Article Figures & Data
Figures
- FIGURE 1.
Model neurodegenerative disease time course. Neurodegenerative process is indicated in red as starting insidiously and remaining silent for years before clinical symptoms manifest (green line). Effects of interventions on green curve are indicated by blue curves on right, whereas diagnosis, prodromal symptoms, and at-risk assessment period tied to pathophysiology suggest that imaging biomarkers may be changing years before clinical symptoms. (Adapted with permission of (47).)
- FIGURE 2.
(A) Number of papers in neurodegenerative disease published between 2010 and 2021 for which PET imaging was performed. These were largely amyloid and, later, tau studies. (B) Data showing high percentage of amyloid PET studies with tau PET coming in last 5 y. Source: PubMed. (C and D) Percentage breakdown of PET radiopharmaceuticals for amyloid and tau in AD for studies with status “completed” (C) or “recruiting” (D), demonstrating more recent focus on tau in research activity. Source: clinicaltrials.gov.
- FIGURE 3.
Percentage of normal scan results in early PD trials for patients with clinical diagnosis of PD demonstrate that at earlier time points after symptom presentation, percentage of dopamine transporter SPECT scans known as SWEDD increases. Diagnostic certainty improves with longer duration of illness. (Adapted with permission of (48).)
- FIGURE 4.
Correlation between PET amyloid SUVr and cerebrospinal fluid measures of Aβ(1–42) in BioFINDER study and Alzheimer Disease Neuroimaging Initiative (ADNI). Triangles indicate positive scans on visual read, whereas circles are negative on visual read. There is inverse correlation between PET SUVr and cerebrospinal fluid Aβ in both studies. (Reprinted with permission of (38).)
Tables
Disease Key clinical features Pathology AD Progressive memory loss β-amyloid, tau (3R,4R) PD Tremor, rigidity, bradykinesia, gait disturbance α-synuclein Progressive supranuclear palsy Motor disturbance, gaze palsy Tau (4R) Multiple-system atrophy Autonomic dysregulation, motor disturbance α-synuclein Dementia with Lewy bodies Memory loss, motor disturbance, hallucinations α-synuclein Chronic traumatic encephalopathy Variable cognitive, behavioral, mood, and motor changes Tau (3R,4R) Corticobasal degeneration Akinesia, rigidity, dystonia, disequilibrium Astroglial plaques and tau (4R) Huntington disease Affective lability, choreiform movements, memory loss Mutated huntingtin protein Amyotrophic lateral sclerosis Progressive loss of voluntary muscle control TDP-43 proteinopathy (SOD1, FUS variants) Down syndrome Intellectual impairment, subsequent memory loss β-amyloid Role Study phase Example Showing target engagement 0 D1 receptor agonists 18F-MNI-800 and 18F-MNI-968 Aiding dosing determinations 1 Displacement (44) Enriching at-risk cohorts 2, 3 PARS study (17) Describing pathologic phenotype 2, 3 18F-AV-1451 (Avid Radiopharmaceuticals) (45) Serving as gatekeeper for trial eligibility 2, 3 Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease Trial (32) Assessing natural progression of disease 3 Alzheimer Disease Neuroimaging Initiative, Parkinson Disease Progression Marker Initiative (46) Evaluating efficacy of therapeutic intervention 3 Aducanumab (Biogen) Disease Amyloid Tau α-synuclein DAT AD Increased Increased Normal uptake Normal uptake Idiopathic PD Normal uptake Normal uptake Increased Decreased Dementia with Lewy bodies Normal uptake or increased Normal uptake Increased Decreased Multiple-system atrophy Normal uptake Normal uptake or increased Increased Decreased Older healthy volunteer Normal uptake or increased Normal uptake Normal uptake Normal uptake Progressive supranuclear palsy Normal uptake Increased Normal uptake Decreased Essential tremor Normal uptake Normal uptake Normal uptake Normal uptake Drug-induced PD Normal uptake Normal uptake Normal uptake Normal uptake Stage Activities Benchmarks Discovery Identification of candidate structures; in vitro testing for best compounds; optimization of radiolabeling Good yield, high specific activity, stability Assessment Affinity Postmortem human brain homogenates or sections, Ki < 1 nM Selectivity >200-fold selectivity Lipophilicity Log D7.4 = 2 to 3.5 Stability 4 half-lives Blood–brain barrier P-glycoprotein substrate (MDR1-MDCK) < 20 Metabolite identification Ex vivo analysis (characterize all major metabolites with radiolabel) Validation Correlation and safety High signal-to-noise ratio; correlation with histopathology; correlation with clinical dosimetry Quantitative accuracy Full kinetic modeling, including arterial input function corrected for metabolites; streamlining of protocol for clinical use; testing–retesting of all outcome measures Application Logistic feasibility Production/distribution network; imaging site technical standardization Disease Tau isoform Primary pathology Brain localization Regions with highest PET uptake AD 3R,4R Paired helical filaments Cortical Temporal, postcingulate Progressive supranuclear palsy 4R Straight filaments Subcortical Globus pallidus, putamen, subthalamic nucleus Corticobasal degeneration 4R Straight filaments Subcortical Globus pallidus, putamen Chronic traumatic encephalopathy 3R,4R Paired helical filaments Cortical Frontal, temporal, diencephalon Down syndrome 3R,4R Paired helical filaments Cortical Temporal, postcingulate
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- Article
- Abstract
- THE CHALLENGE OF DEVELOPING DRUGS FOR NEURODEGENERATIVE DISORDERS
- DEVELOPING IMAGING BIOMARKERS
- ISSUES AND CONTROVERSIES
- QUANTITATIVE PET OUTCOME MEASURES
- PET VISUAL READS
- CORRELATION WITH CLINICAL MEASURES
- COMPLEMENTARITY AND INTEGRATION OF BIOMARKERS IN CLINICAL TRIALS
- FUTURE OUTLOOK AND RELEVANCE TO CLINICAL PRACTICE
- DISCLOSURE
- ACKNOWLEDGMENT
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