Alterations in driving ability and their relationship with morphometric magnetic resonance imaging indicators in patients with amnestic mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Drivers with dementia are at a higher risk of motor vehicle accidents. The characteristics of driving behaviour of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) have not been fully elucidated. We investigated driving ability and its relationship with cognitive function and magnetic resonance imaging (MRI) morphometry indicators. METHODS: The driving abilities of 19 patients with AD and 11 with amnestic MCI (aMCI) were evaluated using a driving simulator. The association between each driving ability parameter and the Mini-Mental State Examination (MMSE) score or voxel-based specific regional analysis system for AD (VSRAD) was assessed. RESULTS: Patients with AD made a significantly higher number of operational errors than those with aMCI in attention allocation in the complex task test (P = 0.0008). The number of operational errors in attention allocation in the complex task test significantly and negatively correlated with MMSE scores in all participants (r = -0.4354, P = 0.0162). The decision time in the selective reaction test significantly and positively correlated with the severity and extent of medial temporal structural atrophy (r = 0.4807, P = 0.0372; r = 0.4862, P = 0.0348; respectively). CONCLUSION: An increase in the operational errors for attention allocation in the complex task test could be a potential indicator of progression from aMCI to AD. Atrophy of the medial temporal structures could be a potential predictor of impaired judgement in driving performance in aMCI and AD. A driving simulator could be useful for evaluating the driving abilities of individuals with aMCI and AD.

Endothelial expression of human amyloid precursor protein leads to amyloid ß in the blood and induces cerebral amyloid angiopathy in knock-in mice.

The deposition of amyloid ß (Aß) in blood vessels of the brain, known as cerebral amyloid angiopathy (CAA), is observed in most patients with Alzheimer's disease (AD). Compared with the pathology of CAA in humans, the pathology in most mouse models of AD is not as evident, making it difficult to examine the contribution of CAA to the pathogenesis of AD. On the basis of biochemical analyses that showed blood levels of soluble amyloid precursor protein (APP) in rats and mice were markedly lower than those measured in human samples, we hypothesized that endothelial APP expression would be markedly lower in rodents and subsequently generated mice that specifically express human WT APP (APP770) in endothelial cells (ECs). The resulting EC-APP770+ mice exhibited increased levels of serum Aß and soluble APP, indicating that endothelial APP makes a critical contribution to blood Aß levels. Even though aged EC-APP770+ mice did not exhibit Aß deposition in the cortical blood vessels, crossing these animals with APP knock-in mice (AppNL-F/NL-F) led to an expanded CAA pathology, as evidenced by increased amounts of amyloid accumulated in the cortical blood vessels. These results highlight an overlooked interplay between neuronal and endothelial APP in brain vascular Aß deposition. We propose that these EC-APP770+:AppNL-F/NL-F mice may be useful to study the basic molecular mechanisms behind the possible breakdown of the blood-brain barrier upon administration of anti-Aß antibodies.

Dual Antiplatelet Therapy With Cilostazol for Secondary Prevention in Lacunar Stroke: Subanalysis of the CSPS.com Trial.

BACKGROUND: The effectiveness of long-term dual antiplatelet therapy (DAPT) to prevent recurrent strokes in patients with lacunar stroke remains unclarified. Therefore, this study aimed to compare and to elucidate the safety and effectiveness of DAPT and single antiplatelet therapy (SAPT) in preventing recurrence in chronic lacunar stroke. METHODS: CSPS.com (Cilostazol Stroke Prevention Study for Antiplatelet Combination) was a prospective, multicenter, randomized controlled trial. In this prespecified subanalysis, 925 patients (mean age, 69.5 years; 69.4% men) with lacunar stroke were selected from 1884 patients with high-risk noncardioembolic stroke, enrolled in the CSPS.com trial after 8 to 180 days following stroke. Patients were randomly assigned to receive either SAPT or DAPT using cilostazol and were followed for 0.5 to 3.5 years. The primary efficacy outcome was the first recurrence of ischemic stroke. The safety outcomes were severe or life-threatening bleeding. RESULTS: The DAPT group receiving cilostazol and either aspirin or clopidogrel and SAPT group receiving aspirin or clopidogrel alone comprised 464 (50.2%) and 461 (49.8%) patients, respectively. Ischemic stroke occurred in 12 of 464 patients (1.84 per 100 patient-years) in the DAPT group and 31 of 461 patients (4.42 per 100 patient-years) in the SAPT group, during follow-up. After adjusting for multiple potential confounding factors, ischemic stroke risk was significantly lower in the DAPT group than in the SAPT group (hazard ratio, 0.43 [95% CI, 0.22-0.84]). The rate of severe or life-threatening hemorrhage did not differ significantly between the groups (2 patients [0.31 per 100 patient-years] versus 6 patients [0.86 per 100 patient-years] in the DAPT and SAPT groups, respectively; hazard ratio, 0.36 [95% CI, 0.07-1.81]). CONCLUSIONS: In patients with lacunar stroke, DAPT using cilostazol had significant benefits in reducing recurrent ischemic stroke incidence compared with SAPT without increasing the risk of severe or life-threatening bleeding. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000012180.

High frequency of HTRA1 AND ABCC6 mutations in Japanese patients with adult-onset cerebral small vessel disease.

BACKGROUND: This study aimed to clarify the frequency and clinical features of monogenic cerebral small vessel disease (mgCSVD) among patients with adult-onset severe CSVD in Japan. METHODS: This study included patients with adult-onset severe CSVD with an age of onset ≤55 years (group 1) or >55 years and with a positive family history (group 2). After conducting conventional genetic tests for NOTCH3 and HTRA1, whole-exome sequencing was performed on undiagnosed patients. Patients were divided into two groups according to the results of the genetic tests: monogenic and undetermined. The clinical and imaging features were compared between the two groups. RESULTS: Group 1 and group 2 included 75 and 31 patients, respectively. In total, 30 patients had NOTCH3 mutations, 11 patients had HTRA1 mutations, 6 patients had ABCC6 mutations, 1 patient had a TREX1 mutation, 1 patient had a COL4A1 mutation and 1 patient had a COL4A2 mutation. The total frequency of mutations in NOTCH3, HTRA1 and ABCC6 was 94.0% in patients with mgCSVD. In group 1, the frequency of a family history of first relatives, hypertension and multiple lacunar infarctions (LIs) differed significantly between the two groups (monogenic vs undetermined; family history of first relatives, 61.0% vs 25.0%, p=0.0015; hypertension, 34.1% vs 63.9%, p=0.0092; multiple LIs, 87.8% vs 63.9%, p=0.0134). CONCLUSIONS: More than 90% of mgCSVDs were diagnosed by screening for NOTCH3, HTRA1 and ABCC6. The target sequences for these three genes may efficiently diagnose mgCSVD in Japanese patients.

Relationship between Neurological Deterioration and Blood Pressure/Heart Rate Variability in Patients with Acute Cerebral Infarction.

OBJECTIVES: Neurological deterioration (ND) during hospitalization is an independent predictor of poor prognosis after stroke. Risk factors affecting early ND within 48 h post stroke have been intensively investigated, while few data are available on those for late ND after transfer to a wheelchair. Therefore, it was investigated whether hemodynamic factors may affect the late ND during hospitalization. MATERIALS AND METHODS: A retrospective study was conducted on 135 patients with atherothrombotic or cardiogenic cerebral infarction who were admitted to our hospital between April 1st, 2014 and July 31st, 2017. During hospitalization, average, maximum, and minimum values were determined for systolic blood pressure (sBP), diastolic BP (dBP), and heart rate (HR), respectively.135 patients were classified into two groups; ND (+) group, in which modified Barthel index score at the time of transfer to a wheelchair showed five points or more decrease between wheelchair transfer and discharge, and ND (-) group, which did not. Vital indices were compared between the two groups and subjected to ROC-curve analysis. RESULTS: The ND (+) group included 32 patients, and the ND (-) 103. Significant differences were found between the groups in four items; sBPmin (p = 0.029), dBPmin (p = 0.019), HRave (p = 0.028), and HRmax (p < 0.01). The ND (+) group showed lower sBPmin and dBPmin, and higher HRave and HRmax than the ND (-) group. CONCLUSIONS: Late ND after transfer to a wheelchair is related to the vital indices during hospitalization and should be cautiously managed to prevent late ND.

Quantitative Analysis of White Matter Hyperintensity: Comparison of Magnetic Resonance Imaging Image Analysis Software.

OBJECTIVE: White matter hyperintensity (WMH), defined as abnormal signals on magnetic resonance imaging (MRI), is an important clinical indicator of aging and dementia. Although MRI image analysis software can automatically detect WMH, the quantitative accuracy of periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH) is unknown. MATERIALS AND METHODS: This study was a sub-analysis of MRI data from an ongoing hospital-based prospective cohort study (the Gimlet study). Between March 2016 and March 2017, we enrolled patients who visited our memory clinic and agreed to undergo medical assessments of cognitive function and fecal examination to study the gut microbiome. Participants with a history of stroke were excluded. WMH was independently quantitatively analyzed using two MRI imaging analysis software modalities: SNIPER and FUSION. Intraclass correlation coefficients and the mean difference in volume were calculated and compared between modalities. RESULTS: The data of 87 patients (49 women, mean age 74.8 ± 7.9 years) were analyzed. Both total WMH and DWMH volumes obtained using FUSION were greater (p < 0.001), and PVH volume was smaller (p < 0.001) than those obtained using SNIPER. Intraclass correlation coefficients for the lesion measurements of WMH, PVH, and DWMH between the different software were 0.726 (p < 0.001), 0.673 (p < 0.001), and 0.048 (p = 0.231), respectively. CONCLUSIONS: There were significant differences in the quantitative data of WMH between the two MRI imaging analysis software modalities. Thus, care should be taken for quantitative assessments of WMH.

Dual Antiplatelet Therapy Using Cilostazol With Aspirin or Clopidogrel: Subanalysis of the CSPS.com Trial.

Background and Purpose: Although dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the recurrence of ischemic stroke while significantly increasing the bleeding events compared with monotherapy, the CSPS.com trial (Cilostazol Stroke Prevention Study combination) showed that DAPT using cilostazol was more effective without the bleeding risk. In the CSPS.com trial, aspirin or clopidogrel was used as the underlying antiplatelet drug. The effectiveness and safety of each combination were examined and clarified. Methods: In the CSPS.com trial, a multicenter, open-label, randomized controlled study, patients with high-risk, noncardioembolic ischemic stroke 8 to 180 days after onset treated with aspirin or clopidogrel alone at the discretion of the physician in charge were recruited. Patients were randomly assigned to receive either monotherapy or DAPT using cilostazol and followed for 0.5 to 3.5 years. The primary efficacy outcome was first recurrence of ischemic stroke. The safety outcome was severe or life-threatening bleeding. The analysis was based on the underlying antiplatelet agents. Results: A total of 763 patients taking aspirin and 1116 taking clopidogrel were included in the intention-to-treat analysis. Although the clopidogrel group had more risk factors than the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the 2 groups. In the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the DAPT group and the aspirin-monotherapy group. In the clopidogrel group, the primary end point occurred at a rate of 2.31 per 100 patient-years in the DAPT group and 5.19 per 100 patient-years in the clopidogrel-monotherapy group (hazard ratio, 0.447 [95% CI, 0.258­0.774]). Safety outcome did not differ significantly between groups (0.51 per 100 patient-years versus 0.71 per 100 patient-years, respectively; hazard ratio, 0.730 [95% CI, 0.206­2.588]). Conclusions: The combination of cilostazol and clopidogrel significantly reduced the recurrence of ischemic stroke without increasing the bleeding risk in noncardioembolic, high-risk patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012180.

Deletion of B-cell translocation gene 2 (BTG2) alters the responses of glial cells in white matter to chronic cerebral hypoperfusion.

BACKGROUND: Subcortical ischemic vascular dementia, one of the major subtypes of vascular dementia, is characterized by lacunar infarcts and white matter lesions caused by chronic cerebral hypoperfusion. In this study, we used a mouse model of bilateral common carotid artery stenosis (BCAS) to investigate the role of B-cell translocation gene 2 (BTG2), an antiproliferation gene, in the white matter glial response to chronic cerebral hypoperfusion. METHODS: Btg2-/- mice and littermate wild-type control mice underwent BCAS or sham operation. Behavior phenotypes were assessed by open-field test and Morris water maze test. Brain tissues were analyzed for the degree of white matter lesions and glial changes. To further confirm the effects of Btg2 deletion on proliferation of glial cells in vitro, BrdU incorporation was investigated in mixed glial cells derived from wild-type and Btg2-/- mice. RESULTS: Relative to wild-type mice with or without BCAS, BCAS-treated Btg2-/- mice exhibited elevated spontaneous locomotor activity and poorer spatial learning ability. Although the severities of white matter lesions did not significantly differ between wild-type and Btg2-/- mice after BCAS, the immunoreactivities of GFAP, a marker of astrocytes, and Mac2, a marker of activated microglia and macrophages, in the white matter of the optic tract were higher in BCAS-treated Btg2-/- mice than in BCAS-treated wild-type mice. The expression level of Gfap was also significantly elevated in BCAS-treated Btg2-/- mice. In vitro analysis showed that BrdU incorporation in mixed glial cells in response to inflammatory stimulation associated with cerebral hypoperfusion was higher in Btg2-/- mice than in wild-type mice. CONCLUSION: BTG2 negatively regulates glial cell proliferation in response to cerebral hypoperfusion, resulting in behavioral changes.

Evaluation of cortical superficial siderosis in patients with cognitive dysfunction using 3D FLAIR and 3D DIR.

OBJECTIVES: Our aim was to evaluate the detectability of cortical superficial siderosis (cSS) by 3D FLAIR and 3D DIR images in comparison with the SWI images in patients with cognitive dysfunction. METHODS: We studied 246 patients with cognitive dysfunction (144 women, 102 men; mean age: 75.5 ± 7.53 years) who visited a memory clinic at our hospital and underwent MR examinations at 3 T. Specifically, 16 patients with Alzheimer disease (AD) (n = 11) and AD with cerebrovascular disease (n = 5) manifested cSS based on SWI. Each set of MR images (3D FLAIR and 3D DIR) was reviewed by two reviewers separately for the detection of sulcal hyperintensity that suggested cSS. RESULTS: SWI detected a greater number of cSS sulci than 3D DIR and 3D FLAIR. The sensitivity and specificity for the detection of sulcal hyperintensity were the same between 3D FLAIR and 3D DIR (87.5%/100%). However, 3D DIR detected a greater number of cSS sulci than 3D FLAIR (p = .005). CONCLUSIONS: Our study showed that 3D DIR and 3D FLAIR can detect sulcal hyperintensity related to cSS although they are less sensitive to cSS lesions than SWI. KEY POINTS: • 3D FLAIR and 3D DIR can show sulcal signal abnormalities related to cSS in patients with cognitive dysfunction. • 3D FLAIR and 3D DIR detect sulcal hyperintensity of cSS, although they are less sensitive to cSS than SWI. • Signal alterations due to cSS are more detectable in 3D DIR than in 3D FLAIR.

Association between cortical microinfarcts and total small vessel disease burden in cerebral amyloid angiopathy on 3-Tesla magnetic resonance imaging.

BACKGROUND AND PURPOSE: Cortical microinfarcts (CMIs) are frequently found in the brains of patients with advanced cerebral amyloid angiopathy (CAA) at autopsy. The small vessel disease (SVD) score for CAA (i.e., the CAA-SVD score) has been proposed to evaluate the severity of CAA-associated vasculopathic changes by a combination of magnetic resonance imaging (MRI) markers. The aim of this study was to examine the association between total CAA-SVD score and features of CMIs on in vivo 3-Tesla MRI. METHODS: Eighty patients with probable CAA were retrospectively analyzed. Lobar cerebral microbleeds, cortical superficial siderosis, enlargement of perivascular space in the centrum semiovale and white matter hyperintensity were collectively assessed, and the total CAA-SVD score was calculated. The presence of CMI was also examined. RESULTS: Of the 80 patients, 13 (16.25%) had CMIs. CMIs were detected more frequently in the parietal and occipital lobes. A positive correlation was found between total CAA-SVD score and prevalence of CMI (ρ = 0.943; p = 0.005). Total CAA-SVD score was significantly higher in patients with CMIs than in those without (p = 0.009). In a multivariable logistic regression analysis, the presence of CMIs was significantly associated with total CAA-SVD score (odds ratio 2.318 [95% confidence interval 1.228-4.376]; p = 0.01, per each additional point). CONCLUSIONS: The presence of CMIs with a high CAA-SVD score could be an indicator of more severe amyloid-associated vasculopathic changes in patients with probable CAA.

Long-term MRI changes in a patient with Kelch-like protein 11-associated paraneoplastic neurological syndrome.

BACKGROUND AND PURPOSE: The aim of this study was to identify the long-term radiological changes, autoantibody specificities, and clinical course in a patient with kelch-like protein 11 (KLHL11)-associated paraneoplastic neurological syndrome (PNS). METHODS: Serial brain magnetic resonance images were retrospectively assessed. To test for KLHL11 autoantibodies, longitudinal cerebrospinal fluid (CSF) and serum samples were screened by Phage-display ImmunoPrecipitation and Sequencing (PhIP-Seq). Immunohistochemistry was also performed to assess for the presence of KLHL11 in the patient's seminoma tissue. RESULTS: A 42-year-old man presented with progressive ataxia and sensorineural hearing loss. Metastatic seminoma was detected 11 months after the onset of the neurological symptoms. Although immunotherapy was partially effective, his cerebellar ataxia gradually worsened over the next 8 years. Brain magnetic resonance imaging revealed progressive brainstem and cerebellar atrophy with a "hot-cross-bun sign", and low-signal intensity on susceptibility-weighted imaging (SWI) in the substantia nigra, red nucleus and dentate nuclei. PhIP-Seq enriched for KLHL11-derived peptides in all samples. Immunohistochemical staining of mouse brain with the patient CSF showed co-localization with a KLHL11 commercial antibody in the medulla and dentate nucleus. Immunohistochemical analysis of seminoma tissue showed anti-KLHL11 antibody-positive particles in cytoplasm. CONCLUSIONS: This study suggests that KLHL11-PNS should be included in the differential diagnosis for patients with brainstem and cerebellar atrophy and signal changes not only on T2-FLAIR but also on SWI, which might otherwise be interpreted as secondary to a neurodegenerative disease such as multiple system atrophy.

Miller Fisher syndrome following BNT162b2 mRNA coronavirus 2019 vaccination.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began in late 2019. One of the vaccines approved against COVID-19 is the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). CASE PRESENTATION: We present the case of a 71-year-old man with no history of the SARS-CoV-2 infection or any recent viral or bacterial illnesses who presented with bilateral oculomotor palsy and limb ataxia after BNT162b2 mRNA COVID-19 vaccination. The diagnosis of Miller Fisher syndrome (MFS) was established based on physical examination, brain magnetic resonance imaging (MRI), cerebrospinal fluid analysis (CSF), and positron emission tomography (PET). There was no evidence of other predisposing infectious or autoimmune factors, and the period from COVID-19 vaccination to the appearance of neurological symptoms was similar to that of other vaccines and preceding events, such as infection. CONCLUSION: Guillain-Barré syndrome (GBS) and its variants after COVID-19 vaccination are extremely rare. Note that more research is needed to establish an association between MFS and COVID-19 vaccines. In our opinion, the benefits of COVID-19 vaccination largely outweigh its risks.

Cortical Microinfarcts Detected by 3-Tesla Magnetic Resonance Imaging: Differentiation Between Cerebral Amyloid Angiopathy and Embolism.

Background and Purpose- Cortical microinfarcts (CMIs) are small ischemic lesions found in cerebral amyloid angiopathy (CAA) and embolic stroke. This study aimed to differentiate CMIs caused by CAA from those caused by microembolisms, using 3-Tesla magnetic resonance imaging. Methods- We retrospectively investigated 70 patients with at least 1 cortical infarct <10 mm on 3-dimensional double inversion recovery imaging. Of the 70 patients, 43 had an embolic stroke history (Emboli-G) while 27 had CAA-group. We compared the size, number, location, and distribution of CMIs between groups and designed a radiological score for differentiation based on the comparisons. Results- CAA-group showed significantly more lesions <5 mm, which were restricted to the cortex (P<0.01). Cortical lesion number was significantly higher in Emboli-G than in CAA-group (4 versus 2; P<0.01). Lesions in CAA-group and Emboli-G were disproportionately located in the occipital lobe (P<0.01) and frontal or parietal lobe (P=0.04), respectively. In radiological scoring, ≥3 points strongly predicted microembolism (sensitivity, 63%; specificity, 92%) or CAA (sensitivity, 63%; specificity, 91%). The areas under the receiver operating characteristic curve were 0.85 and 0.87 for microembolism and CAA, respectively. Conclusions- Characteristics of CMIs on 3T-magnetic resonance imaging may differentiate CMIs due to CAA from those due to microembolisms.

Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by NOTCH3, and characterized by recurrent cerebral ischemic events without vascular risk factors, mood disturbance, and dementia. MRI testing shows cerebral white matter hyperintensities, especially in the external capsule and temporal pole. Typical mutations are cysteine-related missense ones located in one of 34 EGF-like repeats (EGFr) in the NOTCH3 receptor. To identify genotype-phenotype correlations, 179 Japanese CADASIL probands were recruited. Of the 68 mutations identified, p.Cys388Arg, p.Cys435Phe, p.Gly481Cys, p.Cys743Tyr, and p.Cys1009Phe were novel ones. The genotype-phenotype correlation was analyzed based on the three most common mutations: p.Arg75Pro, p.Arg141Cys, and p.Arg182Cys. p.Arg141Cys showed typical CADASIL phenotypes, whereas p.Arg75Pro showed mild and atypical phenotypes, a low frequency of stroke/TIA, high frequency of hypertension, and low frequency of temporal pole lesions. p.Arg182Cys showed various initial symptoms other than stroke/TIA. Subsequently, we analyzed the effect of the mutation location on the age at onset of stroke/TIA. We found that mutations in EGFr 1-6 excluding the cysteine-sparing mutation p.Arg75Pro were significantly correlated with a younger age at onset of stroke/TIA compared with those in EGFr 7-34. This was in agreement with a recent European report, suggesting that the effect of the mutation location is a consensus finding in CADASIL worldwide.

Myasthenia gravis with anti-muscle-specific tyrosine kinase antibodies during therapy for multiple myeloma: a case report.

BACKGROUND: The onset of myasthenia (MG) gravis with anti-muscle-specific tyrosine kinase (MuSK) antibodies most commonly peaks in the fourth decade of life, and MG with MuSK antibodies (MuSK-MG) rarely coexists with a malignant tumor. To date, MuSK-MG has not been reported in multiple myeloma (MM). CASE PRESENTATION: A 60-year-old male with MM who was receiving treatment with bortezomib and thalidomide presented diplopia, ptosis, and limb weakness. A diagnosis of MM with Bence-Jones proteinuria was established when he was 56 years old, and he received chemotherapy with four courses of bortezomib and dexamethasone. Although he received thalidomide as maintenance therapy, it was discontinued a year before hospital admission because of sensory neuropathy as a side effect. Six months before hospital admission, he developed mild diplopia. One month before admission, his chemotherapy was interrupted because of viral infection and fatigability. Then he developed neck weakness and bilateral ptosis. A diagnosis of MuSK-MG was made based on neurological and serological examinations. According to the previous relevant literature, this is the first report of MuSK-MG in a patient with MM. CONCLUSIONS: In patients with MM, the possibility of co-existing of autoimmune disease, including MuSK-MG, should be considered. This case emphasizes the need to still consider testing for anti-MuSK antibodies in older MM patients where there is clinical suspicion for possible MG despite negative anti-acetylcholine receptor antibodies and lacking classic MuSK MG phenotype at onset.

Small Cortical Infarcts Transformed to Lobar Cerebral Microbleeds: A Case Series.

Cerebral microbleeds (MBs) have been often observed due to the development of imaging devices, and are classified to deep and lobar MBs. Lobar MBs are strongly associated with cerebral amyloid angiopathy. Here, we report 3 cases of lobar MBs that developed after small cortical ischemic stroke. One case underwent carotid artery stenting for severe carotid stenosis, one was diagnosed with artery-to-artery embolism, and the other was embolic stroke of undetermined source. New small cortical infarctions were detected with diffusion-weighted magnetic resonance imaging (MRI). Initial MRI revealed no hemorrhage around the ischemic lesion on T2*-weighted gradient-recalled echo or susceptibility-weighted imaging (SWI) at the onset of stroke. Follow-up SWI after 12-20 months revealed lobar MBs in the previously detected ischemic lesions, and high-intensity lesions remained around the MBs on fluid-attenuated inversion recovery imaging. These cases revealed that cerebral MBs developed through the transformation of small cortical infarctions. All cases showed lobar MBs, and these MBs existed in the previously detected ischemic lesions at a chronic stage. Lobar MBs present around ischemic lesions may predict embolic infarcts.

3D double inversion recovery MR imaging: Clinical applications and usefulness in a wide spectrum of central nervous system diseases.

Double inversion recovery (DIR) imaging provides two inversion pulses that attenuate signals from cerebrospinal fluid and normal white matter. This review was undertaken to describe the principle of the DIR sequence, the clinical applications of 3D DIR in various central nervous system diseases and the clinical benefits of the 3D DIR compared with those of other MR sequences. 3D DIR imaging provides better lesion conspicuity and topography than other MR techniques. It is particularly useful for diagnosing the following disease entities: cortical and subcortical abnormalities such as multiple sclerosis, cortical microinfarcts and cortical development anomalies; sulcal abnormalities such as meningitis and subacute/chronic subarachnoid hemorrhage; and optic neuritis caused by multiple sclerosis or neuromyelitis optica.

Comparison of Premortem Magnetic Resonance Imaging and Postmortem Autopsy Findings of a Cortical Microinfarct.

An 85-year-old woman diagnosed with amyotrophic lateral sclerosis died of pneumonia and was autopsied. Magnetic resonance imaging (MRI) performed 16 days before death revealed an intracortical high-intensity lesion in her right temporal cortex on three-dimensional (3D)-double inversion recovery (DIR) and 3D-fluid-attenuated inversion recovery (FLAIR) images. Histopathological examination indicated a cortical microinfarct (CMI) juxtaposed to cerebral amyloid angiopathy. Recently, in vivo detection of CMIs using 3D-DIR and 3D-FLAIR on 3-tesla MRI has been reported, and postmortem MRI study confirmed the presence of CMIs. This is the first case study to compare CMI findings detected upon premortem MRI to the CMI itself discovered upon postmortem neuropathological examination.

Complement Activation in Capillary Cerebral Amyloid Angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is classified as type 1 with capillary amyloid ß (Aß) or type 2 without capillary Aß. While it is known that CAA activates complement, an inflammatory mediator, there is no information on the relationship between capillary Aß and complement activation. METHODS: We evaluated 34 autopsy brains, including 22 with CAA and 12 with other neurodegenerative diseases. We assessed the vascular density of CAA by analyzing the expression of complement (C1q, C3d, C6, C5b-9), macrophage scavenger receptor (MSR), and apolipoprotein E (ApoE). RESULTS: Capillary immunostaining for C1q, C3d, MSR, and ApoE was identified almost exclusively in CAA-type1 brains. There was intense expression of C1q, C3d, MSR, and ApoE, as well as weaker expression of C5b-9 and C6 in the arteries/ arterioles of both CAA subtypes, but not in control brains. C5b-9 and C6 were preferentially expressed in arteries/arterioles with subcortical hemorrhage or cortical superficial siderosis. Triple immunofluorescence revealed that C1q, C3d, and ApoE were colocalized with Aß in CAA brain capillaries. CONCLUSION: Complement, MSR, and ApoE were only coexpressed in the presence of Aß accumulation in capillaries, suggesting a role for complement activation in the propagation of Aß. Additionally, C5b-9 expression may be associated with hemorrhagic brain injury in CAA.