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Background: Atherosclerosis has been considered as the main cause of morbidity, mortality, premature incapacity, and disability worldwide. For early and sensitive diagnosis, development of novel biomarkers is expected and of significant practical importance.Methods: The first screening for antigen markers was conducted using the serological identification of antigens by recombinant cDNA expression cloning (SEREX). Serum antibody levels were examined using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) using a recombinant protein as an antigen.Results: SEREX screening has identified adaptor-related protein complex 3 subunit delta 1 (AP3D1) as an antigen recognized by serum IgG antibodies of patients with atherosclerosis. As per the results of AlphaLISA, it was determined that the serum antibody levels against AP3D1 were higher in patients with acute ischemic stroke (AIS), transient ischemic attack (TIA), diabetes mellitus (DM), cardiovascular disease (CVD), chronic kidney disease (CKD), esophageal squamous cell carcinoma (ESCC), and colorectal carcinoma than those in the healthy donors. The area under the curve values of DM, nephrosclerosis type of CKD, and ESCC calculated using receiver operating characteristic curve analysis were noted to be higher than that of other diseases. Correlation analysis showed that the anti-AP3D1 antibody levels were highly associated with maximum intima-media thickness, which indicates that this marker reflected the development of atherosclerosis. The Japan Public Health Center-based Prospective Study results have verified that the serum antibody levels against AP3D1 showed significantly higher odds ratios with the risk of AIS for persons with the third quartiles and the highest quartiles versus the lowest quartile, indicating that this antibody marker is deemed useful as risk factors for AIS.Conclusions: Serum anti-AP3D1 antibodies, which are broad-spectrum biomarkers of atherosclerotic diseases and digestive organ cancers, could be useful in predicting the onset of AIS.

Background Serum antibody markers have been increasingly identified not only for cancer and autoimmune diseases but also for atherosclerosis-related diseases such as acute ischemic stroke (AIS), acute myocardial infarction (AMI), diabetes mellitus (DM), and chronic kidney disease (CKD). Biomarkers for transient ischemic attack (TIA) and non-ST segment elevation acute coronary syndrome (NSTEACS) are potentially useful for detection of early phase of atherosclerotic changes against AIS and AMI, respectively. Methods We utilized serological identification of antigens by recombinant cDNA expression cloning (SEREX) using a human aortic endothelial cell cDNA phage library and sera from patients with TIA or NSTEACS. Serum antibody levels were measured by amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) using purified recombinant antigens. Results Screening of sera from patients with TIA identified DnaJ heat shock protein family (Hsp40) member C2 (DNAJC2) as a candidate antigen, which was also isolated by SEREX screening using sera of patients with NSTEACS. The validation cohort revealed significantly higher DNAJC2 antibody (DNAJC2-Ab) levels in the sera of patients with TIA or AIS than those in healthy donors (HDs). Multivariate logistic regression analysis indicated that the predictive odds ratios (OR) of DNAJC2-Ab levels for TIA and AIS were 2.54 (95% confidence interval [CI]: 1.36–4.74, p = 0.0034) and 2.14 (95% CI: 1.39–3.30, p = 0.0005), respectively. Serum DNAJC2-Ab levels were also higher in patients with AMI, DM, and CKD than those in HDs. Conclusion Serum DNAJC2-Ab level may be useful for early detection of atherosclerotic lesions, which lead to AIS and AMI., Cardiovascular system; Hematological system; Neurology; Neurosurgery; Clinical research; Diagnostics; Biomarkers; DNAJC2; Acute ischemic stroke; Acute myocardial infarction; Autoantibody biomarker; Atherosclerosis, Cardiology

Background Ischemic stroke, including transient ischemic attack (TIA) and acute-phase cerebral infarction (aCI), is a serious health problem in the aging society. Thus, this study aimed to identify TIA and aCI biomarkers. Methods In 19 patients with TIA, candidate antigens recognized by serum IgG autoantibodies were screened using a human aortic endothelial cell cDNA library. Through amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA), serum antibody levels against the candidate antigens were examined in healthy donor (HD), TIA, and aCI cohorts (n = 285, 92, and 529). The plasma antibody levels in the Japan Public Health Center-based Prospective Cohort Study (1991–1993) were also examined. Results The candidate antigens were aldolase A (ALDOA) and fumarate hydratase (FH). In AlphaLISA, patients with TIA or aCI had higher anti-ALDOA antibody (ALDOA-Ab) and anti-FH antibody (FH-Ab) levels than the HDs (P P = 0.0050) and FH-Ab (OR: 2.49, P = 0.0037) levels were independent predictors of TIA. According to the case–control study, the ALDOA-Ab (OR: 2.50, P P Conclusions ALDOA-Abs and FH-Abs can be novel potential biomarkers for predicting atherosclerotic TIA and aCI.

Transient ischemic attack (TIA) is a predictor for cerebral infarction (CI), and early diagnosis of TIA is extremely important for the prevention of CI. We set out to identify novel antibody biomarkers for TIA and CI, and detected matrix metalloproteinase 1 (MMP1), chromobox homolog 1 (CBX1), and chromobox homolog 5 (CBX5) as candidate antigens using serological identification of antigens by recombinant cDNA expression cloning (SEREX) and Western blotting to confirm the presence of serum antibodies against the antigens. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) revealed that serum antibody levels were significantly higher in patients with TIA or acute-phase CI (aCI) compared with healthy donors (P < 0.01). Spearman’s correlation analysis and multivariate logistic regression analysis demonstrated that levels of anti-MMP1, anti-CBX1, and anti-CBX5 antibodies were associated with age, cigarette-smoking habits, and blood pressure. Thus, serum levels of antibodies against MMP1, CBX1, and CBX5 could potentially serve as useful tools for diagnosing TIA and predicting the onset of aCI.

// Yoichi Yoshida 1,2,3 , Hao Wang 2,4 , Takaki Hiwasa 2 , Toshio Machida 5 , Eiichi Kobayashi 1,3 , Seiichiro Mine 5,6 , Go Tomiyoshi 2,7 , Rika Nakamura 2,7 , Natsuko Shinmen 2,7 , Hideyuki Kuroda 7 , Hirotaka Takizawa 8 , Koichi Kashiwado 9 , Ikuo Kamitsukasa 10,11 , Hideo Shin 12 , Takeshi Wada 13 , Akiyo Aotsuka 13 , Eiichiro Nishi 14 , Mikiko Ohno 14 , Minoru Takemoto 15 , Koutaro Yokote 15 , Sho Takahashi 16 , Jun Matsushima 17 , Xiao-Meng Zhang 2 , Masaki Takiguchi 2 and Yasuo Iwadate 1 1 Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan 2 Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan 3 Comprehensive Stroke Center, Chiba University Hospital, Chiba, Japan 4 Department of Anesthesia, The First Affiliated Hospital, Jinan University, Guangzhou, P. R. China 5 Department of Neurosurgery, Chiba Cerebral and Cardiovascular Center, Ichihara, Chiba, Japan 6 Department of Neurosurgery, Sawara Prefectural Hospital, Chiba, Japan 7 Medical Project Division, Research Development Center, Fujikura Kasei Co., Saitama, Japan 8 Port Square Kashiwado Clinic, Kashiwado Memorial Foundation, Chiba, Japan 9 Department of Neurology, Kashiwado Hospital, Chiba, Japan 10 Department of Neurology, Chiba Rosai Hospital, Chiba, Japan 11 Department of Neurology, Chibaken Saiseikai Narashino Hospital, Chiba, Japan 12 Department of Neurosurgery, Higashi Funabashi Hospital, Chiba, Japan 13 Department of Internal Medicine, Chiba Aoba Municipal Hospital, Chiba, Japan 14 Department of Pharmacology, Shiga University of Medical Science, Shiga, Japan 15 Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 16 Clinical Research Center, Chiba University Hospital, Chiba, Japan 17 Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan Correspondence to: Takaki Hiwasa, email: // Keywords : TIA; PDCD11; cerebral infarction; autoantibody; biomarker; Gerotarget Received : August 08, 2017 Accepted : November 16, 2017 Published : December 24, 2017 Abstract Background: Disease specific autoantibodies have been detected in the sera of patients with atherosclerosis-related diseases, such as cerebral infarction, cardiovascular disease. In the present study, we aimed to identify novel autoantibodies responsible for transient ischemic attack (TIA), a prodromal condition for cerebral infarction. Methods: To identify candidate antigens, we screened a human aortic endothelial cell cDNA library using sera from 20 patients with TIA. Serum antibody levels were measured using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) in 2 independent patient/healthy donor (HD) cohorts ( n = 192 and n = 906 in the second screening and validation cohort, respectively). Results: First screening identified 3 candidate antigens. Of these, programmed cell death 11 (PDCD11) was determined to be associated with stroke ( p < 0.0001), as evidenced from the second screening using AlphaLISA. The validation cohort revealed significantly higher antibody levels against PDCD11 (PDCD11-Ab levels) in patients with TIA than in HDs. Multivariate logistic regression analysis indicated that the predictive value of PDCD11-Ab levels for TIA [Odds ratio (OR): 2.44, 95% confidence interval (CI): 1.33-4.57, p = 0.0039] was not inferior to other known risk factors for ischemic stroke, including age (OR: 4.97, 95% CI: 2.67–9.48, p < 0.0001); hypertension (OR: 3.21, 95% CI: 1.76–5.86, p = 0.0001); and diabetes (OR: 4.31, 95% CI: 1.74–11.2, p = 0.0015). Conclusion: Serum PDCD11-Ab level may serve as a potential biomarker for TIA.

Background: The discovery and development of novel biomarkers that could facilitate early diagnosis and thus prevent the progression of atherosclerosis-related diabetes mellitus (DM), cerebral infarction (CI), and cardiovascular disease (CVD) has garnered much research interest. Notably, recent reports have described a number of highly sensitive antibody markers. In this study, we aimed to identify additional antibody markers that would facilitate screening. Methods: The amplified luminescent proximity homogeneous assay (AlphaLISA) method, which incorporates glutathione- or streptavidin-donor beads and anti-human-IgG-acceptor beads, was used to evaluate serum antibody levels in serum samples. The protein array method was used for the initial screening, and peptide arrays were used to identify epitope sites. Results: The protein array identified SH3 domain-binding protein 5 (SH3BP5) as a target antigen of serum IgG antibodies in the sera of patients with atherosclerosis. We prepared recombinant glutathione S-transferase (GST)- fused SH3BP5 protein. Peptide arrays revealed that the epitope site recognized by serum antibodies is located within amino acids 161–174 of SH3BP5. AlphaLISA revealed significantly higher serum antibody levels against both the SH3BP5 protein and peptide in patients with DM, acute-phase CI, transient ischemic attack, CVD or chronic kidney disease (CKD), than in healthy donors. Furthermore, areas under the receiver operating characteristic curves of these antibodies were higher in patients with CKD and DM than in other patients. Spearman correlation analysis revealed associations between the serum antibody levels against SH3BP5 peptide and artery stenosis, hypertension, and smoking. Conclusions: The serum anti-SH3BP5 antibody marker appears to be useful for estimating the progress of atherosclerosis and may discriminate atherosclerosis associated with hypertension and/or habitual smoking.

To characterize brain cholinergic deficits in Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB).Participants included 18 patients with PD, 21 patients with PDD/DLB, and 26 healthy controls. The PD group consisted of nine patients with early PD, each with a disease duration of less than 3 years, five of whom were de novo PD patients, and nine patients with advanced PD, each with a disease duration greater than or equal to 3 years. The PDD/DLB group consisted of 10 patients with PDD and 11 patients with DLB. All subjects underwent PET scans with N-[11C]-methyl-4-piperidyl acetate to measure brain acetylcholinesterase (AChE) activity. Brain AChE activity levels were estimated voxel-by-voxel in a three-compartment analysis using the arterial input function, and compared among our subject groups through both voxel-based analysis using the statistical parametric mapping software SPM5 and volume-of-interest analysis.Among patients with PD, AChE activity was significantly decreased in the cerebral cortex and especially in the medial occipital cortex (% reduction compared with the normal mean = -12%) (false discovery rate-corrected p value0.01). Patients with PDD/DLB, however, had even lower AChE activity in the cerebral cortex (% reduction = -27%) (p0.01). There was no significant difference between early PD and advanced PD groups or between DLB and PDD groups in the amount by which regional AChE activity in the brain was reduced.Brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. It begins in early Parkinson disease, and is more widespread and profound in both Parkinson disease with dementia and dementia with Lewy bodies.

Adiponectin secreted from the adipocytes plays pleiotropic, anti-atherosclerotic roles, such as enhancement of insulin secretion and an increase in energy expenditure. The measurement of levels of circulating adiponectin is useful to evaluate the progression of atherosclerosis-related diseases, such as coronary artery disease (CAD), cerebral infarction (CI) and diabetes mellitus (DM). We examined the serum antibody levels against recombinant adiponectin protein via the amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) method. The results revealed that the antibody levels were significantly higher in patients with CAD, CI and type 2 DM, than in healthy donors. Receiver operating curve analysis showed that the sensitivity was in a range of 41–48% for CAD, CI and DM. Thus, the serum anti-adiponectin antibody levels could be a common marker for atherosclerosis-related diseases.

Cerebral infarction (CI), cardiovascular disease (CVD), diabetes mellitus (DM) and chronic kidney disease (CKD) are atherosclerosis-related diseases, which are major causes of health damage. For early and sensitive diagnosis, development of novel biomarkers is expected and of significant practical importance. First screening was carried out by phage expression cloning to identify antigen proteins recognized by serum IgG antibodies in patients with atherosclerosis. RPA2, LRPAP1, EEF1A1, SPOCK1, LOC729260, tubulin beta 2C (TUBB2C) and KIAA0020 markers were identified. We then compared the serum antibody levels against the candidate proteins between healthy donors (HD) and patients with CI, CVD, DM, or CKD by Alpha (amplified luminescent proximity homogeneous assay)-LISA method. The results showed that the serum TUBB2C antibody levels were significantly higher in patients with CI, DM, or CKD than those in HD. Using the average + 2SD of HD as the cut-off value, the positive thresholds of TUBB2C antibody markers were 14.8% in CI, 25.8% in DM, and 18.3% in CKD. TUBB2C antibody levels were well correlated with artery stenosis degrees such as plaque score, maximum intima-media thickness and cardio ankle vascular index. Consequently, TUBB2C antibody markers are useful to diagnose atherosclerosis, DM, and CKD, and can be applied to the prediction of the onset of CI. The serum anti-TUBB2C antibody markers are useful for the diagnosis of DM and CKD. Keywords: Atherosclerosis; Diabetes mellitus; Chronic kidney disease; Cerebral infarction; Cardiovascular disease; Antibody biomarker

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease which may be caused by development of the autoantibodies. On the other hand, SLE is a high-risk group of atherosclerosis, so it is possible that some of autoantibodies in SLE are the result of atherosclerosis-related diseases such as cerebral infarction (CI), cardiovascular disease (CVD) and diabetes mellitus (DM). Methods: The initial screening of autoantibodies was performed using the protein array method. AlphaLISA was used to analyze the serum antibody levels using synthetic polypeptides as antigens. Results: After the initial screening using protein array, we identified 67 antigens that were recognized by IgG antibodies in sera of patients with SLE. In the second screening, 170 peptides derived from amino acid sequences of 67 antigens were synthesized and used as antigens for analysis of serum antibody levels by AlphaLISA. The antibody levels for ten peptides were significantly higher in the sera of patients with SLE than in those of healthy donors. Further AlphaLISA analysis of sera of patients with CI, CVD or DM revealed that the serum antibody levels for four peptides derived from SOSTDC1, CTNND1, CLDND1 and CCNG2 were elevated in patients as compared to those of healthy donors. Conclusions: Serum antibody levels against peptide antigens of SOSTDC1, CTNND1, CLDND1 and CCNG2 are useful markers for diagnosis of the progression of CI, CVD and/or DM.

Background: Atherosclerosis-related life-style diseases such as cerebral infarction (CI), cardiovascular disease (CVD), diabetes mellitus (DM), and chronic kidney disease (CKD) are a serious problem in the recently aging society. The development of novel and sensitive diagnostic markers is necessary and expected for the early treatment. Methods and Results: Through the first screening by phage expression cloning, we identified ATPase, Ca++ transporting, plasma membrane 4 (ATP2B4) and bone morphogenetic protein 1 (BMP-1) as antigens recognized by IgG antibodies in the sera of patients with atherosclerosis. The presence of autoantibodies against these antigens in serum specimens was confirmed by Western blotting. We then compared serum antibody levels against recombinant ATP2B4 and BMP-1 proteins between healthy donors (HD) and patients with atherosclerotic diseases, such as CI, transient ischemic attack (TIA), CVD, DM, or CKD, by the Alpha (amplified luminescent proximity homogeneous assay)-LISA method. The results revealed that both antibody levels were significantly higher in patients with these diseases than in HD and exhibited most prominent differences in CKD vs. HD. Correlation analysis showed that both antibody levels were well correlated with the degree of artery stenosis, such as maximum intima-media thickness with some different patterns, i.e., anti-ATP2B4 antibody levels were related to hypertension, whereas anti-BMP-1 antibodies were related to smoking habits. Conclusions: The serum antibody levels against ATP2B4 and BMP-1 can be useful diagnostic markers for atherosclerosis and its related diseases caused by hypertension and smoking habits, respectively.

The primary transmitter deficit is cholinergic in Alzheimer's disease (AD), and the amygdala receives a major cholinergic projection from the nucleus basalis of Meynert (Ch4), which may play an important role in the retention of affective conditioning and/or memory consolidation. We measured brain acetylcholinesterase (AChE) activity in 54 patients with AD and in 22 normal controls by positron emission tomography and N-[(11)C]methylpiperidin-4-yl acetate to characterize the cholinergic pathology in AD. The k(3) values were calculated as an index of AChE activity in a three-compartment model analysis using the metabolite-corrected arterial input function. The k(3) values were highly significantly reduced by 20% in the cerebral neocortex (P

The applicability of two reference tissue-based analyses without arterial blood sampling for the measurement of brain regional acetylcholinesterase (AChE) activity using N-[11C]methylpiperidin-4-yl propionate ([11C]MP4P) was evaluated in 12 healthy subjects. One was a linear least squares analysis derived from Blomqvist's equation, and the other was the analysis of the ratio of target-tissue radioactivity relative to reference-tissue radioactivity proposed by Herholz and coworkers. The standard compartment analysis using arterial input function provided reliable quantification of k3 (an index of AChE activity) estimates in regions with low (neocortex and hippocampus), moderate (thalamus), and high (cerebellum) AChE activity with a coefficient of variation (COV) of 12% to 19%. However, the precise k3 value in the striatum, where AChE activity is the highest, was not obtained. The striatum was used as a reference because its time-radioactivity curve was proportional to the time integral of the arterial input function. Reliable k3 estimates were also obtained in regions with low-to-moderate AChE activity with a COV of less than 21% by striatal reference analyses, though not obtained in the cerebellum. Shape analysis, the previous method of direct k3 estimation from the shape of time-radioactivity data, gave k3 estimates in the cortex and thalamus with a somewhat larger COV. In comparison with the standard analysis, a moderate overestimation of k3 by 9% to 18% in the linear analysis and a moderate underestimation by 2% to 13% in the Herholz method were observed, which were appropriately explained by the results of computer simulation. In conclusion, simplified kinetic analyses are practical and useful for the routine analysis of clinical [11C]MP4P studies and are nearly as effective as the standard analysis for detecting regions with abnormal AChE activity.

N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) is a radiotracer that has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET) using a standard compartment model analysis and a metabolite-corrected arterial input function. In the current study, the authors evaluated the applicability of a simple kinetic analysis without blood sampling, namely shape analysis. First, the authors used computer simulations to analyze factors that affect the precision and bias of shape analysis, then optimized the shape analysis procedure for [11C]MP4A. Before shape analysis execution, the later part of dynamic PET data except for the initial 3 minutes were smoothed by fitting to a bi-exponential function followed by linear interpolation of 8 data points between each of adjacent scan frames. Simulations showed that shape analysis yielded estimates of regional metabolic rates of [11C]MP4A by AChE (k3) with acceptable precision and bias in brain regions with low k3 values such as neocortex. Estimates in regions with higher k3 values became progressively more inaccurate. The authors then applied the method to [11C]MP4A PET data in 10 healthy subjects and 20 patients with Alzheimer's disease (AD). There was a highly significant linear correlation in regional k3 estimates between shape and compartment analyses (300 neocortical regions, [shape k3] = 0.93 × [NLS k3], r = 0.89, P < 0.001). Significant reductions in k3 estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral cortices in patients with AD as compared with controls were observed when using shape analysis ( P < 0.013, two-tailed t-test), although these reductions (17% to 20%) were somewhat less than those obtained by compartment analysis (22% to 27%). The sensitivity of shape analysis for detecting neocortical regions with abnormally low k3 in the 20 patients with AD (92 out of 200 regions, 46%) also was somewhat less than compartment analysis (136 out of 200 regions, 68%). However, taking its simplicity and noninvasiveness into account, the authors conclude that quantitative measurement of neocortical AChE activity with shape analysis and [11C]MP4A PET is practical and useful for clinical diagnosis of AD.

We measured brain acetylcholinesterase activity in 30 patients with Alzheimer's disease (AD) and 14 age-matched controls by positron emission tomography (PET) and using a carbon 11–labeled acetylcholine analogue. Seven AD patients had repeat PET scans. The k3 values were calculated as an index of acetylcholinesterase activity in a three-compartment analysis using the metabolite corrected arterial input function. Twenty-eight of the 30 AD patients (14 each in the early and late onset subgroups) were retained in the study so as to equalize the range and average severity of cognitive impairment within the early and late onset subgroups. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala in the early onset AD patients, although the k3 values were significantly reduced only in the temporoparietal cortex and amygdala in the late onset AD patients. In the longitudinal study, all 7 repeat AD patients showed further reduction of cortical k3 values in the second PET scans, with a mean interval of 2 years, suggesting a progressive loss of the ascending cholinergic system from the nucleus basalis of Meynert in AD. In 37 AD patients, there was a highly significant correlation between the cortical k3 values and Mini-Mental State Examination scores, supporting the cholinergic hypothesis in AD. Ann Neurol 2000;48:194–200

Brain acetylcholinesterase activity was measured in 14 patients with Alzheimer disease and 14 age-matched control subjects by positron emission tomography with a radioactive acetylcholine analogue. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala of all patients with Alzheimer disease, suggesting a loss of cholinergic innervation from the basal forebrain. Most profound reductions of k3 values were observed in the temporal (-30%) and parietal cortices (-31%), although reductions of k3 values were relatively uniform in the cerebral neocortex. This technique may be a powerful tool for early diagnosis of Alzheimer disease and also for therapeutic monitoring of acetylcholinesterase inhibitors in Alzheimer disease.

IC-P-017 LEWY BODY DISEASE WITH DEMENTIA CAN BE WELL-DIFFERENTIATED FROM ALZHEIMER’S DISEASE BY MEASUREMENT OF CEREBRAL CORTICAL ACETYLCHOLINESTERASE ACTIVITY BY PET Hitoshi Shimada, Hitoshi Shinotoh, Shigeki Hirano, Michie Miyoshi, Koichi Sato, Noriko Tanaka, Tsuneyoshi Ota, Masato Asahina, Akiyo Aotsuka, Kiyoshi Fukushi, Hiroshi Ito, Satoshi Kuwabara, Toshiaki Irie, Tetsuya Suhara, Molecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Section for Human Neurophysiology, Research Center for Frontier Medical Engineering, Chiba University, Chiba, Japan; Asahi Hospital for Neurological Diseases and Rehabilitation, Chiba, Japan; Department of Neurology, JR Tokyo General Hospital, Tokyo, Japan; Department of Clinical Neuroscience and Therapeutics, Hiroshima University, Hiroshima, Japan; Department of Psychiatry, Ichihara Hospital, Teikyo University School of Medicine, Chiba, Japan; Department of Neurosurgery, Tokyo Women’s Medical University Medical Center East, Tokyo, Japan; Department of Psychiatry, Juntendo University School of Medicine, Tokyo, Japan; Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan; Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Department of Rehabilitation Medicine, Chiba Aoba Municipal Hospital, Chiba, Japan. Contact e-mail: shim@alpha.ocn.ne.jp

Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [11C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6+/-5.9 years), 12 with progressive supranuclear palsy (68.5+/-4.1 years), eight with frontotemporal dementia (59.8+/-6.9 years) and 16 healthy controls (61.2+/-8.5 years). Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k3 values) in the paracentral region, frontal, parietal and occipital cortices (P

To elucidate characteristic changes of brain acetylcholinesterase (AChE) in cerebellar degenerative disorders. Eight patients with the cerebellar variant of multiple system atrophy (MSA-C), 7 patients with spinocerebellar ataxia type-3 (SCA-3), 3 patients with SCA-6, and 13 healthy age-matched volunteers participated in this study. Brain AChE activity was measured by [(11)C] N-methylpiperidin-4-yl propionate PET in all subjects. Brain AChE activities were significantly decreased in the thalamus (-27%) and the posterior lobe of cerebellar cortex (-36%) in patients with MSA-C and in the thalamus (-23%) in patients with SCA-3 compared with healthy controls (P < 0.01). Thalamic AChE activities of SCA-3 patients were negatively correlated with the unified Parkinson's disease rating scale motor subscore (P < 0.001). AChE activities were not significantly altered in the cerebral cortex in any disease group. Reduction of AChE activities in the thalamus and cerebellum in MSA and in the thalamus in SCA-3 suggest that cholinergic modulating drugs may have a role in the treatment of ataxia and other symptoms in these disorders.

A 55-year-old woman was admitted to our hospital because of sudden onset of dizziness and gait ataxia. A brain CT scan revealed a small cerebellar haemorrhage located in the right vermis. Brain MR angiography revealed left persistent primitive trigeminal artery (PPTA) and basilar artery (BA) dysplasia proximal to the shunting PPTA without arteriovenous malformation (AVM) or aneurysm. We speculate that BA dysplasia due to the PPTA, along with poorly controlled hypertension resulted in overload of the superior cerebellar artery blood vessels through the PPTA, leading to a haemorrhage in the right vermis. BA dysplasia and a PPTA without an obvious AVM or aneurysm possibly leading to cerebellar haemorrhage is rare. PPTA is a relatively common vascular anomaly; hence, we must consider it in the differential diagnosis for brain haemorrhages that may be caused by the specific haemodynamic consequences of PPTA.

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant tauopathy. To date, 33 distinct mutations in the tau gene have been reported.1 The clinical features of the N279K tau mutation include parkinsonism, personality changes, and supranuclear gaze palsy.2 Occasionally, cognitive impairment resembling Alzheimer disease (AD) can occur in FTDP-17. In AD, acetylcholinesterase (AChE) activities are depleted in the cerebral cortex. Although impairment of the nigrostriatal dopaminergic pathway has been demonstrated in FTDP-17,3 functional imaging of the cholinergic system in FTDP-17 has not been reported. Using PET and 11C-labeled N -methylpiperidin-4-yl acetate ([11C]MP4A),4 we measured AChE activity in the brains of two patients with FTDP-17 carrying the N279K tau mutation. ### Patients and control subjects. A 50-year-old man with congenital nystagmus began having neck and right arm rigidity and a shuffling gait at age 44. His symptoms improved with trihexyphenidyl and levodopa. During the next several years, however, he began to fall frequently and became forgetful and depressed. A half year before the PET study, he scored 17 of 30 points (cut-off …

A 58-year-old woman had a 3-year history of numbness in the right leg, which developed into thoracic transverse myelopathy and urinary retention. After referral to our department, MRI scans revealed a lesion with a target appearance at the T10-11 spinal cord with multiple silent cerebral lesions, which confirmed the diagnosis of cavernous angioma. Gamma-knife surgery was not indicated, considering the risk of adverse effects. The patient gradually became able to urinate, but had urge urinary incontinence. The first urodynamic studies (conducted 3 months after full clinical manifestations of transverse myelopathy) showed detrusor hyperreflexia (DH), decreased bladder sensation during bladder filling, detrusor-sphincter dyssynergia (DSD), and weak detrusor on voiding. However, urinary retention appeared again without change of neurologic signs. The second urodynamic studies (conducted 2 months later) showed less marked DH during bladder filling, and equivocal DSD but marked weak detrusor on voiding. The patient started taking oral prazosin hydrochloride (6 mg/day), which gradually ameliorated her voiding difficulty. Lesions in the lateral and dorsal columns of the spinal cord seem to be responsible for the micturitional disturbance in our patient with spinal cavernous angioma.

N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) is an acetylcholine analog. It has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET). [11C]MP4A is specifically hydrolyzed by AChE in the brain to a hydrophilic metabolite, which is irreversibly trapped locally in the brain. The authors propose a new method of kinetic analysis of brain AChE activity by PET without arterial blood sampling, that is, reference tissue-based linear least squares (RLS) analysis. In this method, cerebellum or striatum is used as a reference tissue. These regions, because of their high AChE activity, act as a biologic integrator of plasma input function during PET scanning, when regional metabolic rates of [11C]MP4A through AChE (k3; an AChE index) are calculated by using Blomqvist's linear least squares analysis. Computer simulation studies showed that RLS analysis yielded k3 with almost the same accuracy as the standard nonlinear least squares (NLS) analysis in brain regions with low (such as neocortex and hippocampus) and moderately high (thalamus) k3 values. The authors then applied these methods to [11C]MP4A PET data in 12 healthy subjects and 26 patients with Alzheimer disease (AD) using the cerebellum as the reference region. There was a highly significant linear correlation in regional k3 estimates between RLS and NLS analyses (456 cerebral regions, [RLS k3] = 0.98 × [NLS k3], r = 0.92, P < 0.001). Significant reductions were observed in k3 estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral neocortices ( P < 0.001, single-tailed t-test), and hippocampus ( P = 0.012) in patients with AD as compared with controls when using RLS analysis. Mean reductions (19.6%) Fin these 6 regions by RLS were almost the same as those by NLS analysis (20.5%). The sensitivity of RLS analysis for detecting cortical regions with abnormally low k3 in the 26 patients with AD (138 of 312 regions, 44%) was somewhat less than NLS analysis (52%), but was greater than shape analysis (33%), another method of [11C]MP4A kinetic analysis without blood sampling. The authors conclude that RLS analysis is practical and useful for routine analysis of clinical [11C]MP4A studies.

Acetylcholinesterase (AChE) activities in the brain of three patients with AD were measured once before and once during donepezil treatment (5 mg/d in two patients, 3 mg/d in one patient) using PET and N-[11C]methylpiperidin-4-yl acetate. Donepezil reduced k(3) values, an index of AChE activity, in the cerebral cortex by 39 +/- 5%. All patients showed some degree of symptomatic improvement, and it was concluded that this improvement was likely caused by improved cholinergic activity by inhibition of AChE in the brain.

Picture 1. (a) T2-weighted brain MRI showing a hyperintense lesion in the right posterior cerebral artery (PCA) territory. Difusion-weighted brain MRI showing no hyperintense lesions (figure not shown). (b, c) Brain MR angiography demonstrating right persistent primitive persistent hypoglossal artery (PPHA) originating from the right internal carotid artery (ICA) to the basilar artery. Bilateral vertebral arteries appeared hypoplastic and almost al the blood flow to the basilar artery was supplied by PPHA. (d) Carotid ultrasonography demonstrating iso-echoic plaque of 2 mm at the origin of the right ICA (white arrow). □ PICTURES IN CLINICAL MEDICINE □

The recent development of a high resolution positron emission tomography and appropriate radioligands labelled with positron emitter has made it possible to clearly delineate distribution of neuroreceptors in the human brain.