Neurological disorders associated with immune checkpoint inhibitors: an association with autoantibodies.

Among diverse neurological immune-related adverse events (irAEs), autoimmune encephalitis, aseptic meningitis, Guillain-Barré syndrome (GBS), myasthenia gravis (MG), and myositis are particularly important. The clinical presentation may be different from that of patients with conditions unrelated to immune checkpoint inhibitors (ICIs). Many of the autoantibodies detected in patients' sera are committed to the pathogenesis, while the clinical significance of such autoantibodies in cases of neurological irAEs is different from the significance in cases of typical neuronal disorders. A broad range of clinical symptoms complicates the diagnosis of autoimmune encephalitis. The clinical features of aseptic meningitis induced by classical drugs are different from those of aseptic meningitis induced by ICIs. Although autoantibodies against synaptic receptors or neuronal cell surface proteins are not detected, anti-Ma2 antibodies, which are onconeural antibodies against intracellular proteins, are detected in patients with autoimmune encephalitis associated with ICIs. GBS induced by ICIs sometimes shows gradual progression and a relapse of symptoms, suggesting chronic inflammatory demyelinating polyneuropathy. Bulbar symptoms and myasthenic crisis are frequently observed in ICI-induced MG. Anti-acetylcholine receptor antibodies are found in only half of patients with MG occurring as an irAE. ICI-induced myositis is accompanied by ocular muscle symptoms, such as ptosis and diplopia, which can suggest MG. Patients receiving ICI treatment present clinical features and laboratory findings that represent a mixture of MG and myositis. Anti-striational antibodies may act as biomarkers in cases in which MG and myositis overlap. A correct understanding of neurological adverse events is required to achieve the best management of patients.

Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study.

BACKGROUND: Levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. METHODS: This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30-84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300-400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. DISCUSSION: This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031180248 ; registered 12 March 2019.

A diagnostic strategy for Parkinsonian syndromes using quantitative indices of DAT SPECT and MIBG scintigraphy: an investigation using the classification and regression tree analysis.

PURPOSE: We aimed to evaluate the diagnostic performances of quantitative indices obtained from dopamine transporter (DAT) single-photon emission computed tomography (SPECT) and 123I-metaiodobenzylguanidine (MIBG) scintigraphy for Parkinsonian syndromes (PS) using the classification and regression tree (CART) analysis. METHODS: We retrospectively enrolled 216 patients with or without PS, including 80 without PS (NPS) and 136 with PS [90 Parkinson's disease (PD), 21 dementia with Lewy bodies (DLB), 16 progressive supranuclear palsy (PSP), and 9 multiple system atrophy (MSA). The striatal binding ratio (SBR), putamen-to-caudate ratio (PCR), and asymmetry index (AI) were calculated using DAT SPECT. The heart-to-mediastinum uptake ratio (H/M) based on the early (H/M [Early]) and delayed (H/M [Delay]) images and cardiac washout rate (WR) were calculated from MIBG scintigraphy. The CART analysis was used to establish a diagnostic decision tree model for differentiating PS based on these quantitative indices. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 87.5, 96.3, 93.3, 92.9, and 93.1 for NPS; 91.1, 78.6, 75.2, 92.5, and 83.8 for PD; 57.1, 95.9, 60.0, 95.4, and 92.1 for DLB; and 50.0, 98.0, 66.7, 96.1, and 94.4 for PSP, respectively. The PCR, WR, H/M (Delay), and SBR indices played important roles in the optimal decision tree model, and their feature importance was 0.61, 0.22, 0.11, and 0.05, respectively. CONCLUSION: The quantitative indices showed high diagnostic performances in differentiating NPS, PD, DLB, and PSP, but not MSA. Our findings provide useful guidance on how to apply these quantitative indices in clinical practice.

Electroconvulsive Therapy for Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Electroconvulsive therapy (ECT) is a well-established treatment for psychiatric disorders, including depression and psychosis. ECT has been reported to be effective in treating such psychiatric symptoms in patients with Parkinson's disease (PD) and has been also reported to be effective in treating motor symptoms. The aim of the study is to summarize previous clinical studies investigating the efficacy of ECT for symptoms in patients with PD. METHODS: A systematic review and meta-analysis of any study designs assessing motor and/or non-motor symptoms in patients with PD before and after ECT. Co-primary outcomes were set as motor manifestations assessed using the Unified Parkinson's Disease Rating Scale or other rating scales, and non-motor symptoms included depression and psychosis. Secondary outcomes were wearing-off phenomenon and cognitive function. The impact of ECT on those symptoms was examined by comparing the severity of the symptoms before and after ECT using a random effect model and was expressed in standardized mean difference. RESULTS: Of 1219 identified citations, 14 studies (n = 129; 1 randomized controlled study, 9 prospective observational studies, and 4 retrospective studies) were analyzed. The findings were as follows: ECT significantly improved motor manifestations in patients with PD, and the improvement was significant in the subpopulation without psychiatric symptoms; ECT significantly improved depression and psychosis; and ECT significantly relieved wearing-off phenomenon and did not worsen cognitive functioning. CONCLUSION: The current meta-analysis suggests the potential benefit of ECT on motor and non-motor symptoms in presumably complicated and difficult-to-treat subgroups. © 2020 International Parkinson and Movement Disorder Society.

Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study.

Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.

Inflammatory myopathy associated with PD-1 inhibitors.

OBJECTIVE: To characterize the inflammatory myopathy associated with programmed cell death 1 inhibitors (PD-1 myopathy). METHODS: We studied 19 Japanese patients with PD-1 myopathy (13 men and 6 women, mean age 70 years), who were referred to Keio University. As control groups, we used 68 patients with anti-signal recognition particle antibodies, 51 patients with anti-aminoacyl transfer RNA synthetase antibodies and 460 healthy subjects. RESULTS: In regard to muscle-disease severity, 10 patients showed a mild form of disease and 9 patients showed a severe form. Non-small cell lung cancer was the most common underlying cancer. PD-1 inhibitor consisted of 11 nivolumab and 8 pembrolizumab. PD-1 myopathy occurred 29 days on average after the first administration of PD-1 inhibitor. The initial manifestation of muscle weakness was ptosis in 10 patients, 15 patients had ptosis, 13 diplopia, 8 facial muscle weakness, 10 bulbar symptoms, 13 limb weakness, 14 neck weakness, 4 cardiac involvement, 6 respiratory involvement and 16 myalgia. Ocular, facial, cardiac and respiratory involvement and myalgia were more frequently observed than controls. Serum creatine kinase was increased to 5247 IU/L on average. Autoantibodies related to inflammatory myopathy were negative, while anti-striational antibodies were found in 13 (68%) patients. HLA-C*12:02 alleles were more frequently detected than healthy controls. Muscle pathology was characterized by multifocal necrotic myofibers with endomysial inflammation and expression of MHC class I. Immunosuppressive therapy with corticosteroids was generally effective for muscle weakness. CONCLUSIONS: Based on our clinical, histological and immunological findings, PD-1 myopathy is a discrete subset of inflammatory myopathy.

Myelopathy due to human T-cell leukemia virus type-1 from the donor after ABO-incompatible liver transplantation.

We report the case of a 53-year-old-man who developed human T-cell leukemia virus type-1-associated myelopathy (HAM) after ABO-incompatible liver transplantation for alcoholic liver cirrhosis. The living donor was seropositive for human T-cell leukemia virus type-1 (HTLV-1) and the recipient was seronegative for HTLV-1 before transplantation. After transplantation, the recipient developed steroid-resistant acute cellular rejection, which was successfully treated using anti-thymocyte globulin, and he was eventually discharged. He underwent spinal surgery twice after the transplantation for the treatment of cervical spondylosis that had been present for a period of 9 months before the transplantation. The surgery improved his gait impairment temporarily. However, his gait impairment progressed, and magnetic resonance imaging revealed multiple sites of myelopathy. He was diagnosed with HAM 16 months after the transplantation. Pulse steroid therapy (1000mg) was administered over a period of 3 days, and his limb paresis improved. Presently, steroid therapy is being continued, with a plan to eventually taper the dose, and he is being carefully followed up at our institution. Our case suggests that liver transplantation involving an HTLV-1-positive living donor carries the risk of virus transmission and short-term development of HAM after transplantation.

Possible Involvement of Hypotension in Postprandial Headache: A Case Series.

BACKGROUND: It is commonly known that headaches are induced by intake of specific food, drink, and/or additive. In addition, some patients experience postprandial headache independent of ingestion of specific items. Currently, information on the pathophysiology underlying this particular type of headache is scarce. CASE REPORTS: We report two cases in which headaches were observed after each meal. Postprandial hypotension was demonstrated in both cases. Tonometry-based continuous blood pressure measurement during head-up tilt revealed sympathetic dysfunction. In one patient, meta-iodobenzylguanidine (MIBG) myocardial scintigraphy detected cardiac sympathetic denervation, and diagnosis of pure autonomic failure was made. In both cases, treatment of postprandial hypotension was effective in relieving postprandial headache. DISCUSSION: The possibility of postprandial hypotension should be explored in patients with headache that occurs after meal. To this end, tonometry-based blood pressure measurement and MIBG myocardial scintigraphy may be useful diagnostic investigations. Treating postprandial hypotension may be effective in alleviating the symptoms.

Intracerebral Hemorrhage due to Venous Thrombosis of Developmental Venous Anomaly during Pregnancy.

BACKGROUND: Nowadays, developmental venous anomaly (DVA) is recognized as the most common cerebral vascular malformation. Most DVAs are diagnosed incidentally on routine brain imaging, but they are occasionally symptomatic. We report the case of a 26-year-old Japanese woman with intracerebral hemorrhage due to venous thrombosis of DVA. METHODS: We examined her neurologic examinations carefully. We also observed her laboratory data, brain computed tomography (CT), and magnetic resonance imaging (MRI) findings. RESULTS: She was 8 weeks pregnant and suffered from nausea, vomiturition, and appetite loss because of hyperemesis gravidarum. She presented with a sudden generalized seizure and was referred to our hospital. Brain CT showed a small hemorrhage and a tubular high-density structure compatible with an acutely thrombosed collecting vein in the right frontal lobe. T2*-weighted MRI also revealed a thrombosed collecting vein along with multiple medullary veins, which looked like caput medusa. She was diagnosed with an intracerebral hemorrhage and symptomatic epilepsy secondary to thrombosis of the DVA. After the acute phase of the disease, systemic anticoagulation therapy was administered to the patient to prevent the recurrence of venous thrombosis. We suspected that hyperemesis gravidarum with intravascular dehydration might have increased the risk of thrombosis in this patient. CONCLUSIONS: Thrombosis of the collecting vein of DVA is extremely rare. This is the first report regarding DVA thrombosis during pregnancy, to our knowledge.

Fatal intracranial hemorrhage after intravenous thrombolytic therapy for acute ischemic stroke associated with cancer-related nonbacterial thrombotic endocarditis.

Nonbacterial thrombotic endocarditis (NBTE) is associated with hypercoagulability in patients with inflammatory states such as cancer and autoimmune diseases. Cardiac vegetations caused by NBTE often lead to life-threatening systemic thromboembolism that most frequently affects the brain, spleen, and kidneys. A 54-year-old woman diagnosed with ovarian cancer suddenly developed back pain and left hemiparesis. Although intravenous alteplase (rt-PA) therapy was administered to treat hyperacute ischemic infarction detected by magnetic resonance imaging, intracranial hemorrhage occurred in the left hemisphere several hours later as the patient started to lose consciousness. Transthoracic echocardiography then detected aseptic vegetations on the mitral and aortic valves, indicating NBTE associated with ovarian cancer. Because therapies for NBTE are limited to heparinization and control of underlying diseases, thrombolytic therapy for acute embolic stroke in NBTE has not yet been validated. We postulated that thrombolytic therapy for cancer-related NBTE might easily cause hemorrhagic complications because cancer-related NBTE is often similar to the state of disseminated intravascular coagulation.

The Early Onset of Levodopa-induced Dyskinesia in a Patient with Multiple System Atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by Parkinsonism, cerebellar ataxia, and autonomic dysfunction. While less frequent than Parkinson's disease, MSA patients with a beneficial levodopa response may occasionally present with levodopa-induced dyskinesia (LID). We herein report a 50-year-old woman diagnosed with MSA-parkinsonism who developed LID in the unilateral lower extremity 10 months after the start of levodopa treatment. In this case, the distribution of LID, the timing of its onset, and the presence of LID despite relatively poor levodopa responsiveness were distinctive.

Amyloid-ß prediction machine learning model using source-based morphometry across neurocognitive disorders.

Previous studies have developed and explored magnetic resonance imaging (MRI)-based machine learning models for predicting Alzheimer's disease (AD). However, limited research has focused on models incorporating diverse patient populations. This study aimed to build a clinically useful prediction model for amyloid-beta (Aß) deposition using source-based morphometry, using a data-driven algorithm based on independent component analyses. Additionally, we assessed how the predictive accuracies varied with the feature combinations. Data from 118 participants clinically diagnosed with various conditions such as AD, mild cognitive impairment, frontotemporal lobar degeneration, corticobasal syndrome, progressive supranuclear palsy, and psychiatric disorders, as well as healthy controls were used for the development of the model. We used structural MR images, cognitive test results, and apolipoprotein E status for feature selection. Three-dimensional T1-weighted images were preprocessed into voxel-based gray matter images and then subjected to source-based morphometry. We used a support vector machine as a classifier. We applied SHapley Additive exPlanations, a game-theoretical approach, to ensure model accountability. The final model that was based on MR-images, cognitive test results, and apolipoprotein E status yielded 89.8% accuracy and a receiver operating characteristic curve of 0.888. The model based on MR-images alone showed 84.7% accuracy. Aß-positivity was correctly detected in non-AD patients. One of the seven independent components derived from source-based morphometry was considered to represent an AD-related gray matter volume pattern and showed the strongest impact on the model output. Aß-positivity across neurological and psychiatric disorders was predicted with moderate-to-high accuracy and was associated with a probable AD-related gray matter volume pattern. An MRI-based data-driven machine learning approach can be beneficial as a diagnostic aid.

Validation study of the Japanese version of the King's Parkinson's Disease Pain Scale and the King's Parkinson's Disease Pain Questionnaire.

INTRODUCTION: The King's Parkinson's Disease Pain Scale (KPPS)/King's Parkinson's Disease Pain Questionnaire (KPPQ) was developed as a tool to quantitatively assess pain in patients with Parkinson's disease (PwPD). Here, we conducted a Japanese multicenter validation study to verify the reliability of KPPS/KPPQ in Japanese PwPD. METHODS: PwPD, ≥20 years, with unexplained pain were included; those with a definitive primary cause of pain other than PD were excluded. A total of 151 patients who fulfilled the criteria were analyzed, and test-retest reliability was investigated in 25 individuals. RESULTS: The 151 patients included 101 women (66.9 %); mean age 68.3 ± 9.9 years, mean disease duration 9.2 ± 5.2 years. The most frequent pain type in the KPPS classification was musculoskeletal pain (82.8 %). There was a positive correlation between KPPS total score and the Non-Motor Symptoms Scale (NMSS) total score, NMSS item 27, the Parkinson's disease sleep scale-version 2 (PDSS-2) total score, PDSS-2 item 10, the Parkinson's Disease Questionnaire-8 (PDQ-8) summary index and PDQ-8 item 7. Cronbach's alpha of KPPS was 0.626 (0.562-0.658) and the intraclass correlation coefficient of test-retest reliability was 0.740. Cronbach's alpha of KPPQ was 0.660 (0.617-0.705) and a test-retest reliability of kappa coefficient was 0.593 (0.0-1.0). CONCLUSIONS: KPPS correlated well with other scales for assessing pain. KPPS correlated well with patients' quality of life, non-motor symptoms, and sleep disturbances. The reproducibility of KPPS/KPPQ makes it suitable for continuous evaluation of the same patient. On the other hand, the internal consistency of KPPS/KPPQ is rather low.

Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study.

INTRODUCTION: A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off. METHODS: This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400 mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes. RESULTS: The cumulative additional levodopa dose throughout 37 weeks and dose increase over 36 weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36 weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group. CONCLUSION: IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180248.

Prescribing patterns and determinants for elderly patients with Parkinson's disease in Japan: a retrospective observational study using insurance claims databases.

Background: This study aimed to determine real-world prescribing patterns and determinants for Japanese patients with Parkinson's disease (PD), with a focus on patients ≥75 years. Methods: This was a retrospective, observational, longitudinal study of patients with PD (≥30 years, ICD-10: G20 excluding Parkinson's syndrome) from three Japanese nationwide healthcare claim databases. Prescription drugs were tabulated using database receipt codes. Changes in treatment patterns were analyzed using network analysis. Factors associated with prescribing patterns and prescription duration were analyzed using multivariable analysis. Results: Of 18 million insured people, 39,731 patients were eligible for inclusion (≥75-year group: 29,130; <75-year group: 10,601). PD prevalence was 1.21/100 people ≥75 years. Levodopa was the most commonly prescribed anti-PD drug (total: 85.4%; ≥75 years: 88.3%). Network analysis of prescribing patterns showed that most elderly patients switched from levodopa monotherapy to adjunct prescription patterns, as did younger patients, but with less complexity. Elderly patients who newly initiated PD treatment remained on levodopa monotherapy longer than younger patients; factors significantly associated with levodopa prescriptions were older age and cognitive impairment. Commonly prescribed adjunct therapies were monoamine oxidase type B inhibitors, non-ergot dopamine agonists, and zonisamide, regardless of age. Droxidopa and amantadine were prescribed as adjunct levodopa therapy slightly more frequently among elderly patients; levodopa adjunct therapy was prescribed when the levodopa dose was 300 mg, regardless of age. Conclusion: Prescribing patterns for patients ≥75 years were levodopa centered and less complex than for those <75 years. Factors significantly associated with levodopa monotherapy and continued use of levodopa were older age and cognitive disorder. Clinical trial registration: UMIN Clinical Trials Registry, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000053425 (UMIN000046823).

Dysautonomia associated with immune checkpoint inhibitors.

OBJECTIVE: The purpose of this study is to report the clinical characteristics of dysautonomia associated with immune checkpoint inhibitors (ICIs). METHODS: We reported two patients with autoimmune autonomic ganglionopathy (AAG) occurring as immune-related adverse events (irAEs). We also performed a review of previous case reports presenting dysautonomia during ICI therapy. Moreover, we conducted pharmacovigilance analyses using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to investigate dysautonomia associated with ICI. RESULTS: Two patients in our care developed both AAG and autoimmune encephalitis following ICI therapy for lung cancers. We comprehensively reviewed 13 published cases (M:F = 11:2, mean onset age of 53 years) with ICI-associated dysautonomia including AAG (n = 3) and autonomic neuropathy (n = 10). Of these, ICI monotherapy was performed in seven and combination ICI use in six. In 6 of 13 patients, dysautonomia appeared within one month after the start of ICIs. Orthostatic hypotension was observed in 7 and urinary incontinence or retention in five. All patients except three showed gastrointestinal symptoms. Anti-ganglionic acetylcholine receptor antibodies were undetectable. All but two patients received immune-modulating therapy. Immuno-modulating therapy was effective in three patients with AAG and two patients with autonomic neuropathy, but ineffective in the others. Five patients died, of either the neurological irAE (n = 3) or cancer (n = 2). The pharmacovigilance analyses using FAERS showed that ipilimumab monotherapy and the combination of nivolumab and ipilimumab constituted significant risks for developing dysautonomia, consistent with the review of literature. CONCLUSION: ICIs can cause dysautonomia including AAG, and autonomic neuropathy is a neurological irAE.

Performance of plasma Aß42/40, measured using a fully automated immunoassay, across a broad patient population in identifying amyloid status.

BACKGROUND: Plasma biomarkers have emerged as promising screening tools for Alzheimer's disease (AD) because of their potential to detect amyloid ß (Aß) accumulation in the brain. One such candidate is the plasma Aß42/40 ratio (Aß42/40). Unlike previous research that used traditional immunoassay, recent studies that measured plasma Aß42/40 using fully automated platforms reported promising results. However, its utility should be confirmed using a broader patient population, focusing on the potential for early detection. METHODS: We recruited 174 participants, including healthy controls (HC) and patients with clinical diagnoses of AD, frontotemporal lobar degeneration, dementia with Lewy bodies/Parkinson's disease, mild cognitive impairment (MCI), and others, from a university memory clinic. We examined the performance of plasma Aß42/40, measured using the fully automated high-sensitivity chemiluminescence enzyme (HISCL) immunoassay, in detecting amyloid-positron emission tomography (PET)-derived Aß pathology. We also compared its performance with that of Simoa-based plasma phosphorylated tau at residue 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). RESULTS: Using the best cut-off derived from the Youden Index, plasma Aß42/40 yielded an area under the receiver operating characteristic curve (AUC) of 0.949 in distinguishing visually assessed 18F-Florbetaben amyloid PET positivity. The plasma Aß42/40 had a significantly superior AUC than p-tau181, GFAP, and NfL in the 167 participants with measurements for all four biomarkers. Next, we analyzed 99 participants, including only the HC and those with MCI, and discovered that plasma Aß42/40 outperformed the other plasma biomarkers, suggesting its ability to detect early amyloid accumulation. Using the Centiloid scale (CL), Spearman's rank correlation coefficient between plasma Aß42/40 and CL was -0.767. Among the 15 participants falling within the CL values indicative of potential future amyloid accumulation (CL between 13.5 and 35.7), plasma Aß42/40 categorized 61.5% (8/13) as Aß-positive, whereas visual assessment of amyloid PET identified 20% (3/15) as positive. CONCLUSION: Plasma Aß42/40 measured using the fully automated HISCL platform showed excellent performance in identifying Aß accumulation in the brain in a well-characterized cohort. This equipment may be useful for screening amyloid pathology because it has the potential to detect early amyloid pathology and is readily applied in clinical settings.

Impact of Amyloid and Tau PET on Changes in Diagnosis and Patient Management.

BACKGROUND AND OBJECTIVES: Previous studies have evaluated the diagnostic effect of amyloid PET in selected research cohorts. However, these studies did not assess the clinical impact of the combination of amyloid and tau PETs. Our objective was to evaluate the association of the combination of 2 PETs with changes in diagnosis, treatment, and management in a memory clinic cohort. METHODS: All participants underwent amyloid [18F]florbetaben PET and tau PET using [18F]PI-2620 or [18F]Florzolotau, which are potentially useful for the diagnosis of non-Alzheimer disease (AD) tauopathies. Dementia specialists determined a pre- and post-PET diagnosis that existed in both a clinical syndrome (cognitive normal [CN], mild cognitive impairment [MCI], and dementia) and suspected etiology, with a confidence level. In addition, the dementia specialists determined patient treatment in terms of ancillary investigations and management. RESULTS: Among 126 registered participants, 84.9% completed the study procedures and were included in the analysis (CN [n = 40], MCI [n = 25], AD [n = 20], and non-AD dementia [n = 22]). The etiologic diagnosis changed in 25.0% in the CN, 68.0% in the MCI, and 23.8% with dementia. Overall changes in management between pre- and post-PET occurred in 5.0% of CN, 52.0% of MCI, and 38.1% of dementia. Logistic regression analysis revealed that tau PET has stronger associations with change management than amyloid PET in all participants and dementia groups. DISCUSSION: The combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia, and the second-generation tau PET has a strong impact on the changes in diagnosis and management in memory clinics. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that the combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia.