Botha, Hugo

Abstract Agrammatic aphasia affects grammatical language production and can result from a neurodegenerative disease. Although it typically presents with concomitant apraxia of speech, this is not always the case. Little is known about the clinical course and imaging features of patients that present with agrammatism in the absence of apraxia of speech, which we will refer to as progressive agrammatic aphasia. We aimed to make a detailed description of the longitudinal clinical, linguistic, and neuroimaging features of a cohort of 11 patients with progressive agrammatic aphasia to provide a complete picture of this syndrome. All patients underwent detailed speech and language, neurological and neuropsychological assessments, 3 T structural and diffusion tensor imaging MRI, 18F-fluorodeoxyglucose and Pittsburgh compound B PET. The 11 patients were matched by age and gender to 22 patients who had mixed apraxia of speech and agrammatism. The progressive agrammatic aphasia patients performed abnormally on tests of language, general cognition, executive function, and functional ability at baseline and declined in these measures over time. Only two patients eventually developed apraxia of speech, while parkinsonism was absent-to-mild throughout all visits for all patients. When compared to the patients with mixed apraxia of speech and agrammatism, the patients with progressive agrammatic aphasia performed better on tests of motor speech and parkinsonism but more poorly, and declined faster over time, on tests of general aphasia severity, agrammatism, and naming. The patients with progressive agrammatic aphasia also showed different neuroimaging abnormalities, with greater atrophy, hypometabolism and white matter tract degeneration in the prefrontal and anterior temporal lobes compared to patients with mixed apraxia of speech and agrammatism. These differences were more pronounced as the disease progressed. These results demonstrate that progressive agrammatic aphasia has a different clinical disease course and different underlying neuroanatomical abnormalities than patients with the more common syndrome of mixed agrammatism and apraxia of speech. This supports the distinction of progressive agrammatic aphasia and has implications for the classification of patients with agrammatic aphasia.

Abstract Background In 2017, the International Parkinson and Movement Disorder Society put forward new clinical criteria for the diagnosis of PSP, recognizing diverse PSP phenotypes. In this study, we compared the sensitivity and specificity of the new criteria with the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria at different times. Methods Patients with clinical parkinsonism, clinical and/or neuropathological diagnosis of PSP, were identified from the Society for Progressive Supranuclear Palsy brain bank. All patients had neuropathologic diagnoses and detailed clinical examination performed by a neurologist at 1 of the 3 Mayo Clinic sites, in Florida, Arizona, and Minnesota. Clinical symptoms and signs were abstracted retrospectively in a blinded fashion and used to determine whether patients met either diagnostic criterion. Patients were divided into early and late disease stage groups using a 3‐year cutoff. Results A total of 129 patients were included, of whom 66 had PSP pathology (51%). The remainder had other neurodegenerative diseases. The overall sensitivity of the International Parkinson and Movement Disorder Society criteria was 87.9%, compared with 45.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy criteria, whereas the specificity of the International Parkinson and Movement Disorder Society probable PSP criteria was 85.7%, compared with 90.5% for the National Institutes of Neurological Disease and Society for Progressive Supranuclear Palsy. Individual patients were noted to have features of multiple PSP phenotypes. Conclusion The International Parkinson and Movement Disorder Society criteria recognize several phenotypes of progressive supranuclear palsy and hence have higher sensitivity than the previous criteria. © 2019 International Parkinson and Movement Disorder Society

This study examined the rate of producing alternating motion rates, sequential motion rates (SMRs), and repeated words in 27 individuals with the semantic variant of Primary Progressive Aphasia (svPPA). Only the rate of producing SMRs was significantly elevated in svPPA compared to controls. This may be associated with concomitant neuropsychiatric symptoms in svPPA, as correlation analysis showed a relationship between increased SMR rate and the Neuropsychiatric Inventory Questionnaire, which documented anxiety and disinhibition. Future studies will assess these findings in a larger cohort and work to better understand if this phenomenon is a manifestation of behavioral and/or motor changes.

AbstractBackgroundElevated uptake of the [18F]AV‐1451 tau‐PET ligand has been observed cross‐sectionally in subjects with progressive supranuclear palsy (PSP). However, it is unknown how the ligand performs longitudinally in PSP. We aimed to determine how regional measures of change on [18F]AV‐1451 PET perform as longitudinal biomarkers of PSP compared with the more established biomarker of rate of midbrain atrophy.MethodsSixteen subjects with PSP underwent 2 serial [18F]AV‐1451 tau‐PET scans and 3‐Tesla MRI over 12 months and were age‐ and sex‐matched to 39 healthy controls with longitudinal [18F]AV‐1451 PET. Median [18F]AV‐1451 uptake was calculated for each scan for regions of interest across the brain and divided by uptake in cerebellar crus to create standard uptake value ratios. Midbrain volume on MRI was also calculated for each scan. Sample sizes required to power placebo‐controlled treatment trials were calculated.ResultsRate of midbrain atrophy was significantly increased in PSP compared with controls. [18F]AV‐1451 regional change measures were significantly increased in PSP compared with controls in the pallidum, precentral cortex, dentate nucleus of the cerebellum, and midbrain. Change over time in the PSP Rating Scale correlated with change in midbrain volume but did not correlate with change in the [18F]AV‐1451 measures. Smallest sample‐size estimates were obtained with rate of midbrain atrophy, followed by the PSP Rating Scale, with both outperforming [18F]AV‐1451 measures.Conclusions[18F]AV‐1451 tau‐PET measures increase over time in subjects with PSP, but longitudinal [18F]AV‐1451 measures may not perform as well as rate of midbrain atrophy as biomarkers for PSP clinical trials. © 2018 International Parkinson and Movement Disorder Society

Background and purposeThe non‐fluent/agrammatic variant of primary progressive aphasia (agPPA) is a heterogeneous diagnosis wherein some individuals have apraxia of speech (AOS). When agPPA includes AOS, a tauopathy is the likely underlying pathology. Recently, [18F]AV‐1451 was developed for the in‐vivo assessment of tau. In this study, we compared patterns of tau tracer uptake in patients with agPPA with and without AOS.MethodsNine patients with agPPA (four without AOS) underwent tau positron emission tomography imaging with [18F]AV‐1451. Uptake of [18F]AV‐1451 was assessed as cortical to cerebellar crus ratio (standard uptake value ratio) in cortical regions of interest measured using the MCALT atlas and compared voxel‐wise in SPM12. Each patient was age‐ and sex‐matched to three controls.ResultsThe agPPA without AOS showed uptake in the left frontal and temporal lobes, whereas agPPA with AOS showed uptake in the bilateral supplementary motor areas, frontal lobes, precuneus and precentral gyrus relative to controls. The left precentral gyrus had uptake in agPPA with AOS relative to those without AOS.ConclusionsThis cross‐sectional study suggests that [18F]AV‐1451 uptake in the precentral gyrus is implicated in AOS in agPPA.

ObjectivesTo assess [18F]AV‐1451 tau‐PET (positron emission tomography) uptake patterns across the primary progressive aphasia (PPA) variants (logopenic, semantic, and agrammatic), examine regional uptake patterns of [18F]AV‐1451 independent of clinical diagnosis, and compare the diagnostic utility of [18F]AV‐1451, [18F]‐fluorodeoxygluclose (FDG)‐PET and MRI (magnetic resonance imaging) to differentiate the PPA variants.MethodsWe performed statistical parametric mapping of [18F]AV‐1451 across 40 PPA patients (logopenic‐PPA = 14, semantic‐PPA = 13, and agrammatic‐PPA = 13) compared to 80 cognitively normal, Pittsburgh compound B–negative controls, age and gender matched 2:1. Principal component analysis of regional [18F]AV‐1451 tau‐PET standard uptake value ratio was performed to understand underlying patterns of [18F]AV‐1451 uptake independent of clinical diagnosis. Penalized multinomial regression analyses were utilized to assess diagnostic utility.ResultsLogopenic‐PPA showed striking uptake throughout neocortex, particularly temporoparietal, compared to controls, semantic‐PPA, and agrammatic‐PPA. Semantic‐PPA and agrammatic‐PPA showed milder patterns of focal [18F]AV‐1451 uptake. Semantic‐PPA showed elevated uptake (left>right) in anteromedial temporal lobes, compared to controls and agrammatic‐PPA. Agrammatic‐PPA showed elevated uptake (left>right) throughout prefrontal white matter and in subcortical gray matter structures, compared to controls and semantic‐PPA. The principal component analysis of regional [18F]AV‐1451 indicated two primary dimensions, a severity dimension that distinguished logopenic‐PPA from agrammatic‐PPA and semantic‐PPA, and a frontal versus temporal contrast that distinguishes agrammatic‐PPA and semantic‐PPA cases. Diagnostic utility of [18F]AV‐1451was superior to MRI and at least equal to FDG‐PET.Interpretation[18F]AV‐1451binding characteristics differ across the PPA variants and were excellent at distinguishing between the variants. [18F]AV‐1451binding characteristics were as good or better than other brain imaging modalities utilized in clinical practice, suggesting that [18F]AV‐1451 may have clinical diagnostic utility in PPA. Ann Neurol 2018 Ann Neurol 2018;83:599–611