Adenosine A2A Receptor Occupancy by Caffeine After Coffee Intake in Parkinson's Disease.

BACKGROUND: Coffee intake can decrease the risk for Parkinson's disease (PD). Its beneficial effects are allegedly mediated by caffeine through adenosine A2A receptor (A2A R) antagonist action. OBJECTIVE: We aimed to calculate occupancy rates of striatal A2A Rs by caffeine after coffee intake in PD. METHODS: Five patients with PD underwent 11 C-preladenant positron emission tomography scanning at baseline and after intake of coffee containing 129.5 mg (n = 3) or 259 mg (n = 2) of caffeine. Concurrently, serum caffeine levels were measured. RESULTS: The mean serum caffeine level (µg/mL) was 0.374 at baseline and increased to 4.48 and 8.92 by 129.5 and 259 mg of caffeine, respectively. The mean occupancy rates of striatal A2A Rs by 129.5 and 259 mg of caffeine were 54.2% and 65.1%, respectively. CONCLUSIONS: A sufficient A2A R occupancy can be obtained by drinking a cup of coffee, which is equivalent to approximately 100 mg of caffeine. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Relationship between the temporal course of astrogliosis and symptom improvement in cerebral infarction: report of a case monitored using 18F-THK5351 positron emission tomography.

BACKGROUND: 18F-THK5351 was recently shown to bind to monoamine oxidase B (MAO-B) with high affinity. MAO-B is highly concentrated in astrocytes and increases during astrogliosis. Therefore, 18F-THK5351 accumulates in lesions undergoing astrogliosis. Cerebral infarction causes astrogliosis, which may be beneficial for repairing and regenerating injured cells and tissues in the lesions. Therefore, monitoring the degree of astrogliosis and stroke symptoms is essential for understanding the roles of astrogliosis in cerebral infarction. CASE PRESENTATION: A 72-year-old man, complaining of total loss of sensation in the left index finger, was diagnosed with acute cerebral infarction, and underwent 18F-THK5351 positron emission tomography (PET) on two occasions after the stroke. The first PET scan performed on day 27 revealed intense uptake in the infarct lesion located around the right precentral and postcentral gyri. However, the second PET scan on day 391 showed that the uptake had diminished significantly. The sensory deficit in the left index finger had improved by 30 and 70% at the times of the first and second PET scans, respectively. CONCLUSIONS: 18F-THK5351 uptake in the infarct lesion evidently changed between days 27 and 391, along with improved sensory deficit in the left index finger. Astrocytes reportedly play a role in restoring neuronal integrity. Therefore, the temporal course of astrogliosis may have been related to improving stroke symptoms in this patient, suggesting that the degree of astrogliosis in the infarct lesion may aid in assessing the prognosis in stroke patients.

Generation of JC Polyoma Pseudovirus for High-Throughput Measurement of Neutralizing Antibodies.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by reactivation of dormant JC polyomavirus (JCPyV). PML was mainly observed in immunocompromised individuals, such as HIV-positive patients, autoimmune disease patients, and cancer patients. Given that the presence of anti-JCPyV antibodies in serum is a risk indicator for PML development, it is essential to monitor anti-JCPyV antibody levels. In the present study, we established reporter-based single-infection neutralization assays for JCPyV and the genetically similar BK polyoma virus (BKPyV). We then confirmed the lack of cross-reactivity between the two viruses using test sera obtained from mice immunized with plasmids encoding the JCPyV or BKPyV capsid. Next, we compared neutralization antibody titers in sera from healthy donors, patients with multiple sclerosis (MS), and HIV-positive patients using an in-house enzyme-linked immunosorbent assay (ELISA) with JCPyV-like particles (virus-like particles; VLPs). A positive correlation was demonstrated between the neutralization titer (75% infectious concentration; IC75) against JCPyV and the antibody titer obtained by VLP-based JCPyV ELISA. This assay system may be applied to detect antibodies against other PyVs by generation of pseudoviruses using the respective capsid expression plasmids, and is expected to contribute to the surveillance of PyV as well as basic research on these viruses.

Characterization of Japanese multiple sclerosis patients with progression independent of relapse activity: A 2-year multicenter cohort study.

Progression independent of relapse activity (PIRA) is prevalent among Caucasian patients with relapsing and remitting multiple sclerosis (RRMS). However, there is limited knowledge regarding the characteristics of PIRA in Asian patients with RRMS. Therefore, we retrospectively analyzed the clinical and radiological progression of 95 Japanese patients with RRMS during a 2-year observation period. PIRA was observed in three patients who were characterized by young age, large T2 lesion volume, and great reduction in brain volume. Despite having highly active disease, fewer patients with PIRA (33.3%) were treated with high-efficacy drugs compared with those without disease activity (60.7%).

Nationwide Laboratory Surveillance of Progressive Multifocal Leukoencephalopathy in Japan: Fiscal Years 2011-2020.

Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease caused by JC virus (JCV), predominantly affecting patients with impaired cellular immunity. PML is a non-reportable disease with a few exceptions, making national surveillance difficult. In Japan, polymerase chain reaction (PCR) testing for JCV in the cerebrospinal fluid (CSF) is performed at the National Institute of Infectious Diseases to support PML diagnosis. To clarify the overall profile of PML in Japan, patient data provided at the time of CSF-JCV testing over 10 years (FY2011-2020) were analyzed. PCR testing for 1537 new suspected PML cases was conducted, and 288 (18.7%) patients tested positive for CSF-JCV. An analysis of the clinical information on all individuals tested revealed characteristics of PML cases, including the geographic distribution, age and sex patterns, and CSF-JCV-positivity rates among the study subjects for each type of underlying condition. During the last five years of the study period, a surveillance system utilizing ultrasensitive PCR testing and widespread clinical attention to PML led to the detection of CSF-JCV in the earlier stages of the disease. The results of this study will provide valuable information not only for PML diagnosis, but also for the treatment of PML-predisposing conditions.

Characteristics of progressive multifocal leukoencephalopathy clarified through internet-assisted laboratory surveillance in Japan.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML), a rare but fatal demyelinating disease caused by JC virus (JCV), occurs mainly in immunocompromised patients. As PML develops in individuals with various underlying disorders sporadically and infrequently, a nationwide survey of PML is difficult. This study was conducted to elucidate the characteristics of PML in Japan through an internet-assisted laboratory surveillance program. METHODS: A diagnostic support system for PML was established using a real-time PCR assay of JCV DNA in cerebrospinal fluid (CSF), and requests for testing were received from clinicians via specialized websites. Medical histories of patients were collected through standardized questionnaires, and a database of CSF JCV loads and clinical information was created and analyzed. RESULTS: For 4 years from April 2007 to March 2011, CSF specimens from 419 patients were tested. Forty-eight individuals were found positive for JCV DNA in their CSF and were diagnosed with PML. PML primarily occurred not only in HIV-positive patients (33.3%) but also in patients with hematologic disorders after receiving stem cell transplantation, chemotherapy, and/or immunosuppressive treatment (39.6%). The frequencies of PML cases among the subjects in these two categories were 20.3% and 23.5%, respectively. Although no significant features were observed with respect to CSF JCV loads in PML patients with an HIV infection or hematologic disorder, males were predominant in both groups (100% and 89.5%, respectively). The proportion of PML cases with autoimmune disorders (6.3%) or solid-organ transplants (2.1%) was smaller than those with HIV infection or hematologic disorders, probably due to the limited availability of therapeutic monoclonal antibodies and transplantation from brain dead donors. CONCLUSIONS: The results suggest that the internet-assisted laboratory surveillance program might be a useful strategy for collecting precise real-time information on PML on a national level. The current database provides important background information for the diagnosis and treatment of patients with risk factors for PML.

Distribution Pattern of the Monoamine Oxidase B Ligand, 18F-THK5351, in the Healthy Brain.

BACKGROUND: 18F-THK5351 PET estimates the concentrations of monoamine oxidase B (MAO-B) that are preferentially located in astrocytes and can be used to visualize and quantify ongoing astrogliosis. To study images of astrogliosis in neurological disorders, it is essential to understand the detailed binding sites of 18F-THK5351 as the MAO-B ligand under normal conditions. In this study, we examined the detailed distribution pattern of 18F-THK5351 in the healthy brain by comparing 18F-THK5351 uptake between subjects taking and not taking the MAO-B inhibitor. METHODS: Ten healthy controls (HCs: 67.4 [SD, 15.1] years) and 4 patients with Parkinson disease taking the MAO-B inhibitor underwent 18F-THK5351 PET. The uptake ratio index (URI) was defined to quantify 18F-THK5351 uptake, using the cerebellum as a reference region. The cerebellar URI was set to zero. RESULTS: For HCs, regions with URI ≥1 were preferentially observed in the following order: the striatum, globus pallidus, thalamus, hypothalamus, amygdala, periaqueductal gray, substantia nigra, medulla, hippocampus, and pons. The peak URI values in the corresponding regions were 2.93, 2.47, 2.12, 2.04, 1.84, 1.68, 1.67, 1.37, 1.20, and 1.11, respectively. For all patients with Parkinson disease taking the MAO-B inhibitor, the URI values in all these regions were significantly decreased (Z score >2) and were reduced from 60.4% to 99.9%, compared with HCs. CONCLUSIONS: This study presented the detailed distribution pattern of 18F-THK5351 in HCs and suggests that 18F-THK5351 uptake largely reflects MAO-B concentrations under normal conditions.

Imaging findings and pathological correlations of subacute encephalopathy with neuronal intranuclear inclusion disease-Case report.

Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease and may sometimes present with symptoms of subacute encephalopathy, including fever, headache, vomiting, and loss of consciousness. We present a case of adult-onset NIID with subacute encephalopathy, which is confirmed by skin and brain biopsied. The magnetic resonance imaging findings show cortical swelling and hyperintensities in the right temporooccipital lobes on T2-weighted images and magnetic resonance angiography demonstrates vasodilatations of the right middle cerebral artery and posterior cerebral artery. Abnormal enhancement is mainly observed in the gyral crowns (crown enhancement). Pathological examinations reveal new infarcts in the deep layers of the cortices. NIID should be considered in the presence of subacute encephalopathy with cortical swelling, contrast enhancement in the temporooccipital lobes, and vasodilation in adult patients. The encephalopathy targeted on the cortices, and the pathological background included infarctions.

AJM300 (carotegrast methyl), an oral antagonist of α4-integrin, as induction therapy for patients with moderately active ulcerative colitis: a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: AJM300 is an oral, small-molecule α4-integrin antagonist. We assessed the efficacy and safety of AJM300 in patients with moderately active ulcerative colitis. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study consisted of two phases: a treatment phase and an open-label re-treatment phase. The study was done at 82 hospitals and clinics in Japan. Patients with a Mayo Clinic score of 6-10, endoscopic subscore of 2 or more, rectal bleeding subscore of 1 or more, and an inadequate response or intolerance to mesalazine were enrolled. Patients were randomly allocated (1:1) via a website to either AJM300 (960 mg) or placebo by the minimisation method, which was adjusted centrally by dynamic assignment against the Mayo Clinic score (≥6 to ≤7, ≥8 to ≤10 points), any use of corticosteroid, anti-TNFα antibody, or immunosuppressants during the disease-active period (yes vs no), duration of induction therapy until randomisation (<4 weeks vs ≥4 weeks) as the minimisation factors. Patients, investigators, site staff, assessors, and the sponsor were masked to treatment assignments. The study drug was administered orally, three times daily, for 8 weeks, and continued for up to 24 weeks if endoscopic remission was not achieved or rectal bleeding did not stop. The primary endpoint was the proportion of patients with a clinical response at week 8, and was analysed in the full analysis set. Clinical response was defined as a reduction in Mayo Clinic score of 30% or more and 3 or more, a reduction in rectal bleeding score of 1 or more or rectal bleeding subscore of 1 or less, and an endoscopic subscore of 1 or less at week 8. The study is registered with ClinicalTrials.gov, NCT03531892, and is closed to recruitment. FINDINGS: Between June 6, 2018, and July 22, 2020, 203 patients were randomly assigned to AJM300 (n=102) or placebo (n=101). At week 8, 46 (45%) patients in the AJM300 group and 21 (21%) patients in the placebo group had a clinical response (odds ratio 3·30, 95% CI 1·73-6·29; p=0·00028). During the 8-week treatment and 16-week extension treatment periods, adverse events occurred in 39 (39%) of 101 patients in the placebo group and 39 (38%) of 102 patients in the AJM300 group. We found no difference in the incidence of adverse events between groups or after repeated administration of AJM300. The most common adverse event was nasopharyngitis (11 [11%] of 101 patients in the placebo group and ten [10%] of 102 patients in the AJM300 group). The most common treatment-related adverse event was also nasopharyngitis (four [4%] of 101 patients in the placebo group and three [3%] of 102 patients in the AJM300 group). Most adverse events were mild-to-moderate in severity. No deaths were reported. A serious adverse event was reported in the AJM300 group (one patient with anal abscess), but this was judged to be unrelated to study drug. INTERPRETATION: AJM300 was well tolerated and induced a clinical response in patients with moderately active ulcerative colitis who had an inadequate response or intolerance to mesalazine. AJM300 could be a novel induction therapy for the treatment of patients with moderately active ulcerative colitis. FUNDING: EA Pharma and Kissei Pharmaceutical. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Brain 11 C-ITMM PET to longitudinally assess type 1 metabotropic glutamate receptor availability in Alzheimer's disease.

BACKGROUND AND PURPOSE: Little evidence exists on the role of type 1 metabotropic glutamate receptor (mGluR1) in the pathophysiology of Alzheimer's disease (AD), although mGluR1 may be involved in the regulation of neuronal excitability and synaptic plasticity. We have recently reported that mGluR1 availability in the early stage of AD is equivalent to that in healthy subjects. This study aimed to address whether mGluR1 availability changes with the progression of AD. METHODS: Eight patients with AD (79.1 ± 4.6 years) underwent a total of two positron emission tomography (PET) examinations using the mGluR1 radioligand during the early-to-middle stages of AD. The mean interval was 2.8 years. Volumes-of-interest were placed on the frontal, parietal, and temporal cortices, hippocampus, anterior and posterior lobes, and vermis in the cerebellum. The binding potential (BPND ) was calculated to estimate mGluR1 availability, applying partial volume correction to the BPND values. RESULTS: No significant difference was observed in BPND values between the first and second PET examinations in the frontal cortex (p = 0.94), parietal cortex (p = 0.67), temporal cortex (p = 0.20), hippocampus (p = 0.17), anterior lobe (p = 0.73), posterior lobe (p = 0.21), and vermis (p = 0.22). CONCLUSION: This study suggests that mGluR1 availability is unchanged in the follow-up period of a few years during the early-to-middle stages of AD.

Head-to-Head Comparison of the Two MAO-B Radioligands, 18F-THK5351 and 11C-L-Deprenyl, to Visualize Astrogliosis in Patients With Neurological Disorders.

Three patients with neurological disorders (cerebral infarction, progressive multifocal leukoencephalopathy, and multiple sclerosis) underwent F-THK5351 and C-L-deprenyl PET on the same day to visualize lesions undergoing astrogliosis by measuring MAO-B activity. BPND map and SUV image with F-THK5351 as well as Ki map, Ki/K1 map and SUV image with C-L-deprenyl were created. F-THK5351 BPND maps and SUV images clearly identified the lesions undergoing astrogliosis. C-L-deprenyl Ki/K1 maps were close to F-THK5351 images, but very noisy. Ki maps and SUV images were likely affected by the effect of blood flow. Hence, F-THK5351 is superior to C-L-deprenyl for visualizing lesions undergoing astrogliosis.

A CD63 mutant inhibits T-cell tropic human immunodeficiency virus type 1 entry by disrupting CXCR4 trafficking to the plasma membrane.

We have discovered that an N-terminal deletion mutant of a membrane protein, CD63, (CD63DeltaN) blocks entry of CXCR4-using, T-cell tropic human immunodeficiency virus type 1 (X4 HIV-1) by suppressing CXCR4 surface expression. This suppression was observed for CXCR4 but not for CD4, CCR5, CD25, CD71 or other tetraspanin proteins. The suppression of CXCR4 expression on the plasma membrane appeared to be caused by mislocalization of CXCR4 and exclusive transportation of CXCR4 toward intracellular organelles, mainly late endosomes/lysosomes. Our data suggest that CXCR4 trafficking can be modified in terms of its recruitment to the plasma membrane without enhancing the degradation or arresting vesicular transport of CXCR4.

Small intestine CD4+ cell reduction and enteropathy in simian/human immunodeficiency virus KS661-infected rhesus macaques in the presence of low viral load.

Human immunodeficiency virus type 1, simian immunodeficiency virus and simian/human immunodeficiency virus (SHIV) infection generally lead to death of the host accompanied by high viraemia and profound CD4(+) T-cell depletion. SHIV clone KS661-infected rhesus macaques with a high viral load set point (HVL) ultimately experience diarrhoea and wasting at 6-12 months after infection. In contrast, infected macaques with a low viral load set point (LVL) usually live asymptomatically throughout the observation period, and are therefore referred to as asymptomatic LVL (Asym LVL) macaques. Interestingly, some LVL macaques exhibit diarrhoea and wasting similar to the symptoms of HVL macaques and are termed symptomatic LVL (Sym LVL) macaques. This study tested the hypothesis that Sym LVL macaques have the same degree of intestinal abnormalities as HVL macaques. The proviral DNA loads in lymphoid tissue and the intestines of Sym LVL and Asym LVL macaques were comparable and all infected monkeys showed villous atrophy. Notably, the CD4(+) cell frequencies of lymphoid tissues and intestines in Sym LVL macaques were remarkably lower than those in Asym LVL and uninfected macaques. Furthermore, Sym LVL and HVL macaques exhibited an increased number of activated macrophages. In conclusion, intestinal disorders including CD4(+) cell reduction and abnormal immune activation can be observed in SHIV-KS661-infected macaques independent of virus replication levels.

18F-THK5351 PET Can Identify Astrogliosis in Multiple Sclerosis Plaques.

A 26-year-old woman with relapsing-remitting multiple sclerosis (MS) underwent F-THK5351 PET during a remission period. PET imaging showed that small regions with elevated uptake of F-THK5351 were scattered in the brain and that the foci of F-THK5351 accumulations corresponded anatomically to MS plaques identified by MRI. Because F-THK5351 binds to monoamine oxidase B highly expressed in astrocytes, F-THK5351 accumulates in lesions undergoing astrogliosis. Hence, elevated uptake of F-THK5351 in the present case can represent ongoing astrogliosis in inactive MS lesions (plaques).

Human immunodeficiency virus type 1 Vpr inhibits axonal outgrowth through induction of mitochondrial dysfunction.

Human immunodeficiency virus type 1 (HIV-1)-infected macrophages damage mature neurons in the brain, although their effect on neuronal development has not been clarified. In this study, we show that HIV-1-infected macrophages produce factors that impair the development of neuronal precursor cells and that soluble viral protein R (Vpr) is one of the factors that has the ability to suppress axonal growth. Cell biological analysis revealed that extracellularly administered recombinant Vpr (rVpr) clearly accumulated in mitochondria where a Vpr-binding protein adenine nucleotide translocator localizes and also decreased the mitochondrial membrane potential, which led to ATP synthesis. The depletion of ATP synthesis reduced the transportation of mitochondria within neurites. This mitochondrial dysfunction inhibited axonal growth even when the frequency of apoptosis was not significant. We also found that point mutations of arginine (R) residues to alanine (A) residues at positions 73, 77, and 80 rendered rVpr incapable of causing mitochondrial membrane depolarization and axonal growth inhibition. Moreover, the Vpr-induced inhibition was suppressed after treatment with a ubiquinone analogue (ubiquinone-10). Our results suggest that soluble Vpr is a major viral factor that causes a disturbance in neuronal development through the induction of mitochondrial dysfunction. Since ubiquinone-10 protects the neuronal plasticity in vitro, it may be a therapeutic agent that can offer defense against HIV-1-associated neurological disease.

Unchanged type 1 metabotropic glutamate receptor availability in patients with Alzheimer's disease: A study using 11C-ITMM positron emission tomography.

Imaging of type 1 metabotropic glutamate receptor (mGluR1) has recently become possible using positron emission tomography (PET). To date, little evidence exists on the role of mGluR1 in the pathophysiology of Alzheimer's disease (AD). We aimed to examine mGluR1 availability in patients with AD. Ten patients with AD (78.9 ±â€¯5.9 years) and 12 age-matched volunteers (74.6 ±â€¯2.6 years) underwent PET using an mGluR1 radiotracer. All patients were anti-dementia drug-naive. Volumes-of-interest were placed on the anterior and posterior lobes and vermis in the cerebellum and frontal, parietal, and temporal cortices. The binding potential (BPND) was calculated to estimate mGluR1 availability, and partial volume correction was applied to the BPND values. Mini Mental State Examination (MMSE) scores were also obtained (22.0 ±â€¯4.8). No significant difference was observed in BPND between the AD and control groups in the anterior lobe (p = .30), posterior lobe (p = .95), vermis (p = .96), frontal cortex (p = .61), parietal cortex (p = .59), or temporal cortex (p = .27). No significant correlation was observed between BPND and MMSE scores in the anterior lobe (p = .59), posterior lobe (p = .35), vermis (p = .92), frontal cortex (p = .78), parietal cortex (p = .83), or temporal cortex (p = .82). In conclusions, this study suggests that mGluR1 availability is unchanged in the relatively early stage of AD. However, because regional mGluR1 availability may change with the progression of AD, further longitudinal follow-up is necessary.

Simultaneous Development of Progressive Multifocal Leukoencephalopathy and Cryptococcal Meningitis during Methotrexate and Infliximab Treatment.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of the JC virus under an immunosuppressed state. This condition carries a high risk of cryptococcal meningitis. We herein report a 65-year-old woman who simultaneously developed PML and cryptococcal meningitis and presented with bilateral sixth nerve palsy. She had been treated with methotrexate and infliximab for rheumatoid arthritis. Her symptoms improved with antifungal drug treatment and discontinuation of immunosuppression therapy. Although concurrent PML and cryptococcal meningitis is rare, it should be considered in immunosuppressed patients.

Microglial Activation on 11C-CB184 PET in a Patient With Cerebellar Ataxia Associated With HIV Infection.

A 63-year-old man complaining of prolonged imbalance underwent C-CB184 PET to assess microglial activation 3 years after being diagnosed with cerebellar ataxia associated with HIV infection. C-CB184 images revealed significant cerebellar uptake where MRI signal abnormalities were observed at disease onset, although these abnormalities had mostly disappeared at the time of C-CB184 PET. Microglia are believed to be a long-term reservoir for HIV infection, causing persistent immune activation (ie, chronic inflammation). Hence, in this case, increased C-CB184 binding may reflect persistent microglial activation along with HIV persistence in the cerebellum. However, further pathological investigations are desired to validate C-CB184 PET.