Sortilin acts as an endocytic receptor for α-synuclein fibril.

Cell-to-cell spreading of misfolded α-synuclein (αSYN) is supposed to play a key role in the pathological progression of Parkinson's disease (PD) and other synucleinopathies. Receptor-mediated endocytosis has been shown to contributes to the uptake of αSYN in both neuronal and glial cells. To determine the receptor involved in αSYN endocytosis on the cell surface, we performed unbiased, and comprehensive screening using a membrane protein library of the mouse whole brain combined with affinity chromatography and mass spectrometry. The candidate molecules hit in the initial screening were validated by co-immunoprecipitation using cultured cells; sortilin, a vacuolar protein sorting 10 protein family sorting receptor, exhibited the strongest binding to αSYN fibrils. Notably, the intracellular uptake of fibrillar αSYN was slightly but significantly altered, depending on the expression level of sortilin on the cell surface, and time-lapse image analyses revealed the concomitant internalization and endosomal sorting of αSYN fibrils and sortilin. Domain deletion in the extracellular portion of sortilin revealed that the ten conserved cysteines (10CC) segment of sortilin was involved in the binding and endocytosis of fibrillar αSYN; importantly, pretreatment with a 10CC domain-specific antibody significantly hindered αSYN fibril uptake. The presence of sortilin in the core structure of Lewy bodies and glial cytoplasmic inclusions in the brain of synucleinopathy patients was confirmed via immunohistochemistry, and the expression level of sortilin in mesencephalic dopaminergic neurons may be altered with disease progression. These results provide compelling evidence that sortilin acts as an endocytic receptor for pathogenic form of αSYN, and yields important insight for the development of disease-modifying targets for synucleinopathies.

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

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

[Emerging Disease-modifying Strategies Targeting α-synuclein in Parkinson's Disease].

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Although the standard dopamine replacement therapy can alleviate motor symptoms, presently there is no available treatment to stop or reverse disease progression. Thus, there is an urgent need for the development of novel disease-modifying therapies to prevent the accumulation of cytotoxic α-synuclein (αS), a protein involved in PD pathogenesis, in the nervous system. Furthermore, emerging evidence suggests that the toxic αS species can move from one cell to another, thereby affecting the normal physiological state of the neighboring cells in a prion-like manner. The transmissible, extracellular αS is considered to be an ideal target for the disease-modifying treatments including antibody-based therapy. In this review, we will describe the molecular structure and functions of αS, its relevance to PD pathogenesis, and will discuss the current status and future perspectives of disease-modifying strategies targeting αS in PD.

Sensitivity and specificity of meningeal signs in patients with meningitis.

BACKGROUND: Several types of physical examinations are used in the diagnosis of meningitis, including nuchal rigidity, jolt accentuation, Kernig's sign, and Brudzinski's sign. Jolt accentuation was reported to have sensitivity of nearly 100% and to be highly efficient for excluding meningitis, but more recent studies showed that a number of patients with meningitis may present negative in this test. METHODS: We systematically reviewed studies on the above-mentioned physical examination tests and performed meta-analysis of their diagnostic characteristics to evaluate the clinical usefulness. Nine studies, comprising a total of 599 patients with pleocytosis in the cerebrospinal fluid (CSF) and 1216 patients without CSF pleocytosis, were enrolled in the analysis. RESULTS: Jolt accentuation showed a decent level of odds ratio (3.62; 99% confidence interval (CI): 1.13-11.60, P = 0.004) comparable to that in nuchal rigidity (2.52; 1.21-5.27, P = 0.001) for the correct prediction of CSF pleocytosis among subjects with suspected meningitis. The estimated sensitivity was relatively high (40%-60%) in nuchal rigidity or jolt accentuation tests. On the other hand, Kernig's and Brudzinski's signs exhibited relatively low sensitivity (20%-30%). The estimated specificity was higher in Kernig's and Brudzinski's signs (85%-95%) than in nuchal rigidity or jolt accentuation tests (65%-75%). CONCLUSION: Approximately half of the patients with meningitis may not present typical meningeal signs upon physical examination. Combining several examinations for the detection of meningeal signs may decrease the risk of misdiagnosis.

Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1-assisted dopamine transporter endocytosis.

The neuropathological hallmarks of Parkinson's disease (PD) include the appearance of α-synuclein (α-SYN)-positive Lewy bodies (LBs) and the loss of catecholaminergic neurons. Thus, a potential mechanism promoting the uptake of extracellular α-SYN may exist in susceptible neurons. Of the various differentially expressed proteins, we are interested in flotillin (FLOT)-1 because this protein is highly expressed in the brainstem catecholaminergic neurons and is strikingly up-regulated in PD brains. In this study, we found that extracellular monomeric and fibrillar α-SYN can potentiate FLOT1-dopamine transporter (DAT) binding and pre-endocytic clustering of DAT on the cell surface, thereby facilitating DAT endocytosis and down-regulating its transporter activity. Moreover, we demonstrated that α-SYN itself exploited the DAT endocytic process to enter dopaminergic neuron-like cells, and both FLOT1 and DAT were found to be the components of LBs. Altogether, these findings revealed a novel role of extracellular α-SYN on cellular trafficking of DAT and may provide a rationale for the cell type-specific, functional, and pathologic alterations in PD.-Kobayashi, J., Hasegawa, T., Sugeno, N., Yoshida, S., Akiyama, T., Fujimori, K., Hatakeyama, H., Miki, Y., Tomiyama, A., Kawata, Y., Fukuda, M., Kawahata, I., Yamakuni, T., Ezura, M., Kikuchi, A., Baba, T., Takeda, A., Kanzaki, M., Wakabayashi, K., Okano, H., Aoki, M. Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1-assisted dopamine transporter endocytosis.

Interstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational study.

BACKGROUND: Riluzole is the only approved oral drug for amyotrophic lateral sclerosis (ALS). We performed a retrospective study including ALS patients treated with riluzole, focusing on adverse events. METHODS: Patients diagnosed with ALS according to the revised El Escorial criteria (World Federation of Neurology) in our center and who were administered 50 mg oral riluzole twice daily between January 2011 and September 2017 and followed up for at least 6 months from treatment initiation or until death were included. Data regarding sex, age, disease type, initial symptoms, biochemical analyses performed before and after riluzole administration, and medical history were collected. In case of withdrawal, cause of discontinuation and durations of disease and drug administration were recorded. RESULTS: A total of 92 cases were enrolled. Riluzole administration was discontinued in 20 cases (21.7%). The most frequent reason for discontinuation was elevated liver enzymes (n = 5, 5.4%), followed interstitial pneumonia (IP), nausea and appetite loss, dizziness, general malaise, tongue paresthesia, and urinary urgency. In two cases, administration was discontinued primarily because of progression of bulbar palsy. All adverse events occurred within 6 months from treatment initiation and improved soon after its discontinuation. Three IP cases developed severe respiratory failure and required steroid treatment. CONCLUSION: Riluzole administration was discontinued in 20 cases among total of 92 cases. Careful follow-up is important for the first six months after the initiation of riluzole administration, including through interviews, chemical analyses, and chest X-rays, as required.

Early neurosyphilis presenting with multiple cranial nerve palsies: A case report of management by combined penicillin-corticosteroid treatment.

Early neurosyphilis commonly appears in basilar meninges, and its meningeal inflammation can spread to neighboring cranial nerves, resulting in some cranial nerve palsies. Herein, we report a case of a 51-year-old man who presented with right peripheral facial nerve palsy. His symptoms completely disappeared with prednisolone monotherapy without antibiotics use and were not exacerbated during clinical treatment. However, 2 months after remission of seventh cranial neuropathy, fifth and eighth cranial neuropathies appeared on the right side. Serologic tests for syphilis were revealed to be abnormal. Finally, the patient was diagnosed with early neurosyphilis with multiple cranial palsies. His neurological symptoms were markedly improved by combined penicillin-corticosteroid treatment. Systemic corticosteroids could be effective as adjunctive therapy to ameliorate neurological sequelae in early neurosyphilis.

Paradoxical Cerebral Embolism after Gastrointestinal Endoscopy in a Patient with Crohn's Disease.

Development of paradoxical cerebral embolism requires both unstable venous thrombosis and right-to-left shunt (RLS). Gastrointestinal endoscopy (GE) has the potential to affect intrathoracic and abdominal venous thrombi and to enhance RLS because the procedure alters intrathoracic and abdominal pressure. We describe a patient with Crohn's disease who developed paradoxical cerebral embolism after GE. Both an unstable venous thrombus in the superior vena cava and RLS through patent foramen ovale were thought to be responsible for the stroke. Considering that patients with digestive system diseases undergo GE as a routine examination or therapy, screenings for hypercoagulable state and intrathoracic and abdominal thrombi are important to prevent thromboembolism related to GE.

Parkinson's disease-linked DNAJC13 mutation aggravates alpha-synuclein-induced neurotoxicity through perturbation of endosomal trafficking.

Mutations in DNAJC13 gene have been linked to familial form of Parkinson's disease (PD) with Lewy pathology. DNAJC13 is an endosome-related protein and believed to regulate endosomal membrane trafficking. However, the mechanistic link between DNAJC13 mutation and α-synuclein (αSYN) pathology toward neurodegeneration remains poorly understood. In this study, we showed that PD-linked N855S-mutant DNAJC13 caused αSYN accumulation in the endosomal compartment, presumably due to defective cargo trafficking from the early endosome to the late and/or recycling endosome. In vivo experiments using human αSYN transgenic flies showed that mutant DNAJC13 not only increased the amount of insoluble αSYN in fly head but also induced dopaminergic neurodegeneration, rough eye phenotype and age-dependent locomotor impairment. Together, these findings suggest that DNAJC13 mutation perturbs multi-directional endosomal trafficking, resulting in the aberrant endosomal retention of αSYN, which might predispose to the neurodegenerative process that leads to PD.

DnaJ/Hsp40 Family and Parkinson's Disease.

Parkinson's disease (PD) is the second most common devastating neurodegenerative disorder after Alzheimer's disease. The precise molecular and cellular basis underlying PD still remains uncertain; however, accumulating evidence suggests that neuronal cell death is caused by a combination of environmental and genetic factors. Over the previous two decades, more than 20 genes have been identified as the cause of and/or risk for PD. Because sporadic and familial forms of PD have many similarities in clinical and neuropathological features, common molecular pathways, such as aberrant mitochondrial and protein homeostasis, are likely to exist in both conditions. Of the various genes and proteins involved in PD, the versatile DnaJ/Hsp40 co-chaperones have attracted particular attention since several genes encoding this protein family have been successively identified as the cause of the familial forms of PD/Parkinsonism. In this review, we will introduce the current knowledge regarding the integratory and modulatory effect of DnaJ/Hsp40 in various cellular functions and argue how the failure of these proteins may initiate and/or facilitate of the disease.

In vivo visualization of tau deposits in corticobasal syndrome by 18F-THK5351 PET.

OBJECTIVE: To determine whether 18F-THK5351 PET can be used to visualize tau deposits in brain lesions in live patients with corticobasal syndrome (CBS). METHODS: We evaluated the in vitro binding of 3H-THK5351 in postmortem brain tissues from a patient with corticobasal degeneration (CBD). In clinical PET studies, 18F-THK5351 retention in 5 patients with CBS was compared to that in 8 age-matched normal controls and 8 patients with Alzheimer disease (AD). RESULTS: 3H-THK5351 was able to bind to tau deposits in the postmortem brain with CBD. In clinical PET studies, the 5 patients with CBS showed significantly higher 18F-THK5351 retention in the frontal, parietal, and globus pallidus than the 8 age-matched normal controls and patients with AD. Higher 18F-THK5351 retention was observed contralaterally to the side associated with greater cortical dysfunction and parkinsonism. CONCLUSIONS: 18F-THK5351 PET demonstrated high tracer signal in sites susceptible to tau deposition in patients with CBS. 18F-THK5351 should be considered as a promising candidate radiotracer for the in vivo imaging of tau deposits in CBS.

Cancer-related Stroke due to Mural Thrombus in the Extracranial Carotid Artery.

A 41-year-old man was admitted to our hospital because of a cancer-related stroke (CRS) caused by a thrombus of the extracranial carotid artery. He had undergone neoadjuvant radiochemotherapy for metastatic colorectal adenocarcinoma. The serum D-dimer values were within the normal range. We treated him with intravenous unfractionated heparin followed by warfarin. There were no recurrent stroke events over six months. The leading cause of a CRS is an embolism caused by hypercoagulopathy, mainly represented by non-bacterial thrombotic endocarditis. However, it was unusual that, in the current case, a thrombus of the extracranial carotid artery was formed with no significant residual stenosis, thus resulting in an artery-to-artery embolism.

ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways.

Endosomal sorting required for transport (ESCRT) complexes orchestrate endo-lysosomal sorting of ubiquitinated proteins, multivesicular body formation and autophagic degradation. Defects in the ESCRT pathway have been implicated in many neurodegenerative diseases, but the underlying molecular mechanisms that link them to neurodegeneration remain unknown. In this study, we showed that forebrain-specific ablation of ESCRT-0/Hrs induced marked hippocampal neuronal cell loss accompanied by the accumulation of ubiquitinated proteins, including α-synuclein, TDP-43 and huntingtin as well as the autophagic substrate SQSTM1/p62. Consistent with this, silencing of Hrs in cultured cells not only led to α-synuclein and TDP-43 accumulation in addition to impaired autophagic flux but also suppressed cell viability through the induction of ER stress followed by the activation of JNK and RIPK1, a key regulator of necroptosis. Moreover, necrostatin-1, a specific inhibitor of RIPK1, and pan-caspase inhibitors partially reduced the neurotoxicity in the Hrs-silenced cells. Altogether, these findings suggest that the disruption of ESCRT-0/Hrs in the nervous system compromises autophagic/lysosomal degradation of neurodegenerative disease-related proteins, which thereby triggers ER stress-mediated apoptotic and necroptotic cell death.

Peak Systolic Velocity Measured by Continuous-Wave Doppler Ultrasonography without Angle Correction in Patients with Internal Carotid Artery Stenosis.

BACKGROUND: Peak systolic velocity (PSV) is measured with pulse-wave (PW) Doppler with angle correction in patients with internal carotid artery stenosis (ICAS). However, the correlation between conventional angiography and PSV shows considerable scattering. We hypothesized that measuring PSV without angle correction would lead to better inter-rater reliability. This hypothesis was tested using a sector probe and continuous-wave (CW) Doppler without angle correction. METHODS: Consecutive patients with more than 50% ICAS were enrolled from a prospective database. PSV was measured with PW Doppler with angle correction (PW PSV) and CW Doppler without angle correction (CW PSV) by 2 examiners. The inter-rater reliabilities of PW PSV and CW PSV were analyzed by Spearman's rank correlation test. RESULTS: A total of 37 ICAS sites (median 67 [interquartile range 57-78] % stenosis) were enrolled. Measuring PSV using a sector probe insonating nearly parallel to the flow was feasible in all cases. Inter-rater reproducibility of CW PSV (Spearman's ρ = .810) was similar to that of PW PSV (Spearman's ρ = .796). When limited to patients with a PSV greater than 200 cm/s with both PW Doppler examinations (25 ICAS sites), inter-rater reliability was relatively higher for CW PSV (Spearman's ρ = .674) than for PW PSV (Spearman's ρ = .423). CONCLUSIONS: Measuring PSV with CW Doppler using a sector probe was feasible. Inter-rater reliability was similar between PW Doppler with angle correction and CW Doppler without angle correction in evaluating PSV in patients with ICAS. CW Doppler appears to have better inter-rater reproducibility than PW Doppler in assessing high PSV.

Isolated Posterior Inferior Cerebellar Artery Dissection as a Cause of Ischemic Stroke: Clinical Features and Prognosis.

BACKGROUND: The purpose of this study was to clarify the incidence, clinical and radiological features and outcomes of isolated posterior inferior cerebellar artery (PICA) dissection in isolated PICA territory infarctions. METHODS: We retrospectively reviewed consecutive inpatients with ischemic stroke secondary to isolated PICA dissection from our stroke database between January 2004 and December 2013 and reviewed the literature with regard to those patients. RESULTS: Of 167 consecutive patients with an isolated PICA territory infarction, a total of 10 patients (6.0%, 3 women, 48.1 ± 7.1 years) were diagnosed as having an isolated PICA dissection. Patients with PICA dissection were younger (p < 0.001), more commonly experienced headache at onset (p = 0.008), less commonly had hyperlipidemia (p = 0.044) and showed a lower modified Rankin Scale score at discharge (p = 0.002) when compared with patients without arterial dissection. In 6 of these 10 patients, PICA dissections had not been suspected on initial magnetic resonance angiography (MRA) and were confirmed by follow-up MRA or digital subtraction angiography. In the follow-up period (median 1.5 years, interquartile range 0.5-6.3 years), there were no recurrent ischemic or hemorrhagic stroke events. CONCLUSIONS: Isolated PICA dissection as an etiological mechanism in isolated PICA territory infarctions may be more common than was previously recognized to be. The diagnosis of PICA dissection is often difficult and requires close and repeated morphological evaluation. We should carefully identify PICA dissections as a possible cause of PICA territory infarctions.

Relative systolic blood pressure reduction and clinical outcomes in hyperacute intracerebral hemorrhage: the SAMURAI-ICH observational study.

BACKGROUND AND PURPOSE: Blood pressure lowering is often performed as a part of general acute management in acute intracerebral hemorrhage (ICH) patients. The relationship between relative blood pressure reduction and clinical outcomes is not fully known. METHODS: Hyperacute (<3 h from onset) ICH patients with initial SBP more than 180 mmHg were included in the observational study. All patients received intravenous antihypertensive treatment based on a predefined protocol to lower and maintain SBP between 120 and 160 mmHg. The relative SBP reduction was defined as the ratio of SBP reduction to the admission SBP in the first 24 h, and associations between the relative SBP reduction and neurological deterioration (≥2 points decrease in the Glasgow Coma Scale score or ≥4 increase in the National Institutes of Health Stroke Scale score), hematoma expansion (>33% increase), and unfavorable outcome (modified Rankin scale score 4-6 at 3 months) were assessed with multivariate logistic regression analyses. RESULTS: Of the 211 patients [81 women, median age 65 (interquartile range 58-74) years, and median initial National Institutes of Health Stroke Scale score 13 (8-17)] enrolled, 17 (8%) showed neurological deterioration, 36 (17%) showed hematoma expansion, and 87 (41%) had an unfavorable outcome. On multivariate regression analyses, relative SBP reduction was independently and inversely associated with neurological deterioration (odds ratio 0.053, 95% confidence interval 0.011-0.254 per 10% increment), hematoma expansion (0.289, 0.099-0.841), and unfavorable outcome (0.254, 0.095-0.680) after adjusting for known predictive factors. CONCLUSION: Insufficient relative SBP reduction after standardized antihypertensive therapy in hyperacute ICH was independently associated with poor clinical outcomes. Aggressive antihypertensive treatment may improve clinical outcomes.

Clinical and genetic investigation of 17 Japanese patients with hyperekplexia.

AIM: The aim of the study was to determine clinical and genetic characteristics of Japanese patients with hyperekplexia. METHOD: Clinical courses, responses to antiepileptic drugs, outcomes, and genetic testing were investigated in 17 Japanese patients (nine males, eight females, median age 1y, range birth-45y) with hyperekplexia. RESULTS: In all patients, muscle stiffness and startle responses appeared soon after birth. Only seven patients were diagnosed with hyperekplexia before 1 year of age. Seven patients had been misdiagnosed with other disorders such as epilepsy and adult-onset anxiety neurosis. Umbilical/inguinal hernias were seen in 10 patients. Life-threatening events were noted in four patients. Clonazepam was the most effective drug. Muscle stiffness completely disappeared in 12 patients before 5 years of age, whereas startle responses resolved in only three patients. Mutations in the GLRA1 and GLRB genes were identified in 16 patients and one patient respectively. In 14 patients, the mutation showed autosomal dominant inheritance; in the other three, inheritance was autosomal recessive. p.R271Q of GLRA1 was the most frequent mutation, found in 10 patients. Novel mutations, p.A272P and p.A384P of GLRA1, were detected. Clinical severity and outcome varied even in the same family. INTERPRETATION: Early correct diagnosis is essential for prevention of accidental injuries and to provide appropriate treatments for hyperekplexia. Clonazepam is effective, although the time taken for startle responses to resolve varied.

Blood pressure variability on antihypertensive therapy in acute intracerebral hemorrhage: the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-intracerebral hemorrhage study.

BACKGROUND AND PURPOSE: The associations between early blood pressure (BP) variability and clinical outcomes in patients with intracerebral hemorrhage after antihypertensive therapy, recently clarified by a post hoc analysis of Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2), were confirmed using the Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI)-intracerebral hemorrhage study cohort. METHODS: Patients with hyperacute (<3 hours from onset) intracerebral hemorrhage with initial systolic BP (SBP) >180 mm Hg were registered in a prospective, multicenter, observational study. All patients received antihypertensive therapy based on a predefined standardized protocol to lower and maintain SBP between 120 and 160 mm Hg using intravenous nicardipine. BPs were measured hourly during the initial 24 hours. BP variability was determined as SD and successive variation. The associations between BP variability and hematoma expansion (>33%), neurological deterioration within 72 hours, and unfavorable outcome (modified Rankin Scale, 4-6) at 3 months were assessed. RESULTS: Of the 205 patients, 33 (16%) showed hematoma expansion, 14 (7%) showed neurological deterioration, and 81 (39%) had unfavorable outcomes. The SD and successive variation of SBP were 13.8 (interquartile range, 11.5-16.8) and 14.9 (11.7-17.7) mm Hg, respectively, and those of diastolic BP were 9.4 (7.5-11.2) and 13.1 (11.2-15.9) mm Hg, respectively. On multivariate regression analyses, neurological deterioration was associated with the SD of SBP (odds ratio, 2.75; 95% confidence interval, 1.45-6.12 per quartile) and the successive variation of SBP (2.37; 1.32-4.83), and unfavorable outcome was associated with successive variation of SBP (1.42; 1.04-1.97). Hematoma expansion was not associated with any BP variability. CONCLUSIONS: SBP variability during the initial 24 hours of acute intracerebral hemorrhage was independently associated with neurological deterioration and unfavorable outcomes. Stability of antihypertensive therapy may improve clinical outcomes.

Etiological mechanisms of isolated pontine infarcts based on arterial territory involvement.

BACKGROUND: Pontine infarcts can be classified into four regions based on the vascular anatomy: anteromedial, anterolateral, lateral and posterior. The purpose of this study was to determine if different etiological mechanisms are responsible for these four types of pontine infarcts. METHODS: We studied consecutive patients within 7 days of symptom onset who had isolated pontine infarcts on diffusion-weighted imaging. The factors associated with infarct topography were determined by multivariate logistic regression analysis. RESULTS: A total of 205 patients were enrolled (78 women; mean age, 72 ± 11 years). The distribution of the infarcts was anteromedial in 73%, anterolateral in 14%, lateral in 3% and posterior in 10%. In multivariate logistic regression analysis, major cardioembolic sources (odds ratio (OR), 4.17; 95% confidence interval (CI), 1.21-14.1) and previous ischemic stroke (OR, 2.92; 95% CI, 1.09-7.89) were positively associated with lateral or posterior infarcts compared with anteromedial infarcts. In contrast, advanced age (OR, 0.55; 95% Cl, 0.35-0.81 per 10-year increase), diabetes mellitus (OR, 0.31; 95% CI, 0.11-0.80) and basilar artery disease (OR, 0.27; 95% CI, 0.08-0.75) were negatively associated with lateral or posterior pontine infarcts. CONCLUSIONS: Baseline characteristics were significantly different among patients with isolated pontine infarcts in different topographic locations. Our results suggest that cardioembolism is relatively common in lateral or posterior pontine infarcts, whereas basilar artery atherosclerosis is more common in anteromedial infarcts.