Svetlana Pejoska

Amyloid Imaging with 18 F-Florbetaben in Alzheimer Disease and Other Dementias

Amyloid imaging with 18F-labeled radiotracers will allow widespread use, facilitating research, diagnosis, and therapeutic development for Alzheimer disease. The purpose of the study program was to compare cortical amyloid deposition using 18F-florbetaben and PET in controls and subjects with mild cognitive impairment (MCI), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB), vascular dementia (VaD), Parkinson disease (PD), and Alzheimer disease (AD). Methods: One hundred nine subjects in 3 clinical studies at Austin Health were reviewed: 32 controls, 20 subjects with MCI, and 30 patients with AD, 11 with FTLD, 7 with DLB, 5 with PD, and 4 with VaD underwent PET after intravenous injection of 300 MBq of 18F-florbetaben. Standardized uptake value ratios (SUVR) using the cerebellar cortex as a reference region were calculated between 90 and 110 min after injection. Results: When compared with the other groups, AD patients demonstrated significantly higher SUVRs (P < 0.0001) in neocortical areas. Most AD patients (96%) and 60% of MCI subjects showed diffuse cortical 18F-florbetaben retention. In contrast, only 9% of FTLD, 25% of VaD, 29% of DLB, and no PD patients and 16% of controls showed cortical binding. Although there was a correlation between Mini Mental State Examination and β-amyloid burden in the MCI group, no correlation was observed in controls, FTLD or AD. Conclusion: 18F-florbetaben had high sensitivity for AD, clearly distinguished patients with FTLD from AD, and provided results comparable to those reported with 11C-Pittsburgh Compound B in a variety of neurodegenerative diseases.

Non-invasive assessment of Alzheimer’s disease neurofibrillary pathology using 18F-THK5105 PET

Non-invasive imaging of tau pathology in the living brain would be useful for accurately diagnosing Alzheimers disease, tracking disease progression, and evaluating the treatment efficacy of disease-specific therapeutics. In this study, we evaluated the clinical usefulness of a novel tau-imaging positron emission tomography tracer 18F-THK5105 in 16 human subjects including eight patients with Alzheimers disease (three male and five females, 66-82 years) and eight healthy elderly controls (three male and five females, 63-76 years). All participants underwent neuropsychological examination and 3D magnetic resonance imaging, as well as both 18F-THK5105 and 11C-Pittsburgh compound B positron emission tomography scans. Standard uptake value ratios at 90-100 min and 40-70 min post-injection were calculated for 18F-THK5105 and 11C-Pittsburgh compound B, respectively, using the cerebellar cortex as the reference region. As a result, significantly higher 18F-THK5105 retention was observed in the temporal, parietal, posterior cingulate, frontal and mesial temporal cortices of patients with Alzheimers disease compared with healthy control subjects. In patients with Alzheimers disease, the inferior temporal cortex, which is an area known to contain high densities of neurofibrillary tangles in the Alzheimers disease brain, showed prominent 18F-THK5105 retention. Compared with high frequency (100%) of 18F-THK5105 retention in the temporal cortex of patients with Alzheimers disease, frontal 18F-THK5105 retention was less frequent (37.5%) and was only observed in cases with moderate-to-severe Alzheimers disease. In contrast, 11C-Pittsburgh compound B retention was highest in the posterior cingulate cortex, followed by the ventrolateral prefrontal, anterior cingulate, and superior temporal cortices, and did not correlate with 18F-THK5105 retention in the neocortex. In healthy control subjects, 18F-THK5105 retention was ∼10% higher in the mesial temporal cortex than in the neocortex. Notably, unlike 11C-Pittsburgh compound B, 18F-THK5105 retention was significantly correlated with cognitive parameters, hippocampal and whole brain grey matter volumes, which was consistent with findings from previous post-mortem studies showing significant correlations of neurofibrillary tangle density with dementia severity or neuronal loss. From these results, 18F-THK5105 positron emission tomography is considered to be useful for the non-invasive assessment of tau pathology in the living brain. This technique would be applicable to the longitudinal evaluation of tau deposition and allow a better understanding of the pathophysiology of Alzheimers disease.

Comparison of 11C-PiB and 18F-florbetaben for Aβ imaging in ageing and Alzheimer's disease.

PurposeAmyloid imaging with 18F-labelled radiotracers will allow widespread use of this technique, facilitating research, diagnosis and therapeutic development for Alzheimer’s disease (AD). The purpose of this analysis was to compare data on cortical Aβ deposition in subjects who had undergone both 11C-PiB (PiB) and 18F-florbetaben (FBB) PET imaging.MethodsWe identified ten healthy elderly controls (HC) and ten patients with AD who had undergone PET imaging after intravenous injection of 370xa0MBq of PiB and 300xa0MBq of FBB under separate research protocols. PiB and FBB images were coregistered so that placement of regions of interest was identical on both scans and standard uptake value ratios (SUVR) using the cerebellar cortex as reference region were calculated between 40 and 70xa0min and between 90 and 110xa0min after injection for PiB and FBB, respectively.ResultsSignificantly higher SUVR values (pu2009<u20090.0001) in most cortical areas were observed in AD patients when compared with HC with both radiotracers. Global SUVR values in AD patients were on average 75% higher than in HC with PiB and 56% higher with FBB. There was an excellent linear correlation between PiB and FBB global SUVR values (ru2009=u20090.97, pu2009<u20090.0001) with similar effect sizes for distinguishing AD from HC subjects for both radiotracers (Cohen’su2009d 3.3 for PiB and 3.0 for FBB).ConclusionFBB, while having a narrower dynamic range than PiB, clearly distinguished HC from AD patients, with a comparable effect size. FBB seems a suitable 18F radiotracer for imaging AD pathology in vivo.

In vivo evaluation of a novel tau imaging tracer for Alzheimer’s disease

PurposeDiagnosis of tauopathies such as Alzheimer’s disease (AD) still relies on post-mortem examination of the human brain. A non-invasive method of determining brain tau burden in vivo would allow a better understanding of the pathophysiology of tauopathies. The purpose of the study was to evaluate 18F-THK523 as a potential tau imaging tracer.MethodsTen healthy elderly controls, three semantic dementia (SD) and ten AD patients underwent neuropsychological examination, MRI as well as 18F-THK523 and 11C-Pittsburgh compound B (PIB) positron emission tomography (PET) scans. Composite memory and non-memory scores, global and hippocampal brain volume, and partial volume-corrected tissue ratios for 18F-THK523 and 11C-PIB were estimated for all participants. Correlational analyses were performed between global and regional 18F-THK523, 11C-PIB, cognition and brain volumetrics.Results18F-THK523 presented with fast reversible kinetics. Significantly higher 18F-THK523 retention was observed in the temporal, parietal, orbitofrontal and hippocampi of AD patients when compared to healthy controls and SD patients. White matter retention was significantly higher than grey matter retention in all participants. The pattern of cortical 18F-THK523 retention did not correlate with Aβ distribution as assessed by 11C-PIB and followed the known distribution of tau in the AD brain, being higher in temporal and parietal areas than in the frontal region. Unlike 11C-PIB, hippocampal 18F-THK523 retention was correlated with several cognitive parameters and with hippocampal atrophy.Conclusion18F-THK523 does not bind to Aβ in vivo, while following the known distribution of paired helical filaments (PHF)-tau in the brain. Significantly higher cortical 18F-THK523 retention in AD patients as well as the association of hippocampal 18F-THK523 retention with cognitive parameters and hippocampal volume suggests 18F-THK523 selectively binds to tau in AD patients. Unfortunately, the very high 18F-THK523 retention in white matter precludes simple visual inspection of the images, preventing its use in research or clinical settings.

In Vivo Measurement of Vesicular Monoamine Transporter Type 2 Density in Parkinson Disease with 18F-AV-133

PET provides a noninvasive means to evaluate the functional integrity of the presynaptic monoaminergic system in the living human brain. Methods: In this study, a novel 18F-labeled tetrabenazine derivative, 18F-(+)fluoropropyldihydrotetrabenazine (18F-AV-133), was used for the noninvasive assessment of the vesicular monoamine transporters type 2 (VMAT2) in 17 Parkinson disease (PD) patients and 6 healthy controls. The binding potential (BP) of 18F-AV-133 was calculated using Logan graphical analysis. Voxel-based and volume-of-interest–based analyses of BP images were performed to examine brain regional reductions in VMAT2 density in PD. Results: VMAT2 BP was decreased by 81% in the posterior putamen, 70% in the anterior putamen, and 48% in the caudate nucleus of PD patients. Voxel-based analysis demonstrated VMAT2 reductions in the striatum and mid brain of PD patients. Furthermore, VMAT2 BPs in the caudate nuclei significantly correlated with the clinical severity of PD. Conclusion: These findings indicate that the novel 18F-labeled ligand 18F-AV-133 can sensitively detect monoaminergic terminal reductions in PD patients. Studies with 18F-AV-133 may allow the presymptomatic identification of individuals with disorders characterized by degeneration of dopaminergic nigrostriatal afferents.

Head-to-Head Comparison of 11C-PiB and 18F-AZD4694 (NAV4694) for β-Amyloid Imaging in Aging and Dementia

11C-Pittsburgh compound-B (11C-PiB) is the benchmark radiotracer for imaging of β-amyloid (Aβ) plaque in Alzheimer disease (AD). 18F-labeled Aβ tracers subsequently developed for clinical use show higher nonspecific white matter binding and, in some cases, lower cortical binding in AD that could lead to less accurate interpretation of scans. We compared the cortical and white matter binding of a new 18F-labeled Aβ tracer, 18F-AZD4694 (recently renamed NAV4694), with 11C-PiB in the same subjects. Methods: Forty-five participants underwent PET imaging with 11C-PiB and 18F-AZD4694 (25 healthy elderly controls [HCs], 10 subjects with mild cognitive impairment, 7 subjects with probable AD, and 3 subjects with probable frontotemporal dementia). Images were coregistered so that region-of-interest placement was identical on both scans, and standardized uptake value ratios (SUVRs) using the cerebellar cortex as a reference region were calculated between 40 and 70 min after injection for both tracers. Results: 18F-AZD4694 showed reversible binding kinetics similar to 11C-PiB, reaching an apparent steady state at 50 min after injection. Both radiotracers showed a similar dynamic range of neocortical SUVR (1.1–3.3 and 1.0–3.2 SUVR for 11C-PiB and 18F-AZD4694, respectively) and identical low nonspecific white matter binding, with frontal cortex–to–white matter ratios of 0.7 ± 0.2 and 1.3 ± 0.2 for both radiotracers in HCs and AD subjects, respectively. There was an excellent linear correlation between 11C-PiB and 18F-AZD4694 neocortical SUVR (slope of 0.95, r = 0.99, P < 0.0001). Conclusion: 18F-AZD4694 displays imaging characteristics nearly identical to those of 11C-PiB. The low white matter and high cortical binding in AD indicate that this tracer is well suited to both clinical and research use.

In Vivo Assessment of Vesicular Monoamine Transporter Type 2 in Dementia With Lewy Bodies and Alzheimer Disease

OBJECTIVEnTo assess the diagnostic potential of imaging striatal monoaminergic terminal integrity with the vesicular monoamine transporter type 2 (VMAT2) radioligand (18)F 9-fluropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133) and positron emission tomography to distinguish dementia with Lewy bodies (DLB) from Alzheimer disease (AD).nnnDESIGN, SETTING, AND PARTICIPANTSnNine patients with DLB, 10 patients with AD, 20 patients with Parkinson disease (PD), and 10 healthy age-matched control subjects underwent [(18)F]AV-133 positron emission tomography studies. VMAT2 density was calculated through normalized tissue uptake value ratios at 120 to 140 minutes postinjection using the primary visual cortex as the reference region.nnnMAIN OUTCOME MEASUREnComparison of the tissue ratio for [(18)F]AV-133 between the different clinical diagnostic groups.nnnRESULTSnLower VMAT2 densities were observed in patients with DLB when compared with patients with AD especially in the posterior putamen (caudate: mean [SD], 1.24 [0.6] vs 2.83 [0.9]; P < .001; effect size = 2.1; anterior putamen: mean [SD], 0.90 [0.5] vs 3.01 [0.9]; P < .001; effect size = 2.9; posterior putamen: mean [SD], 0.62 [0.5] vs 2.87 [0.8]; P < .001; effect size = 3.4). Compared with healthy controls, [(18)F]AV-133 tissue ratios were significantly lower by 88% and 74% in the posterior putamen, 74% and 65% in the anterior putamen, and 53% and 51% in the caudate nucleus of patients with PD and DLB, respectively. In contrast to patients with PD and DLB, no reductions were observed in patients with AD.nnnCONCLUSIONSn[(18)F]AV-133 allows assessment of nigrostriatal degeneration in Lewy body diseases. [(18)F]AV-133 can robustly detect reductions of dopaminergic nigrostriatal afferents in patients with DLB and assist in the differential diagnosis from AD.

Differential Diagnosis in Alzheimer’s Disease and Dementia with Lewy Bodies via VMAT2 and Amyloid Imaging

Background: The noninvasive evaluation of nigrostriatal dopaminergic integrity by PET can provide useful information for the differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Objectives: To evaluate the diagnostic potential of imaging striatal monoaminergic terminal integrity with the novel vesicular monoamine transporter type 2 (VMAT2) radioligand [18F]AV-133 and PET to distinguish DLB from AD. Methods: Fifty participants [9 DLB, 11 AD, 20 Parkinson’s disease (PD) and 10 healthy age-matched control subjects (HC)] underwent [18F]AV-133 PET studies. Additionally, 20 participants underwent amyloid imaging PET scans with either [11C]PiB or 18F-florbetaben. VMAT2 density was calculated through normalized tissue uptake value ratios (RT) at 120–140 min after injection using the primary visual or the cerebellar cortex as reference region. Comparison of the RT for [18F]AV-133 was done between the different clinical diagnostic groups. Results: Significantly lower striatal VMAT2 densities were observed in DLB and PD when compared to AD and HC, especially in the posterior putamen. In contrast to PD and DLB, no reductions were observed in AD patients when compared to HC. Conclusions: [18F]AV-133 allows assessment of nigrostriatal degeneration in Lewy body diseases. In contrast to amyloid imaging, VMAT2 imaging with [18F]AV-133 can robustly detect reductions of dopaminergic nigrostriatal afferents in DLB patients, assisting in the differential diagnosis from AD.

Standardized Expression of 18F-NAV4694 and 11C-PiB β-Amyloid PET Results with the Centiloid Scale.

A common quantitative output value for PET measures of β-amyloid (Aβ) binding across tracers and methods would allow better comparison of data across sites and application of universal diagnostic and prognostic values. A method has recently been developed that generates a unit of measurement called the centiloid. We applied this method to 2-[2-18F-fluoro-6-(methylamino)-3-pyridinyl]-1-benzofuran-5-ol (18F-NAV4694) and 11C-Pittsburgh compound B (11C-PiB) Aβ images to derive the scaling factor required to express tracer binding in centiloids. Methods: Fifty-five participants, including 10 young controls (33 ± 7 y old), underwent both 11C-PiB and 18F-NAV4694 imaging no more than 3 mo apart, with the images acquired 50–70 min after tracer injection. The images were spatially normalized and analyzed using the standard centiloid method and regions (cortex and whole-cerebellum reference) downloaded from the Global Alzheimer Association Interactive Network website. Results: SUV ratios (SUVRs) showed a strong correlation in tracer binding (18F-NAV4694 SUVR = 1.09 × 11C-PiB SUVR – 0.08, R2 = 0.99). The equation to convert 18F-NAV4694 to centiloids [100 × (18F-NAV4694 SUVR – 1.028)/1.174] was similar to a published equation for 11C-PiB [100 × (11C-PiB SUVR – 1.009)/1.067]. In the young controls, the variance ratio (18F-NAV4694 centiloid SD divided by 11C-PiB centiloid SD) was 0.85. Conclusion: The results for both 11C-PiB and 18F-NAV4694 can now be expressed in centiloids, an important step that should allow better clinical and research use of Aβ imaging. The standard centiloid method also showed that 18F-NAV4694 has slightly higher Aβ binding and lower variance than 11C-PiB, important properties for detecting early Aβ deposition and change over time.

11C-PiB PET ABri imaging in Worster-Drought syndrome (familial British dementia): a case report.

Brain amyloid imaging is becoming an essential tool for the pre-mortem evaluation of Alzheimers disease (AD). This study explores the pattern of 11C-PiB retention in a subject with Worster-Drought syndrome (WDS). A 55 year-old male carrier of the WDS gene mutation with mild signs of ataxia and subtle cognitive impairment underwent MRI and 11C-PiB-PET studies.Brain PiB regional distribution was compared to those from cohorts of healthy controls and AD patients. While no significant cortical 11C-PiB retention was present, a high degree of cerebellar 11C-PiB retention was observed in a genetically confirmed carrier of the WDS gene. We speculate that the sparsity of ABri plaques in the neocortex together with its high deposition in the cerebellum, might explain the observed pattern of 11C-PiB retention.