation linked to FTLD, insufficient DNA damage repair in neural stem/progenitor cells (NSCs) activated DNA-PK and CDK1 that disabled MCM3 essential for the G1/S cell cycle transition. Abnormal neural exit produced neurons carrying over unrepaired DNA damage and induced early-stage transcriptional repression-induced atypical cell death (TRIAD) necrosis accompanied by the specific markers pSer46-MARCKS and YAP. In utero gene therapy expressing normal VCP or non-phosphorylated mutant MCM3 rescued DNA damage, neuronal necrosis, cognitive function, and TDP43 aggregation in adult neurons of VCPT262A-KI mice, whereas similar therapy in adulthood was less effective. The similar early-stage neuronal necrosis was detected in PGRNR504X-KI, CHMP2BQ165X-KI, and TDPN267S-KI mice, and blocked by embryonic treatment with AAV-non-phospho-MCM3. Moreover, YAP-dependent necrosis occurred in neurons of human FTLD patients, and consistently pSer46-MARCKS was increased in cerebrospinal fluid (CSF) and serum of these patients. Collectively, developmental stress followed by early-stage neuronal necrosis is a potential target for therapeutics and one of the earliest general biomarkers for FTLD.

Fabry Nephropathy in a Young Female Patient Presenting with Only Urinary Mulberry Bodies Treated with Chaperone Therapy.

Fabry disease (FD) is an X-linked disorder of the sphingolipid metabolism, caused by deficiency or decreased activity of α-galactosidase A. We report a rare case of Fabry nephropathy (FN) in a 21-year-old Japanese female patient presenting with only urinary mulberry bodies; she was treated with pharmacological chaperone therapy (PCT) after renal biopsy. The patient underwent a detailed examination because her mother was diagnosed with FD in the Division of Community Medicine of our hospital. She did not have renal dysfunction or proteinuria, and only mulberry bodies were detected in the urine. The activity of α-galactosidase A was low, and genetic analysis revealed the R301Q mutation. A percutaneous renal biopsy was performed, and the findings revealed enlargement and vacuolation of glomerular podocytes by light microscopy, and myelin and zebra bodies were detected in podocytes by electron microscopy. She was diagnosed with FN by renal biopsy and gene analysis. PCT was selected as the treatment to prevent cardiac events and renal dysfunction. The present case suggests that renal biopsy may be necessary even for young women with only mulberry bodies for the diagnosis of FN. It could be useful to evaluate the effect of treatment using the counts of mulberry bodies in the urine. In addition, due to its oral administration, PCT may be suitable for patients who are unable to visit the hospital frequently.

YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology.

The timing and characteristics of neuronal death in Alzheimer's disease (AD) remain largely unknown. Here we examine AD mouse models with an original marker, myristoylated alanine-rich C-kinase substrate phosphorylated at serine 46 (pSer46-MARCKS), and reveal an increase of neuronal necrosis during pre-symptomatic phase and a subsequent decrease during symptomatic phase. Postmortem brains of mild cognitive impairment (MCI) rather than symptomatic AD patients reveal a remarkable increase of necrosis. In vivo imaging reveals instability of endoplasmic reticulum (ER) in mouse AD models and genome-edited human AD iPS cell-derived neurons. The level of nuclear Yes-associated protein (YAP) is remarkably decreased in such neurons under AD pathology due to the sequestration into cytoplasmic amyloid beta (Aß) aggregates, supporting the feature of YAP-dependent necrosis. Suppression of early-stage neuronal death by AAV-YAPdeltaC reduces the later-stage extracellular Aß burden and cognitive impairment, suggesting that preclinical/prodromal YAP-dependent neuronal necrosis represents a target for AD therapeutics.