Trial Outcomes & Findings for Cognitive Decline and Alzheimer's Disease in the Dallas Lifespan Brain Study (NCT NCT04080544)

NCT ID: NCT04080544

Last Updated: 2023-09-28

Results Overview

Tau accumulation in the temporal lobe will be measured as the standardized uptake value ratio (SUVR) computed from each participant's \[18F\]AV-1451 PET scans averaged across six bilateral regions of interest (ROls) by normalizing regional counts to the whole cerebellum. The 6 ROls are: inferior temporal gyrus, middle temporal gyrus, superior temporal gyrus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus. Each participant's PET scan and the six bilateral ROIs will be coregistered to their T1-weighted MRI (MP-RAGE). Finally, the mean observed tracer count from each region will be extracted and normalized using whole cerebellum as the reference. Observed tau SUVR scores in humans range from 0.5 to 2.5, with higher scores being indicative of greater tau accumulation. Unless otherwise specified, all subsequent analyses will use this temporal tau SUVR and will involve examination of cross-sectional relationships between tau SUVR and key outcome measures at Wave 3 of the DLBS.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 125 participants
• Primary outcome timeframe: An average of 3-months post-PET study visit
• Results posted on: 2023-09-28

Participant Flow

Scans were acquired from participants previously enrolled in Wave 1 or 2 of the Dallas Lifespan Brain Study (DLBS)

Participant milestones

Measure	Follow up DLBS Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the University of Texas Southwestern Medical Center (UTSW) Positron Emission Tomography/Computed Tomography (PET/CT) scanner for a 20-minute brain scan.
Overall Study STARTED	125
Overall Study COMPLETED	125
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Cognitive Decline and Alzheimer's Disease in the Dallas Lifespan Brain Study

Baseline characteristics by cohort

Measure	Follow up DLBS Participants n=125 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	49 Participants n=5 Participants
Age, Categorical >=65 years	76 Participants n=5 Participants
Age, Continuous	67.70 years STANDARD_DEVIATION 14.74 • n=5 Participants
Sex: Female, Male Female	77 Participants n=5 Participants
Sex: Female, Male Male	48 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	119 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	4 Participants n=5 Participants
Race (NIH/OMB) White	112 Participants n=5 Participants
Race (NIH/OMB) More than one race	5 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants
Region of Enrollment United States	125 participants n=5 Participants
Education, Continuous	16.09 years STANDARD_DEVIATION 2.10 • n=5 Participants
Mini-Mental State Examination	28.36 units on a scale STANDARD_DEVIATION 1.50 • n=5 Participants

PRIMARY outcome

Timeframe: An average of 3-months post-PET study visit

Population: Participants with available data were analyzed. This sample excludes one participant whose scanner data were unusable due to technical issues during acquisition.

Tau accumulation in the temporal lobe will be measured as the standardized uptake value ratio (SUVR) computed from each participant's [18F]AV-1451 PET scans averaged across six bilateral regions of interest (ROls) by normalizing regional counts to the whole cerebellum. The 6 ROls are: inferior temporal gyrus, middle temporal gyrus, superior temporal gyrus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus. Each participant's PET scan and the six bilateral ROIs will be coregistered to their T1-weighted MRI (MP-RAGE). Finally, the mean observed tracer count from each region will be extracted and normalized using whole cerebellum as the reference. Observed tau SUVR scores in humans range from 0.5 to 2.5, with higher scores being indicative of greater tau accumulation. Unless otherwise specified, all subsequent analyses will use this temporal tau SUVR and will involve examination of cross-sectional relationships between tau SUVR and key outcome measures at Wave 3 of the DLBS.

Outcome measures

Measure

Follow up DLBS Participants n=124 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.

Standardized Uptake Value Ratios (SUVrs) Calculated From [18F]AV-1451 PET Scans

1.09 standardized uptake value ratio Standard Deviation 0.10

SECONDARY outcome

Timeframe: 1-year post study completion

Population: Participants with available data were analyzed. This sample excludes one participant whose scanner data were unusable due to technical issues during acquisition.

Episodic memory is a construct that measures how well individuals can store, maintain, and retrieve detailed information in long-term memory. Episodic memory will be a composite score using the Hopkins Verbal Learning test with 3 subcomponents (immediate recall: range 0-12, delayed recall: range 0-12, and recognition: range 0-24) and the immediate recall of the CANTAB Verbal Recognition Memory task (range 0-12). Scores from the tasks will be converted to Z-scores and averaged to form an episodic memory composite, and then this final value with be converted to a Z-score. A higher composite Z-score indicates better episodic memory, a Z-score of 0 represents the population mean, and all Z-scores have a standard deviation of 1. Values in this table represent this Episodic Memory Z-score.

Outcome measures

Measure

Follow up DLBS Participants n=124 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.

Relationship of Tau Burden to Episodic Memory Function

0 Z-score Standard Deviation 1

SECONDARY outcome

Timeframe: 1-year post study completion

Population: Participants with available data were analyzed.

Amyloid accumulation throughout the Dallas Lifespan Brain Study (6-9.8 years) will be measured with Florbetapir F18 and calculated as an Amyloid Standard Uptake Value ratio (SUVR) by normalizing regional counts to the whole cerebellum. Amyloid SUVR scores will be averaged across eight cortical regions spanning most of the cortex: dorsal lateral prefrontal cortex, orbitofrontal cortex, lateral parietal cortex, posterior cingulate cortex, anterior cingulate cortex, precuneus, lateral temporal cortex, and lateral occipital lobe. Amyloid SUVR scores observed in this study have ranged from 0.88 to 1.74, with higher scores being indicative of greater amyloid accumulation. Finally, annualized change scores for these amyloid SUVRs across the full study duration (6-9.8 years) will be calculated to determine the extent that the rate of amyloid accumulation relates to tau burden at the end of the study.

Outcome measures

Measure

Follow up DLBS Participants n=59 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.

Relationship of Amyloid Accumulation to Tau Burden

0.0035 standardized uptake value ratio Standard Deviation 0.0122

SECONDARY outcome

Timeframe: 1-year post study completion

Population: Participants with available data were analyzed. This sample excludes one participant whose scanner data were unusable due to technical issues during acquisition.

Speed of processing is a construct that measures how rapidly individuals can process information. To assess speed of processing, a composite score will be created using the Digit Comparison task and the Wechsler Adult Intelligence Scale (WAIS) Digit Symbol task. Observed DLBS raw scores range from 27 to 116 for Digit Comparison task and 20 to 90 for Digit Symbol task. Participants' raw scores are converted to Z-scores and averaged to form a speed of processing composite, and then this final value with be converted to a Z-score. A higher composite Z-score indicates better speed of processing, a Z-score of 0 represents the population mean, and all Z-scores have a standard deviation of 1. Values in this table represent this Speed of Processing Z-score.

Outcome measures

Measure

Follow up DLBS Participants n=124 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.

Relationship of Tau Burden to Speed of Processing

0 Z-score Standard Deviation 1

SECONDARY outcome

Timeframe: 1-year post study completion

Population: Participants with available data were analyzed. This sample excludes one participant whose scanner data were unusable due to technical issues during acquisition.

The construct of reasoning measures an individual's ability to recognize novel patterns and the conceptual relationship among objects and effectively apply these patterns to solve similar problems. To assess reasoning, a composite score will be created using the Raven's Progressive Matrices task and Educational Testing Service (ETS) Letters Sets task. Observed DLBS raw scores range from 9 to 30 for Raven's Progressive Matrices task and from 0.5 to 30 for ETS Letters Sets task. Raven's Progress Matrices and ETS Letter Sets will be converted to Z-scores and averaged to form a reasoning composite, and then this final value with be converted to a Z-score. A higher composite Z-score indicates higher reasoning ability, a Z-score of 0 represents the population mean, and all Z-scores have a standard deviation of 1. Values in this table represent this Reasoning Z-score.

Outcome measures

Measure

Follow up DLBS Participants n=124 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.

Relationship of Tau Burden to Reasoning

0 Z-scores Standard Deviation 1

SECONDARY outcome

Timeframe: 1-year post study completion

Population: Participants with available data were analyzed. This sample excludes one participant whose scanner data were unusable due to technical issues during acquisition.

Working memory is a construct that measures the ability of individuals to simultaneously manipulate and store information. To assess working memory, a composite score will be created using the CANTAB Spatial Working Memory task (reverse scored) and the Wechsler Adult Intelligence Scale (WAIS-III) Letter Number Sequencing task. Observed DLBS raw scores range from 0 to 86 total errors for the CANTAB Spatial Working Memory task and 2 to 20 for the WAIS-III Letter Number Sequencing task. Participants' raw scores are converted to Z-scores and averaged to form a working memory composite, and then this final value with be converted to a Z-score. A higher working memory composite Z-score indicates better working memory, a Z-score of 0 represents the population mean, and all Z-scores have a standard deviation of 1. Values in this table represent this Working Memory Z-score.

Outcome measures

Measure

Follow up DLBS Participants n=124 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.

Relationship of Tau Burden to Working Memory

0 Z-score Standard Deviation 1

SECONDARY outcome

Timeframe: 1-year post study completion

Population: Participants with available data were analyzed. This sample excludes one participant whose scanner data were unusable due to technical issues during acquisition.

Linear regressions between the AV-1451 SUVR in each of the temporal regions of interest with participant age will be calculated, and in additional analyses, non-linear effects of age will be examined via quadratic and growth modeling. Observed AV-1451 SUVR scores in humans have ranged from 0.5 to 2.5, with higher scores being indicative of greater tau accumulation. The investigators predict that tau accumulation will accelerate in old age, thus supporting a non-linear rate of deposition.

Outcome measures

Measure	Follow up DLBS Participants n=124 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.
Relationship of Tau Burden to Participants' Age parahippocampal SUVR	1.05 standardized uptake value ratio Standard Deviation 0.10
Relationship of Tau Burden to Participants' Age fusiform SUVR	1.13 standardized uptake value ratio Standard Deviation 0.08
Relationship of Tau Burden to Participants' Age inferior temporal SUVR	1.14 standardized uptake value ratio Standard Deviation 0.13
Relationship of Tau Burden to Participants' Age middle temporal SUVR	1.11 standardized uptake value ratio Standard Deviation 0.13
Relationship of Tau Burden to Participants' Age superior temporal SUVR	1.04 standardized uptake value ratio Standard Deviation 0.07
Relationship of Tau Burden to Participants' Age entorhinal SUVR	1.09 standardized uptake value ratio Standard Deviation 0.14

SECONDARY outcome

Timeframe: 1-year post study completion

Population: Participants with available data were analyzed. This sample excludes one participant whose scanner data were unusable due to technical issues during acquisition and three participants did not have a recent MRI.

Regional cortical thickness will be estimated from previously acquired T1-weighted structural magnetic resonance imaging (MRl) scans using FreeSurfer (ver. 5.3), with surface parcellation manually edited when necessary by our team of experts. The regions selected for analyses of cortical thickness were the ROIs used to estimate temporal tau SUVR: inferior temporal gyrus, middle temporal gyrus, superior temporal gyrus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus. Observed cortical thickness in these regions range from 1.38 to 3.83 mm with higher scores indicating greater thickness.

Outcome measures

Measure	Follow up DLBS Participants n=121 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.
Relationship of Tau Burden to Cortical Thickness superior temporal thickness	2.51 mm Standard Deviation 0.25
Relationship of Tau Burden to Cortical Thickness parahippocampal thickness	2.44 mm Standard Deviation 0.26
Relationship of Tau Burden to Cortical Thickness inferior temporal thickness	2.53 mm Standard Deviation 0.22
Relationship of Tau Burden to Cortical Thickness middle temporal thickness	2.68 mm Standard Deviation 0.20
Relationship of Tau Burden to Cortical Thickness entorhinal thickness	2.85 mm Standard Deviation 0.47
Relationship of Tau Burden to Cortical Thickness fusiform thickness	2.46 mm Standard Deviation 0.21

SECONDARY outcome

Timeframe: 1-year post study completion

Population: Participants with available data were analyzed. This sample excludes one participant whose scanner data were unusable due to technical issues during acquisition and three participants did not have a recent MRI.

Hippocampal volume will be estimated from previously acquired T1-weighted structural magnetic resonance imaging (MRl) scans using FreeSurfer (ver. 5.3), with surface parcellation manually edited when necessary by our team of experts. This region was selected for analysis as it was one of the ROIs used to estimate temporal tau SUVR. Observed DLBS hippocampal volume ranged from 1843 to 5342 mm^3 with higher scores indicating greater volume.

Outcome measures

Measure

Follow up DLBS Participants n=121 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.

Relationship of Tau Burden to Hippocampal Volume

3864.98 mm^3 Standard Deviation 626.45

SECONDARY outcome

Timeframe: 1-year post study completion

Population: Participants with available data were analyzed. This sample excludes one participant whose scanner data were unusable due to technical issues during acquisition and three participants who did not have a recent MRI.

White matter integrity will be assessed using the estimated volume of white matter hypointensities from previously acquired T1-weighted structural magnetic resonance imaging (MRl) scans using FreeSurfer (ver. 5.3). Observed DLBS white matter hypointensities range from 796 to 35,037 mm^3 with higher scores indicating greater volume of hypointensities and reflecting worse white matter integrity.

Outcome measures

Measure

Follow up DLBS Participants n=121 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.

Relationship of Tau Burden to White Matter Integrity

3864.48 mm^3 Standard Deviation 4539.80

SECONDARY outcome

Timeframe: 1-year post study completion

Population: Participants with available tau and fMRI data were analyzed.

For functional measures, blood oxygenation level dependent signal from contrasts of interest using selected ROls will be created. For the semantic judgment task (easy judgments - fixation), the investigators will focus on ROIs associated with processing meaning, including inferior frontal gyrus, precuneus, and middle temporal gyrus. Observed BOLD activation values (betas) ranged from -1.00 to 1.30 with higher values indicating greater activation.

Outcome measures

Measure	Follow up DLBS Participants n=98 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.
Relationship of Tau Burden to Functional Magnetic Resonance Imaging (MRI) Inferior frontal gyrus	0.27 fMRI activation beta Standard Deviation 0.31
Relationship of Tau Burden to Functional Magnetic Resonance Imaging (MRI) Middle temporal gyrus	0.07 fMRI activation beta Standard Deviation 0.26
Relationship of Tau Burden to Functional Magnetic Resonance Imaging (MRI) Precuneus	-0.23 fMRI activation beta Standard Deviation 0.36

SECONDARY outcome

Timeframe: 1-year post study completion

Population: Participants with available data were analyzed. This sample excluded 2 statistical outliers.

Resting-state brain system segregation was computed on data collected from a separate resting-state scan using graph theory. System segregation is calculated as (Zw - Zb) / Zw, where Zw is the mean Fisher z-transformed r between nodes with the same system and Zb is the mean Fisher z-transformed r between nodes of one system to all nodes in other systems. Higher values indicate reduced node-node connectivity between systems relative to within-system connectivity. A score of 0 would reflect equal resting-state connectivity between nodes within the same functional system and between nodes of separate systems. Like all Z-scores, these scores typically range from -3 to 3. Higher scores are observed in younger adults than in older adults and may suggest a more youth-like brain, though higher scores are not objectively better. Systems were defined based on Power et al., (2011, Neuron) and more details on this measure are described in Chan et al. (2014, PNAS).

Outcome measures

Measure

Follow up DLBS Participants n=105 Participants Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.

Relationship of Tau Burden to Resting-State Brain System Segregation

0.58 Z-score Standard Deviation 0.07

Adverse Events

Follow up DLBS Participants

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Follow up DLBS Participants n=125 participants at risk Eight to ten year follow-up DLBS participants who were cognitively normal at the time of enrollment from 2008 to 2014. \[18F\]AV-1451: The subject will receive up to a target dose of 370 megabecquerel (MBq) as a single IV bolus of \[18F\]AV-1451. Positron Emission Tomography: Approximately 80 minutes after injection subjects will be placed in the UTSW PET/CT scanner for a 20-minute brain scan.
Blood and lymphatic system disorders Elevated blood pressure	7.2% 9/125 • Day of visit (post-injection, pre-discharge) and follow-up call 48-72 hours post-injection The experimenter inquired about adverse events (AEs) during the time frames described above and, if AEs were reported, they filled out a log indicating the date/time, severity (mild, moderate, severe), possible relation to drug/procedure, action taken, and event resolution (e.g., resolved, ongoing).
Eye disorders Black dot in visual field	0.80% 1/125 • Day of visit (post-injection, pre-discharge) and follow-up call 48-72 hours post-injection The experimenter inquired about adverse events (AEs) during the time frames described above and, if AEs were reported, they filled out a log indicating the date/time, severity (mild, moderate, severe), possible relation to drug/procedure, action taken, and event resolution (e.g., resolved, ongoing).
Musculoskeletal and connective tissue disorders Muscle soreness in injection arm	0.80% 1/125 • Day of visit (post-injection, pre-discharge) and follow-up call 48-72 hours post-injection The experimenter inquired about adverse events (AEs) during the time frames described above and, if AEs were reported, they filled out a log indicating the date/time, severity (mild, moderate, severe), possible relation to drug/procedure, action taken, and event resolution (e.g., resolved, ongoing).
Skin and subcutaneous tissue disorders Neck rash	0.80% 1/125 • Day of visit (post-injection, pre-discharge) and follow-up call 48-72 hours post-injection The experimenter inquired about adverse events (AEs) during the time frames described above and, if AEs were reported, they filled out a log indicating the date/time, severity (mild, moderate, severe), possible relation to drug/procedure, action taken, and event resolution (e.g., resolved, ongoing).
General disorders Diarrhea, drowsiness, nausea	0.80% 1/125 • Day of visit (post-injection, pre-discharge) and follow-up call 48-72 hours post-injection The experimenter inquired about adverse events (AEs) during the time frames described above and, if AEs were reported, they filled out a log indicating the date/time, severity (mild, moderate, severe), possible relation to drug/procedure, action taken, and event resolution (e.g., resolved, ongoing).

Additional Information

Dr. Joseph Hennessee

The University of Texas at Dallas

Phone: 408-813-4488

Email: joseph.hennessee@utdallas.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place