Irina Savitcheva

Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B

This report describes the first human study of a novel amyloid‐imaging positron emission tomography (PET) tracer, termed Pittsburgh Compound‐B (PIB), in 16 patients with diagnosed mild AD and 9 controls. Compared with controls, AD patients typically showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. In the AD patient group, PIB retention was increased most prominently in frontal cortex (1.94‐fold, p = 0.0001). Large increases also were observed in parietal (1.71‐fold, p = 0.0002), temporal (1.52‐fold, p = 0.002), and occipital (1.54‐fold, p = 0.002) cortex and the striatum (1.76‐fold, p = 0.0001). PIB retention was equivalent in AD patients and controls in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Studies in three young (21 years) and six older healthy controls (69.5 ± 11 years) showed low PIB retention in cortical areas and no significant group differences between young and older controls. In cortical areas, PIB retention correlated inversely with cerebral glucose metabolism determined with 18F‐fluorodeoxyglucose. This relationship was most robust in the parietal cortex (r = −0.72; p = 0.0001). The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.

In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography

BACKGROUND Converging lines of evidence are consistent with an inhibitory effect of the antidepressant and smoking-cessation aid bupropion on dopamine and norepinephrine reuptake, but the in vivo effects of the drug at the human dopamine transporter (DAT) have not been studied to date. This study employed positron emission tomography (PET) to assess the extent and duration of DAT receptor occupancy by bupropion and its metabolites under conditions of steady-state oral dosing with bupropion sustained-release (SR) in healthy volunteers. METHODS Six healthy male volunteers received bupropion SR 150 mg daily on days 1 through 3 and 150 mg every 12 hours on day 4 through the morning of day 11. PET investigations were performed between 1 and 7 days before initiation of bupropion SR dosing, as well as 3, 12, and 24 hours after the last dose of bupropion SR on day 11. RESULTS Bupropion and its metabolites inhibited striatal uptake of the selective DAT-binding radioligand (11)C-betaCIT-FE in vivo. Three hours after the last dose of bupropion SR, average DAT occupancy by bupropion and its metabolites was 26%-a level that was maintained through the last PET assessment at 24 hours after dosing. CONCLUSIONS Bupropion and its metabolites induced a low occupancy of the striatal DAT over 24 hours under conditions of steady-state oral dosing with therapeutic doses of bupropion SR. These data are consistent with the hypothesis that dopamine reuptake inhibition may be responsible in part for the therapeutic effects of the drug.

Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer’s disease dementia

The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer’s disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [18F]THK5317 (tau deposition) and [18F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [11C]PIB (amyloid-β deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [18F]THK5317 retention over time, in contrast to significant decreases in [18F]FDG uptake in temporoparietal areas. The pattern of changes in [18F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [18F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [18F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [11C]PIB scan, high [18F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [18F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.

27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation

Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory. Furthermore, patients exhibiting higher 27-OH levels had reduced 18F-fluorodeoxyglucose uptake. This interplay between 27-OH and glucose uptake revealed the engagement of the insulin-regulated aminopeptidase (IRAP). 27-OH increased the levels and activity of IRAP, countered the IRAP antagonist angiotensin IV (AngIV)–mediated glucose uptake, and enhanced the levels of the AngIV-degrading enzyme aminopeptidase N (AP-N). These effects were mediated by liver X receptors. Our results reveal a molecular link between cholesterol, brain glucose, and the brain renin-angiotensin system, all of which are affected in some neurodegenerative diseases. Thus, reducing 27-OH levels or inhibiting AP-N maybe a useful strategy in the prevention of the altered glucose metabolism and memory decline in these disorders.

Longitudinal uncoupling of cerebral perfusion, glucose metabolism, and tau deposition in Alzheimer's disease

Cross‐sectional findings using the tau tracer [18F]THK5317 (THK5317) have shown that [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) data can be approximated using perfusion measures (early‐frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single PET study can provide both functional and molecular information.

Spatial normalization of [18F]flutemetamol PET images utilizing an adaptive principal components template

Though currently approved for visual assessment only, there is evidence to suggest that quantification of amyloid-β (Aβ) PET images may reduce interreader variability and aid in the monitoring of treatment effects in clinical trials. Quantification typically involves a regional atlas in standard space, requiring PET images to be spatially normalized. Different uptake patterns in Aβ-positive and Aβ-negative subjects, however, make spatial normalization challenging. In this study, we proposed a method to spatially normalize 18F-flutemetamol images using a synthetic template based on principal-component images to overcome these challenges. Methods: 18F-flutemetamol PET and corresponding MR images from a phase II trial (n = 70), including subjects ranging from Aβ-negative to Aβ-positive, were spatially normalized to standard space using an MR-driven registration method (SPM12). 18F-flutemetamol images were then intensity-normalized using the pons as a reference region. Principal-component images were calculated from the intensity-normalized images. A linear combination of the first 2 principal-component images was then used to model a synthetic template spanning the whole range from Aβ-negative to Aβ-positive. The synthetic template was then incorporated into our registration method, by which the optimal template was calculated as part of the registration process, providing a PET-only–driven registration method. Evaluation of the method was done in 2 steps. First, coregistered gray matter masks generated using SPM12 were spatially normalized using the PET- and MR-driven methods, respectively. The spatially normalized gray matter masks were then visually inspected and quantified. Second, to quantitatively compare the 2 registration methods, additional data from an ongoing study were spatially normalized using both methods, with correlation analysis done on the resulting cortical SUV ratios. Results: All scans were successfully spatially normalized using the proposed method with no manual adjustments performed. Both visual and quantitative comparison between the PET- and MR-driven methods showed high agreement in cortical regions. 18F-flutemetamol quantification showed strong agreement between the SUV ratios for the PET- and MR-driven methods (R2 = 0.996; pons reference region). Conclusion: The principal-component template registration method allows for robust and accurate registration of 18F-flutemetamol images to a standardized template space, without the need for an MR image.

Novel Features and Abnormal Pattern of Cerebral Glucose Metabolism in Spinocerebellar Ataxia 19

Spinocerebellar ataxia type 19 (SCA19), allelic with spinocerebellar ataxia type 22 (SCA22), is a rare syndrome caused by mutations in the KCND3 gene which encodes the potassium channel Kv4.3. Only 18 SCA19/22 families and sporadic cases of different ethnic backgrounds have been previously reported. As in other SCAs, the SCA19/22 phenotype is variable and usually consists of adult-onset slowly progressive ataxia and cognitive impairment; myoclonus and seizures; mild Parkinsonism occurs in some cases. Here we describe a Swedish SCA19/22 family spanning five generations and harboring the T377M mutation in KCND3. For the first time for this disease, 18F-fluorodeoxyglucose PET was assessed revealing widespread brain hypometabolism. In addition, we identified white matter abnormalities and found unusual features for SCA19/22 including early age of onset and fast rate of progression in the late course of disease in the oldest patient of this family.

Novel Xp21.1 deletion associated with unusual features in a large McLeod syndrome kindred

McLeod syndrome (MLS) is a rare adult-onset, progressive and incurable X-linked multisystemic disorder characterized by chorea, cognitive decline, seizures, polyneuropathy, myopathy and dilated cardiomyopathy with subsequent heart failure and increased risk for arrhythmia [1]. Variable psychiatric symptoms are common; the presence of acanthocytes on blood smears, elevated CK levels and striatal atrophy are other features. MLS is caused by mutation in the XK gene which encodes a membrane transport protein containing the Kx erythrocyte antigen [1]. So far, less than 200 MLS cases have been reported. In general, women harboring XK mutations rarely manifest symptoms. In addition, myoclonus has not been described in association with MLS and functional imaging studies are scarce.

ESTIMATION OF AMYLOID LOAD USING [18F]FLUTEMETAMOL AND A NORMALIZATION DERIVED WEIGHTING FACTOR: POTENTIAL APPLICATIONS IN AMYLOID PET

Composite RO Left Temporal Right Tempora Left Frontal Right Frontal Left Precuneu Right Precune Left Parietal Right Parietal F-FLORBETABEN PET USING MACHINE LEARNING TECHNIQUE Jun Pyo Kim, Jeonghun Kim, Yeshin Kim, Seung Hwan Moon, Yuhyun Park, Sole Yoo, Hee Jin Kim, Duk L. Na, Sang Won Seo, Joon-Kyung Seong, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Korea University, Seoul, South Korea. Contact e-mail: torch0703@gmail.com

INVESTIGATING THE CLINICAL IMPACT OF [ 18 F]FLUTEMETAMOL PET IN A TERTIARY MEMORY CLINIC SETTING IN PATIENTS WITH UNCERTAIN DIAGNOSIS

60-90, who participated in the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), were included in this study. All the subjects underwent comprehensive clinical and neuropsychological assessment, 11C-labelled Pittsburgh Compound B (PiB) positron emission tomography (PET), and Brain Magnetic resonance imaging(MRI). Mean cortical thickness values were obtained from AD-signature regions including the entorhinal, inferior temporal, middle temporal, and fusiform gyrus. BMI values for past lifetime periods((i.e., young adulthood: 20-30s and midlife: 40-50s) were calculated from self-recalled body weight and height, and current BMI was calculated from measured body weight and height. Multiple regression analyses were performed controlling age, gender, APOE e4 carrier status, and vascular risk scores. Results: For the overall subjects, past BMI, BMI at young adulthood in particular, was negatively associated with global cerebral Ab deposition, while current BMI was not. In contrast, current BMI showed significant positive association with AD-signature region cortical thickness, while past BMI did not. When subgroup analyses were performed for each gender, very similar relationships between lifetime BMIs and Ab deposition and cortical thickness were still found for males, whereas no significant association was observed between the variables for females. Conclusions: Our results suggest that relatively low past