Seung Ha Lee

Subcortical 18F-AV-1451 binding patterns in progressive supranuclear palsy

Accumulation of cortical and subcortical tau pathology is the primary pathological substrate for progressive supranuclear palsy (PSP). 18F‐AV‐1451, a radiotracer that binds to the pathological tau protein, may be helpful for in vivo visualization and quantitation of tau pathology in PSP.

18 F-AV-1451 binds to motor-related subcortical gray and white matter in corticobasal syndrome

Objective: To investigate tau distribution in patients with corticobasal syndrome (CBS) using 18F-AV-1451 PET. Methods: Six consecutively recruited patients with CBS and 20 age-matched healthy controls underwent 2 PET scans with 18F-AV-1451 (for tau) and 18F-florbetaben (for β-amyloid). We compared standardized uptake value ratio maps of the 18F-AV-1451 PET images between the patients with CBS and controls. Results: Compared to controls, patients with CBS exhibited asymmetrically increased 18F-AV-1451 binding in the putamen, globus pallidus, and thalamus contralateral to the clinically more affected side and in the ipsilateral globus pallidus and dentate nucleus. Voxel-based comparison additionally showed asymmetrically increased 18F-AV-1451 binding in the focal regions of the precentral gray and white matter and in the midbrain, predominantly in the contralateral side. 18F-AV-1451 binding in the precentral white matter correlated with motor severity. Conclusions: 18F-AV-1451 asymmetrically binds to motor-related subcortical gray and white matter structures in patients with CBS. This pattern corresponds to tau pathology distribution in postmortem studies, and motor deficit in patients with CBS may be associated with tau accumulation predominantly in the subcortical white matter underlying the motor cortex, leading to disruptions in motor-related networks.

Excessive tau accumulation in the parieto-occipital cortex characterizes early-onset Alzheimer's disease

Early-onset Alzheimers disease (EOAD) is characterized by greater nonmemory dysfunctions, more rapid progression, and greater hypometabolism and atrophy than late-onset AD (LOAD). We sought to investigate the differences in tau accumulation patterns between early- and late-onset patients with AD and mild cognitive impairment (MCI). In 90 patients who completed 18F-AV-1451 and 18F-florbetaben positron emission tomography scans, only 59 amyloid-positive patients (11 EOAD, 10 EOMCI, 21 LOAD, and 17 LOMCI) were included in this study. We compared cortical 18F-AV-1451 binding between each patient group and corresponding amyloid-negative age-matched controls. In contrast to no difference in cortical binding between the EOMCI and LOMCI groups, EOAD showed greater binding in the parieto-occipital cortex than LOAD. The parieto-occipital binding correlated with visuospatial dysfunction in the EOAD spectrum, whereas binding in the temporal cortex correlated with verbal memory dysfunction in the LOAD spectrum. Our findings suggest that distinct topographic distribution of tau may influence the nature of cognitive impairment in EOAD patients.

18F‐AV‐1451 binds to putamen in multiple system atrophy

MSA is a synucleinopathy. It may exhibit a binding pattern similar to that expected for Parkinson’s disease (PD) in the PET studies with F-AV-1451, a recently developed radiotracer specific for pathological tau protein. Contrary to our expectations, we report on 4 consecutive probable parkinsonian-type MSA patients in whom increased F-AV1451 binding was detected in the atrophic putamen. Nigrostriatal dopaminergic deficit was confirmed by the FN-3-fluoropropyl-2-betacarboxymethoxy-3-beta-(4-iodophenyl) nortropane (FP-CIT) PET scan in all 4 patients, who underwent F-AV-1451 PET scans. Subcortical binding patterns in these patients were compared with that of 30 healthy controls. This study was approved by the institutional review board of Gangnam Severance Hospital (Seoul, Republic of Korea), and written informed consent was obtained from all participants. All 4 MSA patients showed volume atrophy and reduced F-FP-CIT uptake in the putamen, which clearly mirrored increased F-AV-1451 binding in the posterior putamen (Fig. 1A–C). When compared to the mean standard uptake value ratio (SUVR) values of controls, 3 patients (patients 2–4) showed greater F-AV-1451 binding in the posterior FIG. 1. A: Native [18F]-AV-1451 PET scan showing an axial view of the basal ganglia. B: T1 weighted MRI showing an axial view of the midbrain. C/D: Axial and midsagittal view of z-transformed deviations of [18F]-AV-1451 uptake from a norm cohort.

Feasibility of Computed Tomography-Guided Methods for Spatial Normalization of Dopamine Transporter Positron Emission Tomography Image

Background Spatial normalization is a prerequisite step for analyzing positron emission tomography (PET) images both by using volume-of-interest (VOI) template and voxel-based analysis. Magnetic resonance (MR) or ligand-specific PET templates are currently used for spatial normalization of PET images. We used computed tomography (CT) images acquired with PET/CT scanner for the spatial normalization for [18F]-N-3-fluoropropyl-2-betacarboxymethoxy-3-beta-(4-iodophenyl) nortropane (FP-CIT) PET images and compared target-to-cerebellar standardized uptake value ratio (SUVR) values with those obtained from MR- or PET-guided spatial normalization method in healthy controls and patients with Parkinson’s disease (PD). Methods We included 71 healthy controls and 56 patients with PD who underwent [18F]-FP-CIT PET scans with a PET/CT scanner and T1-weighted MR scans. Spatial normalization of MR images was done with a conventional spatial normalization tool (cvMR) and with DARTEL toolbox (dtMR) in statistical parametric mapping software. The CT images were modified in two ways, skull-stripping (ssCT) and intensity transformation (itCT). We normalized PET images with cvMR-, dtMR-, ssCT-, itCT-, and PET-guided methods by using specific templates for each modality and measured striatal SUVR with a VOI template. The SUVR values measured with FreeSurfer-generated VOIs (FSVOI) overlaid on original PET images were also used as a gold standard for comparison. Results The SUVR values derived from all four structure-guided spatial normalization methods were highly correlated with those measured with FSVOI (P < 0.0001). Putaminal SUVR values were highly effective for discriminating PD patients from controls. However, the PET-guided method excessively overestimated striatal SUVR values in the PD patients by more than 30% in caudate and putamen, and thereby spoiled the linearity between the striatal SUVR values in all subjects and showed lower disease discrimination ability. Two CT-guided methods showed comparable capability with the MR-guided methods in separating PD patients from controls and showed better correlation between putaminal SUVR values and the parkinsonian motor severity than the PET-guided method. Conclusion CT-guided spatial normalization methods provided reliable striatal SUVR values comparable to those obtained with MR-guided methods. CT-guided methods can be useful for analyzing dopamine transporter PET images when MR images are unavailable.

Correlation between Hyperintense Vessels on FLAIR Imaging and Arterial Circulation Time on Cerebral Angiography

PURPOSE Hyperintense vessels (HVs) on fluid-attenuated inversion recovery (FLAIR) imaging are associated with the leptomeningeal collateral circulation in cases of arterial occlusive lesions. Nevertheless, the relationship between HVs on FLAIR imaging and arterial circulation time (ACT) on cerebral angiography has not been defined. METHODS We analyzed images of 11 patients with acute occlusion of the distal internal carotid artery or proximal middle cerebral artery and calculated the difference in ACT (DACT) between infarcted and normal hemispheres. ACT was defined as the time interval from the initial opacification of the ipsilateral or contralateral cavernous internal carotid artery to the late arterial phase of the carotid artery territories. We scored HVs on FLAIR imaging using a modified Alberta Stroke Program Early Computerized Tomography Score (ASPECTS) and determined collateral circulation by grading collateral flow. RESULTS We detected HVs on FLAIR images in 10 patients (median score, 4; range, 0 to 6). Comparison of infarcted and normal hemispheres demonstrated absent or subtle HVs on FLAIR imaging when the DACT was too short (7.98 s) and prominent HVs with moderate DACT (2 to 5 s). The score of HVs on FLAIR was estimated well by DACT using a quadratic regression model (R(2) = 0.602) and better than by grading collateral flow (R(2) = 0.256). CONCLUSION In cases of large arterial occlusion, the hyperintensity of vessels on FLAIR images may be dependent on arterial circulation time via retrograde filling of the leptomeningeal collateral circulation.

Distinct patterns of amyloid-dependent tau accumulation in Lewy body diseases

Background: In addition to Lewy body pathology, amyloid‐β plaques and neurofibrillary tangles that are characteristic for Alzheimers disease are also frequently found in Lewy body diseases.

Clinical Features Indicating Nigrostriatal Dopaminergic Degeneration in Drug-Induced Parkinsonism.

Objective Patients with drug-induced parkinsonism (DIP) may have nigrostriatal dopaminergic degeneration. We studied the clinical features that may indicate nigrostriatal dopaminergic degeneration in patients with DIP. Methods Forty-one DIP patients were classified into normal and abnormal [18F] FP-CIT scan groups. Differences in 32 clinical features and drug withdrawal effects were studied. Results Twenty-eight patients had normal (Group I) and 13 patients had abnormal (Group II) scans. Eight patients of Group I, but none of Group II, had taken calcium channel blockers (p = 0.040). Three patients of Group I and six of Group II had hyposmia (p = 0.018). After drug withdrawal, Group I showed greater improvement in Unified Parkinson’s Disease Rating Scale total motor scores and subscores for bradykinesia and tremors than Group II. Only hyposmia was an independent factor associated with abnormal scans, but it had suboptimal sensitivity. Conclusion None of the clinical features were practical indicators of nigrostriatal dopaminergic degeneration in patients with DIP.

Brain regional iron contents in progressive supranuclear palsy

INTRODUCTION To determine motor-related brain regions in which iron contents correlate with the degree of motor deficits of progressive supranuclear palsy (PSP). METHODS Twenty-four patients with probable PSP and 20 controls were included. Using a 3.0T magnetic resonance imaging scanner, R2* values were measured in the putamen, globus pallidus (GP), substantia nigra (SN), subthalamic nucleus, and dentate nucleus. After adjustment for disease duration and age at examination, correlations between regional brain R2* values and Unified Parkinson Disease Rating Scale (UPDRS) total motor scores or subscores for bradykinesia, rigidity, tremor, or axial motor deficits were investigated. RESULTS Compared to controls, patients with PSP had significantly higher R2* values in all of the five brain regions. UPDRS total motor scores and subscores for bradykinesia and axial motor deficits did not correlate with R2* values of the five brain regions. However, UPDRS subscores for unilateral rigidity were correlated with R2* values of the contralateral putamen and GP. In addition, unilateral UPDRS subscores for tremor were associated with R2* values of the ipsilateral dentate nucleus, contralateral putamen, GP, and SN. CONCLUSION In PSP, excessive iron accumulation occurs in motor-related subcortical regions. Iron-related PSP pathologies in the lenticular nucleus are associated with rigidity severity, while those in the nigro-striato-pallidal unit and dentate nucleus are associated with tremor severity. Bradykinesia and axial motor deficits of PSP seem to be associated with widespread pathologies in the cerebrum, brainstem, cerebellum, as well as the basal ganglia.

HORMONE REPLACEMENT THERAPY AND RISK OF DEMENTIA IN POSTMENOPAUSAL WOMEN: A NATIONWIDE COHORT STUDY

impairment. Many of these contain neurotoxic and carcinogenic properties known to cause cancer, reproductive problems, and central nervous system impairments that have been linked to Alzheimer’s disease. Nail salon technicians are continuously exposed to them, and this exposure may occur at greater frequency and at higher levels than in other occupational settings. This research aims to examine the association of neurotoxin-exposure with mild cognitive impairment among Vietnamese female nail technicians aged 50 or above in the Northern California areas. Methods: Quasi-experimental interviews were conducted with 45 Vietnamese female nail technicians to assess the association between mild cognitive impairment and early dementia (e.g. MOCA) with occupational exposure (e.g. years of employment, work hours per week), demographics (e.g. education, age), depression (e.g. CESD scale) and acculturation level (e.g. US citizenship). Results: Multiple regression analysis revealed that among Vietnamese female nail technicians, level of education (b 1⁄4 1.36, p 1⁄4 0.010) and depression (b 1⁄4 -4.22, p 1⁄4 0.007) significantly predict mild cognitive impairment. Work hours per week (b 1⁄4 2.53, p 1⁄4 0.065) and having US citizenship (b 1⁄4 -3.79, p 1⁄4 0.63) are also marginally significant. Conclusions: Preliminary results from Year 1 show that Vietnamese female nail technicians may be at risk for mild cognitive impairment. Explanations for why working more hours are positively associated with higher MOCA score will be discussed. Research is funded by the Alzheimer’s Association.