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Abstract Introduction A standardised method for quantifying β-amyloid PET tracers would allow comparison across different tracers and different sites. The development of the Centiloid scale has aimed to achieve this, applying a common scale to better aid the diagnosis and prognosis of Alzheimer’s disease (AD) and to monitor anti-amyloid therapeutic interventions. Here, we apply the Centiloid method to [18F]flutemetamol and [11C]PiB (PiB, Pittsburgh compound B) PET images and derive the scaling factor to express their binding in Centiloids. Methods Paired PiB and [18F]flutemetamol scans for 74 subjects, including 24 young healthy controls (37 ± 5 years), were analysed using the standard Centiloid method. The same subjects were also analysed using PMOD- and FSL-based pipelines as well as SPM8. Test-retest analysis of 10 AD subjects was also performed with each pipeline. Results The standard uptake value ratios (SUVR), determined using the standard SPM8 Centiloid process, showed a strong correlation between [18F]flutemetamol (Flute) and PiB binding (SUVR-Flute = 0.77 × SUVR-PiB + 0.22, R 2 = 0.96). Application of the standard Centiloid process allowed the calculation of a direct conversion equation for SUVR-Flute to Centiloid units (CL) (CL = (121.42*SUVR-Flute) − 121.16). Analysis of the data via the two alternate Centiloid pipelines allowed us to derive standardised, SPM8-equivalent equations for both PMOD (CL = (115.24*SUVR-Flute) − 107.86) and FSL (CL = (120.32*SUVR-Flute) − 112.75) respectively. Test-retest analysis of 10 AD subjects showed an approximate 2% difference for each pipeline. Conclusions [18F]flutemetamol data can now be expressed in Centiloid units, enhancing its utility in clinical and research applications for β-amyloid imaging. The standard Centiloid method also demonstrates that [18F]flutemetamol has favourable performance compared with PiB and other β-amyloid tracers. Test-retest difference averaged 2%, with no difference between image processing pipelines. Centiloid scaling is robust and can be implemented on a number of platforms.

Abstract The Centiloid Project describes a post-hoc data transformation to standardize amyloid PET measurements to enable direct data comparisons across sites and studies using differing acquisition/analysis methods. It uses linear regression that transforms values using different measurement scales to match those from a standard Centiloid unit scale. Our group’s measurement method differs from the Centiloid’s standard method in both acquisition and analysis methods. In this work we examine multiple variations for performing these transformations and compare several approaches. We hypothesized that using Deming regression, which accounts for error on both axes, would produce a more optimal transformation than the recommended standard linear regression. We also examined the effects of performing separate regressions for differences in acquisition and analysis methods, rather than a direct single-regression approach. Our results found that all transformation approaches had very similar performance and were within the recommended tolerance thresholds.

The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial (11)C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources--ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm(3) by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm(3)/year) < amnestic mild cognitive impairment (2.5 cm(3)/year) < Alzheimer's disease (7.7 cm(3)/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = -0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =-0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =-0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimer's disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimer's disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration.

There is a longstanding ambiguity regarding the clinical diagnosis of dementia syndromes predominantly targeting executive functions versus behaviour and personality. This is due to an incomplete understanding of the macro-scale anatomy underlying these symptomatologies, a partial overlap in clinical features and the fact that both phenotypes can emerge from the same pathology and vice versa. We collected data from a patient cohort of which 52 had dysexecutive Alzheimer's disease, 30 had behavioural variant frontotemporal dementia (bvFTD), seven met clinical criteria for bvFTD but had Alzheimer's disease pathology (behavioural Alzheimer's disease) and 28 had amnestic Alzheimer's disease. We first assessed group-wise differences in clinical and cognitive features and patterns of fluorodeoxyglucose (FDG) PET hypometabolism. We then performed a spectral decomposition of covariance between FDG-PET images to yield latent patterns of relative hypometabolism unbiased by diagnostic classification, which are referred to as 'eigenbrains'. These eigenbrains were subsequently linked to clinical and cognitive data and meta-analytic topics from a large external database of neuroimaging studies reflecting a wide range of mental functions. Finally, we performed a data-driven exploratory linear discriminant analysis to perform eigenbrain-based multiclass diagnostic predictions. Dysexecutive Alzheimer's disease and bvFTD patients were the youngest at symptom onset, followed by behavioural Alzheimer's disease, then amnestic Alzheimer's disease. Dysexecutive Alzheimer's disease patients had worse cognitive performance on nearly all cognitive domains compared with other groups, except verbal fluency which was equally impaired in dysexecutive Alzheimer's disease and bvFTD. Hypometabolism was observed in heteromodal cortices in dysexecutive Alzheimer's disease, temporo-parietal areas in amnestic Alzheimer's disease and frontotemporal areas in bvFTD and behavioural Alzheimer's disease. The unbiased spectral decomposition analysis revealed that relative hypometabolism in heteromodal cortices was associated with worse dysexecutive symptomatology and a lower likelihood of presenting with behaviour/personality problems, whereas relative hypometabolism in frontotemporal areas was associated with a higher likelihood of presenting with behaviour/personality problems but did not correlate with most cognitive measures. The linear discriminant analysis yielded an accuracy of 82.1% in predicting diagnostic category and did not misclassify any dysexecutive Alzheimer's disease patient for behavioural Alzheimer's disease and vice versa. Our results strongly suggest a double dissociation in that distinct macro-scale underpinnings underlie predominant dysexecutive versus personality/behavioural symptomatology in dementia syndromes. This has important implications for the implementation of criteria to diagnose and distinguish these diseases and supports the use of data-driven techniques to inform the classification of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The implications of positive tau positron emission tomography (T) with negative beta amyloid positron emission tomography (A) are not well understood. We investigated cognitive performance in participants who were T+ but A‐. METHODS: We evaluated 98 participants from the Mayo Clinic who were T+ and A‐. Participants were matched 2:1 to A‐ and T‐ cognitively unimpaired (CU) controls. Cognitive test scores were compared between different groups. RESULTS: The A‐T+ group demonstrated lower performance than the A‐T‐ group on the Mini‐Mental Status Exam (MMSE) (p < 0.001), Wechsler Memory Scale‐Revised Logical Memory I (p < 0.001) and Logical Memory II (p < 0.001), Auditory Verbal Learning Test (AVLT) delayed recall (p = 0.004), category fluency (animals p = 0.005; vegetables p = 0.021), Trail Making Test A and B (p < 0.001), and others. There were no significant differences in demographic features or apolipoprotein E (APOE) e4 genotype between CU A‐T+ and CI A‐T+. DISCUSSION: A‐T+ participants show an association with lower cognitive performance. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European‐DLB consortium and the Mayo Clinic. Sex differences and sex‐by‐age interactions were assessed through visual atrophy rating scales (n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 ± 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex‐by‐age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. Highlights: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales.Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods.Sex differences in gray matter measures in DLB tended to disappear with increasing age. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co‐evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers. METHODS: We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aβ) PET, tau PET, plasma p‐tau217, p‐tau181, and glial fibrillary acidic protein (GFAP) as endpoints. RESULTS: Individual timing of plasma p‐tau progression was strongly associated with Aβ PET and GFAP progression. In the population, GFAP became abnormal first, then Aβ PET, plasma p‐tau, and tau PET temporal meta‐regions of interest when applying cut points based on young, cognitively unimpaired participants. DISCUSSION: Plasma p‐tau is a stronger indicator of a temporally linked response to elevated brain Aβ than of tau pathology. While Aβ deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p‐tau and Aβ PET was the strongest. Highlights: Plasma p‐tau progression was more strongly associated with Aβ than tau PET.Progression on plasma p‐tau was associated with Aβ PET and GFAP progression.P‐tau181 and p‐tau217 become abnormal after Aβ PET and before tau PET.GFAP became abnormal first, before plasma p‐tau and Aβ PET. [ABSTRACT FROM AUTHOR]

Abstract Background 18F-Tetrafluoroborate (18F-TFB) is a promising iodide analog for PET imaging of thyroid cancer and sodium/iodide symporter (NIS) reporter activity in viral therapy applications. The aim of this study was to evaluate the safety, pharmacokinetics, biodistribution, and radiation dosimetry of high-specific activity 18F-TFB in healthy human subjects. Methods 18F-TFB was synthesized with specific activity of 3.2 ± 1.3 GBq/μmol (at the end of synthesis). Dynamic and whole-body static PET/CT scans over 4 h were performed after intravenous administration of 18F-TFB (333–407 MBq) in four female and four male healthy volunteers (35 ± 11 years old). Samples of venous blood and urine were collected over the imaging period and analyzed by ion-chromatography HPLC to determine tracer stability. Vital signs and clinical laboratory safety assays were measured to evaluate safety. Results 18F-TFB administration was well tolerated with no significant findings on vital signs and no clinically meaningful changes in clinical laboratory assays. Left-ventricular blood pool time-activity curves showed a multi-phasic blood clearance of 18F-radioactivity with the two rapid clearance phases over the first 20 min, followed by a slower clearance phase. HPLC analysis showed insignificant 18F-labeled metabolites in the blood and urine over the length of the study (4 h). High uptakes were seen in the thyroid, stomach, salivary glands, and bladder. Urinary clearance of 18F-TFB was prominent. Metabolic stability was evidenced by low accumulation of 18F-radioactivity in the bone. Effective doses were 0.036 mSv/MBq in males and 0.064 mSv/MBq in females (p = 0.08, not significant). Conclusions This initial study in healthy human subjects showed 18F-TFB was safe and distributed in the human body similar to other iodide analogs. These data support further translational studies with 18F-TFB as NIS gene reporter and imaging biomarker for thyroid cancer and other disease processes that import iodide.