Association of ß-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals.

OBJECTIVE: To determine the effect of ß-amyloid (Aß) level on progression risk to mild cognitive impairment (MCI) or dementia and longitudinal cognitive change in cognitively normal (CN) older individuals. METHODS: All CN from the Australian Imaging Biomarkers and Lifestyle study with Aß PET and ≥3 years follow-up were included (n = 534; age 72 ± 6 years; 27% Aß positive; follow-up 5.3 ± 1.7 years). Aß level was divided using the standardized 0-100 Centiloid scale: <15 CL negative, 15-25 CL uncertain, 26-50 CL moderate, 51-100 CL high, >100 CL very high, noting >25 CL approximates a positive scan. Cox proportional hazards analysis and linear mixed effect models were used to assess risk of progression and cognitive decline. RESULTS: Aß levels in 63% were negative, 10% uncertain, 10% moderate, 14% high, and 3% very high. Fifty-seven (11%) progressed to MCI or dementia. Compared to negative Aß, the hazard ratio for progression for moderate Aß was 3.2 (95% confidence interval [CI] 1.3-7.6; p < 0.05), for high was 7.0 (95% CI 3.7-13.3; p < 0.001), and for very high was 11.4 (95% CI 5.1-25.8; p < 0.001). Decline in cognitive composite score was minimal in the moderate group (-0.02 SD/year, p = 0.05), while the high and very high declined substantially (high -0.08 SD/year, p < 0.001; very high -0.35 SD/year, p < 0.001). CONCLUSION: The risk of MCI or dementia over 5 years in older CN is related to Aß level on PET, 5% if negative vs 25% if positive but ranging from 12% if 26-50 CL to 28% if 51-100 CL and 50% if >100 CL. This information may be useful for dementia risk counseling and aid design of preclinical AD trials.

Diagnostic accuracy of imaging brain vesicular monoamine transporter type 2 (VMAT2) in clinically uncertain parkinsonian syndrome (CUPS): a 3-year follow-up study in community patients.

OBJECTIVES: To further validate the diagnostic utility of 18F-AV-133 vesicular monoamine transporter type 2 (VMAT2) positron emission tomography (PET) in patients with clinically uncertain parkinsonian syndromes (CUPS) by comparison to clinical diagnosis at 3 years follow-up. DESIGN, SETTING AND PARTICIPANTS: In a previous study, we reported that 18F-AV-133 PET in community patients with CUPS changed diagnosis and management and increased diagnostic confidence. The current diagnosis of this cohort was obtained from the patient and treating specialist and compared with the diagnosis suggested 3 years earlier by the 18F-AV-133 PET. A second 18F-AV-133 PET was available in those with a discordant or inconclusive final diagnosis. STUDY OUTCOME MEASURES: The primary end point was the proportion of patients who had a follow-up clinical diagnosis, which was concordant with their initial 18F-AV-133 PET scan. Secondary end points were the proportion of patients who had the same diagnosis at follow-up as that reached after the initial scan and the stability of diagnostic changes made after the first scan. RESULTS: 81 of the 85 patients previously recruited to the CUPS study had follow-up of which 79 had a clinical diagnosis and 2 remained CUPS. The diagnosis was in agreement with the initial 18F-AV-133 PET scan result in 74 cases. Five patients had a discordant diagnosis; one patient with rubral tremor had a severely abnormal scan that had worsened when rescanned; four cases with normal initial and repeat scans had a clinical diagnosis of Parkinson's disease. Two patients with suspected genetic disorders remained classified as CUPS and both had normal scans. In the 24 CUPS cohort patients where 18F-AV-133 PET initially changed diagnosis, this change was supported by follow-up diagnosis in all but the one rubral tremor case. CONCLUSION: 18F-AV-133 PET is a useful tool in improving diagnostic accuracy in CUPS providing results and diagnostic changes that remain robust after 3 years follow-up.

18F-Florbetaben PET beta-amyloid binding expressed in Centiloids.

PURPOSE: The Centiloid (CL) method enables quantitative values from Aß-amyloid (Aß) imaging to be expressed in a universal unit providing pathological, diagnostic and prognostic thresholds in clinical practice and research and allowing integration of multiple tracers and methods. The method was developed for 11C-PiB scans with zero CL set as the average in young normal subjects and 100 CL the average in subjects with mild Alzheimer's disease (AD). The method allows derivation of equations to convert the uptake value of any tracer into the same standard CL units but first requires head-to-head comparison with 11C-PiB results. We derived the equation to express 18F-florbetaben (FBB) binding in CL units. METHODS: Paired PiB and FBB PET scans were obtained in 35 subjects. including ten young normal subjects aged under 45 years (33 ± 8 years). FBB images were acquired from 90 to 110 min after injection. Spatially normalized images were analysed using the standard CL method (SPM8 coregistration of PET data to MRI data and the MNI-152 atlas) and standard CL regions (cortex and whole cerebellum downloaded from http://www.gaain.org ). RESULTS: FBB binding was strongly correlated with PiB binding (R 2 = 0.96, SUVRFBB = 0.61 × SUVRPiB + 0.39). The equation to derive CL values from FBB SUVR was CL units = 153.4 × SUVRFBB - 154.9. The CL value in the young normal subjects was -1.08 ± 6.81 for FBB scans compared to -0.32 ± 3.48 for PiB scans, giving a variance ratio of 1.96 (SDFBB CL/SDPiB CL). CONCLUSIONS: 18F-FBB binding is strongly correlated with PiB binding and FBB results can now be expressed in CL units.

Management Impact of Imaging Brain Vesicular Monoamine Transporter Type 2 in Clinically Uncertain Parkinsonian Syndrome with 18F-AV133 and PET.

Idiopathic Parkinson disease is a common neurodegenerative disorder for which misdiagnosis occurs in up to 30% of patients after initial assessment and in 10%-15% even after long-term follow-up. Vesicular monoamine transporter type 2 (VMAT2) imaging with PET allows assessment of the integrity of the presynaptic dopaminergic pathway. We investigated the management impact of VMAT2 imaging in patients with clinically uncertain Parkinsonian syndromes. Methods: Forty-seven patients with clinically uncertain Parkinsonian syndromes (mean age ± SD, 56.9 ± 14.9 y; age range, 21-80 y) were referred from movement disorder specialists. All participants underwent a 20-min PET acquisition 2 h after injection of 250 MBq of 18F-AV-133, and the resulting images were quantitatively assessed. Clinical impact was recorded as high, moderate, or low based on diagnosis and management questionnaires completed by the referring specialists before and after release of the PET results. Management impact was high if there was a change in diagnostic category, moderate if there was a change in medication, and low if there was no change. Results: VMAT2 PET changed the diagnosis in 11 (23%) and medication in 25 (53%) participants. Management impact was high in 23%, moderate in 38%, and low in 39% of the participants. High diagnostic confidence increased from 11% of patients to 80% after the release of the scan results. Conclusion:18F-AV-133 had substantial management impact in patients with clinically uncertain Parkinsonian syndromes. VMAT2 imaging with 18F-AV133 might improve diagnosis, prognosis, and appropriate use of medication, translating into better patient outcomes.

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

UNLABELLED: A common quantitative output value for PET measures of ß-amyloid (Aß) 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-(18)F-fluoro-6-(methylamino)-3-pyridinyl]-1-benzofuran-5-ol ((18)F-NAV4694) and (11)C-Pittsburgh compound B ((11)C-PiB) Aß 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 (11)C-PiB and (18)F-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 ((18)F-NAV4694 SUVR = 1.09 × (11)C-PiB SUVR - 0.08, R(2) = 0.99). The equation to convert (18)F-NAV4694 to centiloids [100 × ((18)F-NAV4694 SUVR - 1.028)/1.174] was similar to a published equation for (11)C-PiB [100 × ((11)C-PiB SUVR - 1.009)/1.067]. In the young controls, the variance ratio ((18)F-NAV4694 centiloid SD divided by (11)C-PiB centiloid SD) was 0.85. CONCLUSION: The results for both (11)C-PiB and (18)F-NAV4694 can now be expressed in centiloids, an important step that should allow better clinical and research use of Aß imaging. The standard centiloid method also showed that (18)F-NAV4694 has slightly higher Aß binding and lower variance than (11)C-PiB, important properties for detecting early Aß deposition and change over time.

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 Alzheimer's 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 Alzheimer's 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 Alzheimer's disease compared with healthy control subjects. In patients with Alzheimer's disease, the inferior temporal cortex, which is an area known to contain high densities of neurofibrillary tangles in the Alzheimer's disease brain, showed prominent 18F-THK5105 retention. Compared with high frequency (100%) of 18F-THK5105 retention in the temporal cortex of patients with Alzheimer's disease, frontal 18F-THK5105 retention was less frequent (37.5%) and was only observed in cases with moderate-to-severe Alzheimer's 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 Alzheimer's disease.

Assessing THK523 selectivity for tau deposits in Alzheimer's disease and non-Alzheimer's disease tauopathies.

INTRODUCTION: The introduction of tau imaging agents such as (18)F-THK523 offers new hope for the in vivo assessment of tau deposition in tauopathies such as Alzheimer's disease (AD), where preliminary (18)F-THK523-PET studies have demonstrated significantly higher cortical retention of (18)F-THK523 in AD compared to age-matched healthy individuals. In addition to AD, tau imaging with PET may also be of value in assessing non-AD tauopathies, such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick's disease (PiD). METHODS: To further investigate the ability of THK523 to recognize tau lesions, we undertook immunohistochemical and fluorescence studies in serial brain sections taken from individuals with AD (n = 3), CBD (n = 2), PSP (n = 1), PiD (n = 2) and Parkinson's disease (PD; n = 2). In addition to the neuropathological analysis, one PSP patient had undergone a (18)F-THK523 PET scan 5 months before death. RESULTS: Although THK523 labelled tau-containing lesions such as neurofibrillary tangles and neuropil threads in the hippocampus and frontal regions of AD brains, it failed to label tau-containing lesions in non-AD tauopathies. Furthermore, though THK523 faintly labelled dense-cored amyloid-ß plaques in the AD frontal cortex, it failed to label α-synuclein-containing Lewy bodies in PD brain sections. CONCLUSION: The results of this study suggest that (18)F-THK523 selectively binds to paired helical filament tau in AD brains but does not bind to tau lesions in non-AD tauopathies, or to α-synuclein in PD brains.

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

PURPOSE: Diagnosis 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 (18)F-THK523 as a potential tau imaging tracer. METHODS: Ten healthy elderly controls, three semantic dementia (SD) and ten AD patients underwent neuropsychological examination, MRI as well as (18)F-THK523 and (11)C-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 (18)F-THK523 and (11)C-PIB were estimated for all participants. Correlational analyses were performed between global and regional (18)F-THK523, (11)C-PIB, cognition and brain volumetrics. RESULTS: (18)F-THK523 presented with fast reversible kinetics. Significantly higher (18)F-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 (18)F-THK523 retention did not correlate with Aß distribution as assessed by (11)C-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 (11)C-PIB, hippocampal (18)F-THK523 retention was correlated with several cognitive parameters and with hippocampal atrophy. CONCLUSION: (18)F-THK523 does not bind to Aß in vivo, while following the known distribution of paired helical filaments (PHF)-tau in the brain. Significantly higher cortical (18)F-THK523 retention in AD patients as well as the association of hippocampal (18)F-THK523 retention with cognitive parameters and hippocampal volume suggests (18)F-THK523 selectively binds to tau in AD patients. Unfortunately, the very high (18)F-THK523 retention in white matter precludes simple visual inspection of the images, preventing its use in research or clinical settings.

Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease.

UNLABELLED: Neurofibrillary tangles in Alzheimer disease (AD) brains are composed of the microtubule-associated protein tau. Noninvasive monitoring of tau protein aggregates in the living brain will provide useful information regarding tau pathophysiology in AD. However, no PET probes are currently available for selective detection of tau pathology in AD. We have previously reported (18)F-labeled THK-523 ((18)F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel (18)F-labeled arylquinoline derivatives, (18)F-THK-5105 and (18)F-THK-5117, for use as tau imaging PET tracers. METHODS: (18)F-labeled compounds were prepared from the corresponding tosylated precursors. The binding affinity of compounds to synthetic tau aggregates and tau-rich AD brain homogenates was determined by saturation and competition binding assays. The binding selectivity of compounds to tau pathology was evaluated by autoradiography of AD brain sections. The pharmacokinetics of compounds were assessed in biodistribution studies in normal mice. A 14-d toxicity study with intravenous administration of compounds was performed using rats and mice. RESULTS: In vitro binding assays demonstrated higher binding affinity of THK-5105 and THK-5117 than THK-523 to tau protein aggregates and tau-rich AD brain homogenates. Autoradiographic analyses of AD brain sections showed that these radiotracers preferentially bound to neurofibrillary tangles and neuropil threads, which colocalized with Gallyas-positive and immunoreactive tau protein deposits. The distribution of this radiotracer binding in AD brain sections was completely different from that of (11)C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than (18)F-THK-523 and other reported (18)F-labeled radiotracers. THK-5105 and THK-5117 showed no toxic effects related to the administration of these compounds in mice and rats and no significant binding for various neuroreceptors, ion channels, and transporters at 1-µM concentrations. CONCLUSION: (18)F-labeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.

Head-to-head comparison of 11C-PiB and 18F-AZD4694 (NAV4694) for ß-amyloid imaging in aging and dementia.

UNLABELLED: (11)C-Pittsburgh compound-B ((11)C-PiB) is the benchmark radiotracer for imaging of ß-amyloid (Aß) plaque in Alzheimer disease (AD). (18)F-labeled Aß 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 (18)F-labeled Aß tracer, (18)F-AZD4694 (recently renamed NAV4694), with (11)C-PiB in the same subjects. METHODS: Forty-five participants underwent PET imaging with (11)C-PiB and (18)F-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: (18)F-AZD4694 showed reversible binding kinetics similar to (11)C-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 (11)C-PiB and (18)F-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 (11)C-PiB and (18)F-AZD4694 neocortical SUVR (slope of 0.95, r = 0.99, P < 0.0001). CONCLUSION: (18)F-AZD4694 displays imaging characteristics nearly identical to those of (11)C-PiB. The low white matter and high cortical binding in AD indicate that this tracer is well suited to both clinical and research use.

(18)F-florbetaben Aß imaging in mild cognitive impairment.

INTRODUCTION: (18)F-florbetaben and positron emission tomography were used to examine the relationships between ß-amyloid (Aß) deposition, cognition, hippocampal volume, and white matter hyperintensities in mild cognitive impairment (MCI). METHODS: Forty-five MCI participants were evaluated. A neocortical standardized uptake value ratio threshold ≥ 1.45 was used to discriminate high from low Aß burden. Correlations were adjusted for age, gender and years of education. RESULTS: High Aß burden was found in 53% of MCI. Regression analyses showed standardized uptake value ratio (r = -0.51, P = 0.0015) and hippocampal volume (r = 0.60, P = 0.024) both contributing to episodic memory impairment in independent fashion. White matter hyperintensities correlated with nonmemory cognition, and this correlation was particularly associated with Aß burden. CONCLUSION: Higher Aß deposition in MCI is associated with more severe memory impairment and is contributing to early amnestic symptoms independent of hippocampal atrophy.

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

PURPOSE: Amyloid imaging with (18)F-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 Aß deposition in subjects who had undergone both (11)C-PiB (PiB) and (18)F-florbetaben (FBB) PET imaging. METHODS: We identified ten healthy elderly controls (HC) and ten patients with AD who had undergone PET imaging after intravenous injection of 370 MBq of PiB and 300 MBq 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 70 min and between 90 and 110 min after injection for PiB and FBB, respectively. RESULTS: Significantly higher SUVR values (p < 0.0001) 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 (r = 0.97, p < 0.0001) with similar effect sizes for distinguishing AD from HC subjects for both radiotracers (Cohen's d 3.3 for PiB and 3.0 for FBB). CONCLUSION: FBB, while having a narrower dynamic range than PiB, clearly distinguished HC from AD patients, with a comparable effect size. FBB seems a suitable (18)F radiotracer for imaging AD pathology in vivo.

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 [(18)F]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 [(18)F]AV-133 PET studies. Additionally, 20 participants underwent amyloid imaging PET scans with either [(11)C]PiB or (18)F-florbetaben. VMAT2 density was calculated through normalized tissue uptake value ratios (R(T)) at 120-140 min after injection using the primary visual or the cerebellar cortex as reference region. Comparison of the R(T) for [(18)F]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: [(18)F]AV-133 allows assessment of nigrostriatal degeneration in Lewy body diseases. In contrast to amyloid imaging, VMAT2 imaging with [(18)F]AV-133 can robustly detect reductions of dopaminergic nigrostriatal afferents in DLB patients, assisting in the differential diagnosis from AD.

Amyloid imaging with (18)F-florbetaben in Alzheimer disease and other dementias.

UNLABELLED: Amyloid imaging with (18)F-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 (18)F-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 (18)F-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 (18)F-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 ß-amyloid burden in the MCI group, no correlation was observed in controls, FTLD or AD. CONCLUSION: (18)F-florbetaben had high sensitivity for AD, clearly distinguished patients with FTLD from AD, and provided results comparable to those reported with (11)C-Pittsburgh Compound B in a variety of neurodegenerative diseases.

In vivo assessment of vesicular monoamine transporter type 2 in dementia with lewy bodies and Alzheimer disease.

OBJECTIVE: To 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). DESIGN, SETTING, AND PARTICIPANTS: Nine 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. MAIN OUTCOME MEASURE: Comparison of the tissue ratio for [(18)F]AV-133 between the different clinical diagnostic groups. RESULTS: Lower 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. CONCLUSIONS: [(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.

18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease.

While considerable effort has focused on developing positron emission tomography ß-amyloid imaging radiotracers for the early diagnosis of Alzheimer's disease, no radiotracer is available for the non-invasive quantification of tau. In this study, we detail the characterization of (18)F-THK523 as a novel tau imaging radiotracer. In vitro binding studies demonstrated that (18)F-THK523 binds with higher affinity to a greater number of binding sites on recombinant tau (K18Δ280K) compared with ß-amyloid(1-42) fibrils. Autoradiographic and histofluorescence analysis of human hippocampal serial sections with Alzheimer's disease exhibited positive THK523 binding that co-localized with immunoreactive tau pathology, but failed to highlight ß-amyloid plaques. Micro-positron emission tomography analysis demonstrated significantly higher retention of (18)F-THK523 (48%; P < 0.007) in tau transgenic mice brains compared with their wild-type littermates or APP/PS1 mice. The preclinical examination of THK523 has demonstrated its high affinity and selectivity for tau pathology both in vitro and in vivo, indicating that (18)F-THK523 fulfils ligand criteria for human imaging trials.

Longitudinal assessment of Aß and cognition in aging and Alzheimer disease.

OBJECTIVE: Assess Aß deposition longitudinally and explore its relationship with cognition and disease progression. METHODS: Clinical follow-up was obtained 20 ± 3 months after [¹¹C]Pittsburgh compound B (PiB)-positron emission tomography in 206 subjects: 35 with dementia of the Alzheimer type (DAT), 65 with mild cognitive impairment (MCI), and 106 age-matched healthy controls (HCs). A second PiB scan was obtained at follow-up in 185 subjects and a third scan after 3 years in 57. RESULTS: At baseline, 97% of DAT, 69% of MCI, and 31% of HC subjects showed high PiB retention. At 20-month follow-up, small but significant increases in PiB standardized uptake value ratios were observed in the DAT and MCI groups, and in HCs with high PiB retention at baseline (5.7%, 2.1%, and 1.5%, respectively). Increases were associated with the number of apolipoprotein E ε4 alleles. There was a weak correlation between PiB increases and decline in cognition when all groups were combined. Progression to DAT occurred in 67% of MCI with high PiB versus 5% of those with low PiB, but 20% of the low PiB MCI subjects progressed to other dementias. Of the high PiB HCs, 16% developed MCI or DAT by 20 months and 25% by 3 years. One low PiB HC developed MCI. INTERPRETATION: Aß deposition increases slowly from cognitive normality to moderate severity DAT. Extensive Aß deposition precedes cognitive impairment, and is associated with ApoE genotype and a higher risk of cognitive decline in HCs and progression from MCI to DAT over 1 to 2 years. However, cognitive decline is only weakly related to change in Aß burden, suggesting that downstream factors have a more direct effect on symptom progression.

Temperature elevation increases GABA(A) -mediated cortical inhibition in a mouse model of genetic epilepsy.

A missense mutation (R43Q) in the γ2 subunit of the γ-aminobutyric acid (GABA)(A) receptor is associated with generalized (genetic) epilepsy with febrile seizures plus (GEFS+). Heterozygous GABA(A) γ2(R43Q) mice displayed a lower temperature threshold for thermal seizures as compared to wild-type littermates. Temperature-dependent internalization of GABA(A) γ2(R43Q)-containing receptors has been proposed as a mechanism underlying febrile seizure genesis in patients with this mutation. We tested this idea using the GABA(A) γ2(R43Q) knockin mouse model and analyzed GABAergic miniature postsynaptic inhibitory currents (mIPSCs) in acute brain slices after exposure to varying temperatures. Incubation of slices at an elevated temperature increased mIPSC amplitude in neurons from heterozygous mice, with no change seen in wild-type controls. [³H]Flumazenil binding measured in whole-brain homogenates from mutant and control mice following elevation of body temperature showed no temperature-dependent differences in γ2-containing receptor density. Therefore, in vivo mouse data do not support earlier in vitro observations that proposed temperature-dependent internalization of γ2 R43Q containing GABA(A) receptors as the cellular mechanism underlying febrile seizure genesis in patients with the GABA(A) γ2(R43Q) mutation.

Quantitative approaches to amyloid imaging.

Alzheimer's disease (AD), an irreversible, progressive neurodegenerative disorder clinically characterized by memory loss and cognitive decline, is the leading cause of dementia in the elderly, leading invariably to death within 7-10 years after diagnosis. In vivo amyloid imaging with positron emission tomography (PET) is allowing new insights into ß-amyloid (Aß) deposition in the brain, facilitating research into the causes, diagnosis, and future treatment of dementias, where Aß may play a role. Non-invasive quantification of Aß burden in the brain with PET has proven useful in the early and differential diagnosis of dementias, showing significantly higher retention in grey matter of AD patients when compared with healthy controls (HC) or patients with frontotemporal lobe degeneration (FTLD). With the advent of new therapeutic strategies aimed at reducing Aß burden in the brain to potentially prevent or delay functional and irreversible cognitive loss, there is increased interest in developing agents that allow assessment of Aß burden in vivo. A key aspect for Aß burden quantification is the application of compartmental or graphical analyses to the kinetic data in order to obtain quantitative and reproducible statements that allow comparison with other nosological groups, correlation with cognitive or biological parameters, and selection, monitoring, and follow-up of individuals in disease modifying therapeutic trials. It is also a necessary step in the validation of simplified approaches that could be applied in routine clinical settings. With the availability of novel amyloid imaging agents radiolabeled with either (11)C (half-life 20 min) or (18)F (half-life 110 min), a description of different image acquisition approaches is provided.

In vivo measurement of vesicular monoamine transporter type 2 density in Parkinson disease with (18)F-AV-133.

UNLABELLED: 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 (18)F-labeled tetrabenazine derivative, (18)F-(+)fluoropropyldihydrotetrabenazine ((18)F-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 (18)F-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 (18)F-labeled ligand (18)F-AV-133 can sensitively detect monoaminergic terminal reductions in PD patients. Studies with (18)F-AV-133 may allow the presymptomatic identification of individuals with disorders characterized by degeneration of dopaminergic nigrostriatal afferents.