Table 5.
Summary of neuroimaging correlates of progressive AOS. Note: The referenced techniques include: magnetic resonance imaging (MRI, to identify atrophy); diffusion tensor imaging (DTI, to estimate MRI-imaged white matter connectivity patterns); functional magnetic resonance imaging (fMRI, to measure brain activity through changes in blood flow); [18F]fluorodeoxyglucose positron emission tomography (FDG-PET, an index of metabolic brain activity); molecular PET imaging using ligands such as C11-Pittsburgh Compound B (PiB) to detect abnormal accumulations of beta-amyloid (Aβ, related to Alzheimer’s disease) or flortaucipir ([18F]AV-1451; related to tau pathology); electroencephalography (EEG; related to overall brain health); and dopamine transporter scans (DaT; related to parkinsonism).
| Reference | Imaging Modality | Key findings |
|---|---|---|
| Description and Differential Diagnosis | ||
| (Botha et al., 2015; Botha, Utianski, et al., 2018; Josephs et al., 2010; Josephs et al., 2013; Josephs et al., 2012; Josephs, Petersen, et al., 2006; Laganaro et al., 2012) | • MRI • DTI • PiB-PET • FDG-PET |
• In PPAOS, grey and white matter involvement in cortical and subcortical regions linked to speech planning/programming, production, and monitoring • Structural and metabolic measures suggest superior lateral premotor area and left SMA are primary areas of involvement • White matter loss in inferior premotor cortex and body of corpus callosum • Basal ganglia sometimes affected |
| Botha et al. (2018) | • Task-free MRI | • In PPAOS, reduced connectivity between right SMA and rest of speech-language network; correlated with AOS articulatory severity • Abnormalities in speech-language, face sensorimotor, and left working memory and salience networks |
| Utianski, Duffy, Clark, Strand, Botha, et al., (2018) | • MRI • FDG-PET • DTI |
• Both Prosodic and Phonetic PPAOS subtypes had abnormalities in premotor regions, particularly in SMA • Phonetic subtype showed bilateral involvement of SMA, precentral gyrus, and cerebellar crus, and hypometabolism in insula • Prosodic subtype had more focal involvement of SMA and right superior cerebellar peduncle |
| (Josephs et al., 2010; Josephs et al., 2013; Josephs, Petersen, et al., 2006; Ogar et al., 2007; Santos-Santos et al., 2016; Tetzloff, Duffy, Clark, et al., 2018) | • MRI • DTI • FDG-PET |
• Areas of involvement in PPAOS typically more focal than in AOS+PAA • In AOS+PAA, abnormalities involve SMA, posterior inferior, middle and superior frontal gyrus, temporal precentral cortex sand parietal lobes • In PAA, abnormalities observed in prefrontal and anterior temporal lobes, particularly on left |
| (Josephs et al., 2013; Josephs et al., 2012; Tetzloff, Duffy, Clark, et al., 2018; Whitwell et al., 2013) | • MRI | • Midbrain atrophy can be evident in PPAOS and AOS+PAA, in contrast to PAA |
| (Botha & Josephs, 2019; Josephs et al., 2010; Josephs, Duffy, Strand, Machulda, Senjem, Gunter, et al., 2014; Josephs et al., 2012) | • MRI • FDG-PET |
• Structural imaging evidence revealing localization pattern of PPAOS and AOS+PAA derives from group analyses that are not necessarily readily apparent at individual level • FDG-PET may be more sensitive to localization and disease progression on individual patient basis than MRI, but can still be quite heterogeneous across individual patients |
| (Josephs et al., 2010; Josephs, Duffy, Strand, Machulda, Senjem, Lowe, et al., 2014; Leyton et al., 2014; Whitwell et al., 2016) | • PiB-PET | • PiB-PET abnormal in 12-20% of PPAOS and AOS+PAA patients |
| Josephs et al. (2016) | • In vivo tau (flortaucipir-PET) • Ex vivo tau at autopsy |
• Abnormal tau uptake correlated with quantitatively measured 4R-tau at autopsy in one patient presenting with PPAOS |
| Utianski, Whitwell, Schwarz, Senjem, et al. (2018) | • In vivo tau (flortaucipir-PET) | • Abnormal tau uptake noted in precentral gyrus, pallidum, and mid and superior frontal gyri in patients with PPAOS |
| Utianski, Whitwell, Schwarz, Duffy, et al. (2018) | In vivo tau (flortaucipir-PET) | • Patients with AOS+PAA had abnormal tau uptake in anatomically relevant areas (SMA bilaterally, frontal lobes, precuneus, and precentral gyrus) • Patients with PAA had abnormal tau uptake in left frontal and temporal lobes and relatively less abnormal uptake in left precentral gyrus |
| Utianski et al. (2019) | • EEG | • Patients with PPAOS had normal EEGs • Theta slowing evident in most patients with AOS+PAA |
| Seckin et al. (2020) | • DaT | • Abnormal DaTscan observed early in disease course in about 30% of patients with AOS+PAA; abnormalities observed in the putamen |
| Disease Progression | ||
| Josephs et al. (2014) | • MRI • FDG-PET • DTI |
• Increased rates of brain atrophy and hypometabolism in PPAOS compared to age-matched controls over average of 2.4 years • Areas of change include prefrontal, premotor, and motor cortex, and basal ganglia and midbrain, with spread into white matter tracts in splenium of corpus callosum and motor cortex |
| Santos-Santos et al. (2016) | • MRI | • Significant longitudinal progression of atrophy in patients with AOS+PAA |
| Whitwell et al. (2019) | • MRI | • Rates of midbrain atrophy greater in patients who develop parkinsonism and PSP features compared to those who do not |
| Whitwell, Duffy, et al. (2017) | • MRI | • Deterioration in Broca area, thalamus, and basal ganglia (putamen) associated with development of agrammatic aphasia over two-year period in patients initially presenting with PPAOS |
| Utianski et al. (2020) | • In vivo tau (flortaucipir-PET) | • Longitudinal changes in tau uptake in PPAOS after average of one year • Patterns of change similar to those seen in PSP |