Characterization of pulsations in the brain and cerebrospinal fluid using ultra-high field magnetic resonance imaging

The development of innovative non-invasive neuroimaging methods and biomarkers is critical for studying brain disease. Imaging of cerebrospinal fluid (CSF) pulsatility may inform the brain fluid dynamics involved in clearance of cerebral metabolic waste. In this work, we developed a methodology to characterize the frequency and spatial localization of whole brain CSF pulsations in humans. Using 7 Tesla (T) human magnetic resonance imaging (MRI) and ultrafast echo-planar imaging (EPI), in-vivo images were obtained to capture pulsations of the CSF signal. Physiological data were simultaneously collected and compared with the 7 T MR data. The primary components of signal pulsations were identified using spectral analysis, with the most evident frequency bands identified around 0.3, 1.2, and 2.4 Hz. These pulsations were mapped spatially and temporally onto the MR image domain and temporally onto the physiological measures of electrocardiogram and respiration. We identified peaks in CSF pulsations that were distinct from peaks in grey matter and white matter regions. This methodology may provide novel in vivo biomarkers of disrupted brain fluid dynamics

Methodology for Positron Emission Tomography Imaging of Amyloid-­‐β Plaques: Cross-­‐Sectional and Longitudinal Validation

<p>The aim of this work was to identify optimal methodological techniques for quantifying 11C-­‐Pittsburgh Compound B (PiB) PET imaging measures of Amyloid-­‐β protein deposition, a neuropathological hallmark of Alzheimer’s disease (AD), in both cross-­‐sectional and longitudinal studies. Simulated phantoms based on existing MR and PiB PET images were generated to characterize and validate the implementation of three partial volume correction (PVC) techniques that account for the limited spatial resolution of PET: the Meltzer, the Müller-­‐Gärtner, and the Region-­‐Based Voxel-­‐Wise methods. The impact of these partial volume correction methods on correlations between region-­‐matched antemortem PiB PET standardized uptake value ratios (SUVR) and postmortem measures of amyloid load was then examined in a unique cohort of 12 subjects. Results indicate that the impact of PVC is not only dependent on the technique utilized, but also highly specific to region placement and subject anatomy. While the Region-­‐Based Voxel-­‐ Wise method outperformed other PVC methods, no PVC method improved correlations between antemortem PiB PET SUVR and postmortem measures of amyloid load, likely due to the noise propagation properties of the techniques. Several PET image analysis methods were also evaluated to assess relative performance in measuring change of amyloid deposition over time: the Simplified Reference Tissue, the Logan graphical, and the SUVR methods. This evaluation was performed in a unique cohort of 48 healthy elderly control, mild cognitive impairment, and AD subjects imaged with PiB PET at baseline and follow-­‐up. The potential impact of non-­‐specific reference region selection, changes in relative PiB delivery between target and reference tissues, and the partial volume effect were examined. The SUVR measure over 40-­‐60 minutes post-­‐injection was found to be optimal in tracking longitudinal changes across diagnostic groups. Results also indicate that the partial volume effects from non-­‐specific binding in white matter can influence measured changes of amyloid load. In conclusion, PVC techniques did not significantly improve correlations between PiB PET and postmortem measures of amyloid load. However, the Region-­‐ Based Voxel-­‐Wise PVC method should be considered for use in longitudinal PiB PET studies.</p

Validation of amyloid PET positivity thresholds in centiloids: a multisite PET study approach

Abstract Background Inconsistent positivity thresholds, image analysis pipelines, and quantitative outcomes are key challenges of multisite studies using more than one β-amyloid (Aβ) radiotracer in positron emission tomography (PET). Variability related to these factors contributes to disagreement and lack of replicability in research and clinical trials. To address these problems and promote Aβ PET harmonization, we used [18F]florbetaben (FBB) and [18F]florbetapir (FBP) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to derive (1) standardized Centiloid (CL) transformations and (2) internally consistent positivity thresholds based on separate young control samples. Methods We analyzed Aβ PET data using a native-space, automated image processing pipeline that is used for PET quantification in many large, multisite AD studies and trials and made available to the research community. With this pipeline, we derived SUVR-to-CL transformations using the Global Alzheimer’s Association Interactive Network data; we used reference regions for cross-sectional (whole cerebellum) and longitudinal (subcortical white matter, brain stem, whole cerebellum) analyses. Finally, we developed a FBB positivity threshold using an independent young control sample (N=62) with methods parallel to our existing FBP positivity threshold and validated the FBB threshold using a data-driven approach in ADNI participants (N=295). Results The FBB threshold based on the young sample (1.08; 18 CL) was consistent with that of the data-driven approach (1.10; 21 CL), and the existing FBP threshold converted to CL with the derived transformation (1.11; 20 CL). The following equations can be used to convert whole cerebellum- (cross-sectional) and composite- (longitudinal) normalized FBB and FBP data quantified with the native-space pipeline to CL units: [18F]FBB: CLwhole cerebellum = 157.15 × SUVRFBB − 151.87; threshold=1.08, 18 CL [18F]FBP: CLwhole cerebellum = 188.22 × SUVRFBP − 189.16; threshold=1.11, 20 CL [18F]FBB: CLcomposite = 244.20 × SUVRFBB − 170.80 [18F]FBP: CLcomposite = 300.66 × SUVRFBP − 208.84 Conclusions FBB and FBP positivity thresholds derived from independent young control samples and quantified using an automated, native-space approach result in similar CL values. These findings are applicable to thousands of available and anticipated outcomes analyzed using this pipeline and shared with the scientific community. This work demonstrates the feasibility of harmonized PET acquisition and analysis in multisite PET studies and internal consistency of positivity thresholds in standardized units.http://deepblue.lib.umich.edu/bitstream/2027.42/173807/1/13195_2021_Article_836.pd

Impact of partial volume correction on the regional correspondence between in vivo [C-11]PiB PET and postmortem measures of Aβ load

The positron emission tomography (PET) radiotracer Pittsburgh Compound B ([C-11]PiB) demonstrates a high affinity for fibrillary amyloid-beta (Aβ) aggregates. However, [C-11]PiB's in vivo sensitivity and specificity is an ongoing area of investigation in correlation studies with postmortem measures of Aβ pathology. One potential confound in PET-to-postmortem correlation studies is the limited spatial resolution of PET and resulting partial volume effects (PVEs). In this work, we evaluated the impact of three partial volume correction (PVC) techniques – the Meltzer, the modified Müller-Gärtner, and the Region-Based Voxel-Wise – on correlations between region-matched in vivo [C-11]PiB standardized uptake value ratios (SUVRs) and postmortem measures of Aβ pathology in a unique cohort of nine subjects. Postmortem Aβ pathology was assessed histologically as percent area coverage of 6-CN-PiB positive and Aβ immunoreactive (4G8 antibody) deposits. The application of all three PVC techniques resulted in minimally reduced PET-to-postmortem correlations relative to no PVC. However, correlations to both 6-CN-PiB and 4G8 percent area across all PVC techniques and no PVC were statistically significant at p < 0.01, suggesting that PVC is of minimal importance in understanding the relationship between Aβ PET and neuropathologically assessed Aβ. Thus, the utility of PVC in Aβ PET imaging should continue to be examined on an application-specific basis. Keywords: Partial volume correction, Amyloid imaging, PiB, PE

Alzheimer's disease pathology in a community-based sample of older adults without dementia: The MYHAT neuroimaging study

A true understanding of the distribution and functional correlates of Alzheimer's disease pathology in dementia-free older adults requires a population-based perspective. Here we report initial findings from a sample of 102 cognitively unimpaired participants (average age 77.2 years, 54.9% women, 13.7% APOE*4 carriers) recruited for neuroimaging from a larger representative population-based cohort participating in an ongoing longitudinal study of aging, the Monongahela-Youghiogheny Healthy Aging Team (MYHAT). All participants scored < 1.0 on the Clinical Dementia Rating (CDR) Scale, with 8 participants (7.8%) scoring CDR = 0.5. Participants completed a positron emission tomography scan using the tracers [C-11]Pittsburgh Compound-B (PiB) and [F-18]AV-1451 to estimate amyloid and tau deposition. PiB positivity was defined on a regional basis using established standardized uptake value ratio cutoffs (SUVR; cerebellar gray matter reference), with 39 participants (38.2%) determined to be PiB(+). Health history, lifestyle, and cognitive abilities were assessed cross-sectionally at the nearest annual parent MYHAT study visit. A series of adjusted regression analyses modeled cognitive performance as a function of global PiB SUVR and [F-18]AV-1451 SUVR in Braak associated regions 1, 3/4, and 5/6. In comparison to PiB(-) participants (n = 63), PiB(+) participants were older, less educated, and were more likely to be APOE*4 carriers. Global PiB SUVR was significantly correlated with [F-18]AV-1451 SUVR in all Braak-associated regions (r = .38-0.53, p < .05). In independent models, higher Global PiB SUVR and Braak 1 [F-18]AV-1451 SUVR were associated with worse performance on a semantic interference verbal memory test. Our findings suggest that brain amyloid is common in a community-based setting, and is associated with tau deposition, but both pathologies show few associations with concurrent cognitive performance in a dementia-free sample

Amyloid accumulation in Down syndrome measured with amyloid load

Introduction: Individuals with Down syndrome (DS) show enhanced amyloid beta (Aβ) deposition in the brain. A new positron emission tomography (PET) index of amyloid load ( ) was recently developed as an alternative to standardized uptake value ratios (SUVrs) to quantify Aβ burden with high sensitivity for detecting and tracking Aβ change.. Methods: was calculated in a DS cohort (N = 169, mean age ± SD = 39.6 ± 8.7 years) using [C-11]Pittsburgh compound B (PiB) PET imaging. DS-specific PiB templates were created for Aβ carrying capacity () and non-specific binding (). Results: The highest values of Aβ carrying capacity were found in the striatum and precuneus. Longitudinal changes in displayed less variability when compared to SUVrs. Discussion: These results highlight the utility of for characterizing Aβ deposition in DS. Rates of Aβ accumulation in DS were found to be similar to that observed in late-onset Alzheimer\u27s disease (AD; ≈3% to 4% per year), suggesting that AD progression in DS is of earlier onset but not accelerated

Characterizing the emergence of amyloid and tau burden in Down syndrome.

Funder: National Institutes of Health ProgramsINTRODUCTION: Almost all individuals with Down syndrome (DS) will develop neuropathological features of Alzheimer's disease (AD). Understanding AD biomarker trajectories is necessary for DS-specific clinical interventions and interpretation of drug-related changes in the disease trajectory. METHODS: A total of 177 adults with DS from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) underwent positron emission tomography (PET) and MR imaging. Amyloid-beta (Aβ) trajectories were modeled to provide individual-level estimates of Aβ-positive (A+) chronicity, which were compared against longitudinal tau change. RESULTS: Elevated tau was observed in all NFT regions following A+ and longitudinal tau increased with respect to A+ chronicity. Tau increases in NFT regions I-III was observed 0-2.5 years following A+. Nearly all A+ individuals had tau increases in the medial temporal lobe. DISCUSSION: These findings highlight the rapid accumulation of amyloid and early onset of tau relative to amyloid in DS and provide a strategy for temporally characterizing AD neuropathology progression that is specific to the DS population and independent of chronological age. HIGHLIGHTS: Longitudinal amyloid trajectories reveal rapid Aβ accumulation in Down syndrome NFT stage tau was strongly associated with A+ chronicity Early longitudinal tau increases were observed 2.5-5 years after reaching A