Longitudinal flortaucipir, metabolism and volume differ between phonetic and prosodic speech apraxia.

Progressive apraxia of speech (PAOS) is a neurodegenerative motor-speech disorder that most commonly arises from a four-repeat tauopathy. Recent studies have established that progressive apraxia of speech is not a homogenous disease but rather there are distinct subtypes: the phonetic subtype is characterized by distorted sound substitutions, the prosodic subtype by slow and segmented speech and the mixed subtype by a combination of both but lack of predominance of either. There is some evidence that cross-sectional patterns of neurodegeneration differ across subtypes, although it is unknown whether longitudinal patterns of neurodegeneration differ. We examined longitudinal patterns of atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose-PET and tau uptake on flortaucipir-PET in a large cohort of subjects with PAOS that had been followed for many years. Ninety-one subjects with PAOS (51 phonetic, 40 prosodic) were recruited by the Neurodegenerative Research Group. Of these, 54 (27 phonetic, 27 prosodic) returned for annual follow-up, with up to seven longitudinal visits (total visits analysed = 217). Volumes, metabolism and flortaucipir uptake were measured for subcortical and cortical regions, for all scans. Bayesian hierarchical models were used to model longitudinal change across imaging modalities with PAOS subtypes being compared at baseline, 4 years from baseline, and in terms of rates of change. The phonetic group showed smaller volumes and worse metabolism in Broca's area and the striatum at baseline and after 4 years, and faster rates of change in these regions, compared with the prosodic group. There was also evidence of faster spread of hypometabolism and flortaucipir uptake into the temporal and parietal lobes in the phonetic group. In contrast, the prosodic group showed smaller cerebellar dentate, midbrain, substantia nigra and thalamus volumes at baseline and after 4 years, as well as faster rates of atrophy, than the phonetic group. Greater hypometabolism and flortaucipir uptake were also observed in the cerebellar dentate and substantia nigra in the prosodic group. Mixed findings were observed in the supplementary motor area and precentral cortex, with no clear differences observed across phonetic and prosodic groups. These findings support different patterns of disease spread in PAOS subtypes, with corticostriatal patterns in the phonetic subtype and brainstem and thalamic patterns in the prosodic subtype, providing insight into the pathophysiology and heterogeneity of PAOS.

Multimodal cross-examination of progressive apraxia of speech by diffusion tensor imaging-based tractography and Tau-PET scans.

Progressive apraxia of speech (PAOS) is a 4R tauopathy characterized by difficulties with motor speech planning. Neurodegeneration in PAOS targets the premotor cortex, particularly the supplementary motor area (SMA), with degeneration of white matter (WM) tracts connecting premotor and motor cortices and Broca's area observed on diffusion tensor imaging (DTI). We aimed to assess flortaucipir uptake across speech-language-related WM tracts identified using DTI tractography in PAOS. Twenty-two patients with PAOS and 26 matched healthy controls were recruited by the Neurodegenerative Research Group (NRG) and underwent MRI and flortaucipir-PET. The patient population included patients with primary progressive apraxia of speech (PPAOS) and non-fluent variant/agrammatic primary progressive aphasia (agPPA). Flortaucipir PET scans and DTI were coregistered using rigid registration with a mutual information cost function in subject space. Alignments between DTI and flortaucipir PET were inspected in all cases. Whole-brain tractography was calculated using deterministic algorithms by a tractography reconstruction tool (DSI-studio) and specific tracts were identified using an automatic fiber tracking atlas-based method. Fractional anisotropy (FA) and flortaucipir standardized uptake value ratios (SUVRs) were averaged across the frontal aslant tract, arcuate fasciculi, inferior frontal-occipital fasciculus, inferior and middle longitudinal fasciculi, as well as the SMA commissural fibers. Reduced FA (p < .0001) and elevated flortaucipir SUVR (p = .0012) were observed in PAOS cases compared to controls across all combined WM tracts. For flortaucipir SUVR, the greatest differentiation of PAOS from controls was achieved with the SMA commissural fibers (area under the receiver operator characteristic curve [AUROC] = 0.83), followed by the left arcuate fasciculus (AUROC = 0.75) and left frontal aslant tract (AUROC = 0.71). Our findings demonstrate that flortaucipir uptake is increased across WM tracts related to speech/language difficulties in PAOS.

Clinicoradiological and neuropathological evaluation of primary progressive aphasia.

BACKGROUND: Primary progressive aphasia (PPA) defines a group of neurodegenerative disorders characterised by language decline. Three PPA variants correlate with distinct underlying pathologies: semantic variant PPA (svPPA) with transactive response DNA-binding protein of 43 kD (TDP-43) proteinopathy, agrammatic variant PPA (agPPA) with tau deposition and logopenic variant PPA (lvPPA) with Alzheimer's disease (AD). Our objectives were to differentiate PPA variants using clinical and neuroimaging features, assess progression and evaluate structural MRI and a novel 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) image decomposition machine learning algorithm for neuropathology prediction. METHODS: We analysed 82 autopsied patients diagnosed with PPA from 1998 to 2022. Clinical histories, language characteristics, neuropsychological results and brain imaging were reviewed. A machine learning framework using a k-nearest neighbours classifier assessed FDG-PET scans from 45 patients compared with a large reference database. RESULTS: PPA variant distribution: 35 lvPPA (80% AD), 28 agPPA (89% tauopathy) and 18 svPPA (72% frontotemporal lobar degeneration-TAR DNA-binding protein (FTLD-TDP)). Apraxia of speech was associated with 4R-tauopathy in agPPA, while pure agrammatic PPA without apraxia was linked to 3R-tauopathy. Longitudinal data revealed language dysfunction remained the predominant deficit for patients with lvPPA, agPPA evolved to corticobasal or progressive supranuclear palsy syndrome (64%) and svPPA progressed to behavioural variant frontotemporal dementia (44%). agPPA-4R-tauopathy exhibited limited pre-supplementary motor area atrophy, lvPPA-AD displayed temporal atrophy extending to the superior temporal sulcus and svPPA-FTLD-TDP had severe temporal pole atrophy. The FDG-PET-based machine learning algorithm accurately predicted clinical diagnoses and underlying pathologies. CONCLUSIONS: Distinguishing 3R-taupathy and 4R-tauopathy in agPPA may rely on apraxia of speech presence. Additional linguistic and clinical features can aid neuropathology prediction. Our data-driven brain metabolism decomposition approach effectively predicts underlying neuropathology.

Clinical and neuroimaging characteristics of primary lateral sclerosis with overlapping features of progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Primary lateral sclerosis (PLS) is a neurodegenerative disorder that primarily affects the central motor system. In rare cases, clinical features of PLS may overlap with those of progressive supranuclear palsy (PSP). We investigate neuroimaging features that can help distinguish PLS with overlapping features of PSP (PLS-PSP) from PSP. METHODS: Six patients with PLS-PSP were enrolled between 2019 and 2023. We compared their clinical and neuroimaging characteristics with 18 PSP-Richardson syndrome (PSP-RS) patients and 20 healthy controls. Magnetic resonance imaging, 18F-flortaucipir positron emission tomography (PET), quantitative susceptibility mapping, and diffusion tensor imaging tractography (DTI) were performed to evaluate eight brain regions of interest. Area under the receiver operating characteristic curve (AUROC) was calculated. RESULTS: Five of the six PLS-PSP patients (83.3%) were male. Median age at symptom onset was 61.5 (52.5-63) years, and all had mixed features of PLS and PSP. Volumes of the pallidum, caudate, midbrain, and cerebellar dentate were smaller in PSP-RS than PLS-PSP, providing good discrimination (AUROC = 0.75 for all). The susceptibilities in pallidum, midbrain, and cerebellar dentate were greater in PSP-RS compared to PLS-PSP, providing excellent discrimination (AUROC ≥ 0.90 for all). On DTI, fractional anisotropy (FA) in the posterior limb of the internal capsule from the corticospinal tract was lower in PLS-PSP compared to PSP-RS (AUROC = 0.86), but FA in the superior cerebellar peduncle was lower in PSP-RS (AUROC = 0.95). Pallidum flortaucipir PET uptake was greater in PSP-RS compared to PLS-PSP (AUROC = 0.74). CONCLUSIONS: Regional brain volume, tractography, and magnetic susceptibility, but not tau-PET, are useful in distinguishing PLS-PSP from PSP.

Behavioral Treatment for Speech and Language in Primary Progressive Aphasia and Primary Progressive Apraxia of Speech: A Systematic Review.

Primary progressive aphasia (PPA) and primary progressive apraxia of speech (PPAOS) are neurodegenerative syndromes characterized by progressive decline in language or speech. There is a growing number of studies investigating speech-language interventions for PPA/PPAOS. An updated systematic evaluation of the treatment evidence is warranted to inform best clinical practice and guide future treatment research. We systematically reviewed the evidence for behavioral treatment for speech and language in this population. Reviewed articles were published in peer-reviewed journals through 31 May 2021. We evaluated level of evidence, reporting quality, and risk of bias using a modified version of the American Speech-Language Hearing Association (ASHA) Levels of Evidence, an appraisal point system, additional reporting quality and internal/external validity items, and, as appropriate, the Single Case Experimental Design Scale or the Physiotherapy Evidence Database - PsycBITE Rating Scale for Randomized and Non-Randomized Controlled Trials. Results were synthesized using quantitative summaries and narrative review. A total of 103 studies reported treatment outcomes for 626 individuals with PPA; no studies used the diagnostic label PPAOS. Most studies evaluated interventions for word retrieval. The highest-quality evidence was provided by 45 experimental and quasi-experimental studies (16 controlled group studies, 29 single-subject designs). All (k = 45/45) reported improvement on a primary outcome measure; most reported generalization (k = 34/43), maintenance (k = 34/39), or social validity (k = 17/19) of treatment for at least one participant. The available evidence supports speech-language intervention for persons with PPA; however, treatment for PPAOS awaits systematic investigation. Implications and limitations of the evidence and the review are discussed.

Autopsy Validation of Progressive Supranuclear Palsy-Predominant Speech/Language Disorder Criteria.

BACKGROUND: Progressive supranuclear palsy (PSP) may present as a speech/language disorder (PSP-SL). OBJECTIVE: We assessed pathological correlates of patients with PSP-SL who retained the suggestive of PSP-SL (s.o. PSP-SL) diagnosis versus those who progressed to possible/probable (poss./prob.) PSP. METHODS: Thirty-four prospectively recruited patient with s.o. PSP-SL completed comprehensive speech/language and neurological assessments longitudinally, died, and underwent autopsy. RESULTS: Twelve patients (35%) evolved to poss./prob PSP, while 22 (65%) remained as s.o. PSP-SL. Pathological diagnoses differed across the groups (P = 0.025). Patients with s.o. PSP-SL had four different neuropathologies (corticobasal degeneration [59%], PSP [13%], Pick's disease [14%], and frontotemporal lobar degeneration with TDP-43 [14%]), while all patients with poss./prob. PSP had a 4R-tauopathy (PSP [67%] and corticobasal degeneration [33%]). Development of poss./prob. PSP increased the chance of having PSP pathology by 2.38 times. CONCLUSIONS: PSP-SL is associated with heterogenous pathologies. Evolution of PSP-SL into poss./prob. PSP is more predictive of underlying PSP pathology than s.o. PSP-SL. © 2021 International Parkinson and Movement Disorder Society.

Brainstem Biomarkers of Clinical Variant and Pathology in Progressive Supranuclear Palsy.

BACKGROUND: Magnetic resonance brainstem measurements are useful structural biomarkers in the Richardson's syndrome variant of progressive supranuclear palsy (PSP). However, it is unclear how these biomarkers differ across the phenotypic spectrum of PSP and how they relate to underlying pathology. OBJECTIVE: The aim of this study was to compare brainstem imaging measures across clinical variants of PSP and determine sensitivity and specificity based on pathologically diagnosed cases. METHODS: A total of 153 patients with PSP who represented eight clinical variants were recruited at Mayo Clinic (Rochester, MN, USA) and underwent structural magnetic resonance imaging (MRI). Midbrain and pons area and superior and middle cerebellar peduncle width measurements were performed, and midbrain/pons ratio and Magnetic Resonance Parkinsonism Index (MRPI) were calculated. Among the 43 patients who later died, PSP pathology was confirmed in 29, whereas 14 had other pathology. RESULTS: Brainstem measurements varied across PSP clinical variants and were most abnormal in PSP-Richardson's syndrome and frontal variants, followed by PSP-corticobasal, PSP-speech/language, and PSP-parkinsonism variants. All these variants showed abnormalities compared with controls. The PSP-gait freezing variant and patients with prominent corticospinal tract signs showed normal brainstem measures. Among cases with confirmed PSP pathology, the midbrain area, midbrain/pons ratio, and MRPI were all more abnormal compared to those with other pathologies, with best differentiation obtained with the MRPI (sensitivity = 83%; specificity = 85%). CONCLUSIONS: MRI brainstem measures show utility as diagnostic biomarkers across PSP clinical variants and have the potential to be useful in predicting underlying pathology. © 2021 International Parkinson and Movement Disorder Society.

Cross-Sectional and Longitudinal Assessment of Behavior in Primary Progressive Apraxia of Speech and Agrammatic Aphasia.

INTRODUCTION: Progressive agrammatic aphasia (PAA) can be associated with abnormal behaviors; however, it is unknown whether behaviors occur and/or are different in patients with primary progressive apraxia of speech (PPAOS). We aimed to compare baseline and longitudinal behavioral symptomatology between PPAOS, patients with PAA, and patients with both apraxia of speech and PAA (AOS-PAA). METHODS: We recruited 89 patients for this study, 40 with PPAOS, 11 with PAA, and 38 with AOS-PAA. Behavioral disturbances were evaluated using the frontal behavior inventory (FBI) which was also split into negative behaviors and disinhibition, and the 20-item behavioral assessment scale (20-BAS). Data analysis was performed using linear regression and linear mixed models. RESULTS: Of the 89 patients in the study, 54% were women and the mean age at onset was 68 years. All patients, regardless of diagnosis, endorsed at least one symptom on the FBI at baseline, most frequently verbal apraxia (100%), logopenia (95.6%), irritability (55.9%), and apathy (42.6%). On the 20-BAS, 47.6% of the patients endorsed at least one symptom, most commonly "crying more easily" (19.5%) and personality change (18.3%). PPAOS was the least behaviorally affected group, with differences between PPAOS and AOS-PAA mainly driven by negative behaviors as opposed to disinhibition for PPAOS and PAA. The behavioral metrics showed average sensitivity and specificity to distinguish between groups. Behavioral disturbances worsened over time although rate of behavioral change across groups was similar. CONCLUSION: Behavioral disturbances are more common and severe in patients with agrammatic aphasia with or without AOS compared to patients with isolated apraxia of speech.

Neuropsychological Profiles of Patients with Progressive Apraxia of Speech and Aphasia.

OBJECTIVE: To characterize and compare the neuropsychological profiles of patients with primary progressive apraxia of speech (PPAOS) and apraxia of speech with progressive agrammatic aphasia (AOS-PAA). METHOD: Thirty-nine patients with PPAOS and 49 patients with AOS-PAA underwent formal neurological, speech, language, and neuropsychological evaluations. Cognitive domains assessed included immediate and delayed episodic memory (Wechsler Memory Scale-Third edition; Logical Memory; Visual Reproduction; Rey Auditory Verbal Learning Test), processing speed (Trail Making Test A), executive functioning (Trail Making Test B; Delis-Kaplan Executive Functioning Scale - Sorting), and visuospatial ability (Rey-Osterrieth Complex Figure copy). RESULTS: The PPAOS patients were cognitively average or higher in the domains of immediate and delayed episodic memory, processing speed, executive functioning, and visuospatial ability. Patients with AOS-PAA performed more poorly on tests of immediate and delayed episodic memory and executive functioning compared to those with PPAOS. For every 1 unit increase in aphasia severity (e.g. mild to moderate), performance declined by 1/3 to 1/2 a standard deviation depending on cognitive domain. The degree of decline was stronger within the more verbally mediated domains, but was also notable in less verbally mediated domains. CONCLUSION: The study provides neuropsychological evidence further supporting the distinction of PPAOS from primary progressive aphasia and should be used to inform future diagnostic criteria. More immediately, it informs prognostication and treatment planning.

Sensitivity-Specificity of Tau and Amyloid ß Positron Emission Tomography in Frontotemporal Lobar Degeneration.

OBJECTIVE: To examine associations between tau and amyloid ß (Aß) molecular positron emission tomography (PET) and both Alzheimer-related pathology and 4-repeat tau pathology in autopsy-confirmed frontotemporal lobar degeneration (FTLD). METHODS: Twenty-four patients had [18 F]-flortaucipir-PET and died with FTLD (progressive supranuclear palsy [PSP], n = 10; corticobasal degeneration [CBD], n = 10; FTLD-TDP, n = 3; and Pick disease, n = 1). All but 1 had Pittsburgh compound B (PiB)-PET. Braak staging, Aß plaque and neurofibrillary tangle counts, and semiquantitative tau lesion scores were performed. Flortaucipir standard uptake value ratios (SUVRs) were calculated in a temporal meta region of interest (meta-ROI), entorhinal cortex and cortical/subcortical regions selected to match the tau lesion analysis. Global PiB SUVR was calculated. Autoradiography was performed in 1 PSP patient, with digital pathology used to quantify tau burden. RESULTS: Nine cases (37.5%) had Aß plaques. Global PiB SUVR correlated with Aß plaque count, with 100% specificity and 50% sensitivity for diffuse plaques. Twenty-one (87.5%) had Braak stages I to IV. Flortaucipir correlated with neurofibrillary tangle counts in entorhinal cortex, but entorhinal and meta-ROI SUVRs were not elevated in Braak IV or primary age-related tauopathy. Flortaucipir uptake patterns differed across FTLD pathologies and could separate PSP and CBD. Flortaucipir correlated with tau lesion score in red nucleus and midbrain tegmentum across patients, but not in cortical or basal ganglia regions. Autoradiography demonstrated minimal uptake of flortaucipir, although flortaucipir correlated with quantitative tau burden across regions. INTERPRETATION: Molecular PET shows expected correlations with Alzheimer-related pathology but lacks sensitivity to detect mild Alzheimer pathology in FTLD. Regional flortaucipir uptake was able to separate CBD and PSP. ANN NEUROL 2020;88:1009-1022.

Gray and White Matter Correlates of Dysphagia in Progressive Supranuclear Palsy.

BACKGROUND: Dysphagia is a common symptom of progressive supranuclear palsy often leading to aspiration pneumonia and death. OBJECTIVE: The aim of this study was to examine how impairments of the oral and pharyngeal phases of the swallow and airway incursion during liquid swallows relate to gray and white matter integrity. METHODS: Thirty-eight participants with progressive supranuclear palsy underwent videofluorographic swallowing assessment and structural and diffusion tensor head magnetic resonance imaging. Penalized linear regression models assessed relationships between swallowing metrics and regional gray matter volumes and white matter fractional anisotropy and mean diffusivity. RESULTS: Oral phase impairments were associated with reduced superior parietal volumes and abnormal diffusivity in parietal and sensorimotor white matter, posterior limb of the internal capsule, and superior longitudinal fasciculus. Pharyngeal phase impairments were associated with disruption to medial frontal lobe, corticospinal tract, and cerebral peduncle. No regions were predictive of airway incursion. CONCLUSIONS: Differential patterns of neuroanatomical impairment corresponded to oral and pharyngeal phase swallowing impairments. © 2021 International Parkinson and Movement Disorder Society.

Neurobehavioral Characteristics of FDG-PET Defined Right-Dominant Semantic Dementia: A Longitudinal Study.

INTRODUCTION: Semantic dementia (SD) is characterized by fluent speech, anomia, and loss of word and object knowledge with varying degrees of right and left anterior-medial temporal lobe hypometabolism on [18F] fluorodeoxyglucose (FDG)-PET. We assessed neurobehavioral features in SD patients across 3 FDG-PET-defined metabolic patterns and investigated progression over time. METHODS: Thirty-four patients with SD who completed FDG-PET were classified into a left- and right-dominant group based on the degree of hypometabolism in each temporal lobe. The left-dominant group was further subdivided depending on whether hypometabolism in the right temporal lobe was more or less than 2 standard deviations from controls (left+ group). Neurobehavioral characteristics determined using the Neuropsychiatric Inventory Questionnaire (NPI-Q) were compared across groups. Progression of NPI-Q scores and FDG-PET hypometabolism was assessed in 14 patients with longitudinal follow-up. RESULTS: The right-dominant group performed worse on the NPI-Q and had a greater frequency of abnormal behaviors and more severe disinhibition compared to the left-dominant group. Performance on the NPI-Q and severity of disinhibition correlated with right medial and lateral, but not left, temporal lobe hypometabolism. Severity of abnormal behaviors worsened over time in most left-dominant and left+ patients but appeared to improve in the 2 right-dominant patients with longitudinal follow-up. All groups showed progressive worsening of metabolism in both temporal lobes over time, with hypometabolism spreading from anteromedial to posterior temporal regions. However, the degree of temporal lobe asymmetry remained relatively constant over time. CONCLUSION: In SD, neurobehavioral features, especially disinhibition, are associated with right medial and lateral temporal lobe hypometabolism and commonly develop over time even in patients that present with left-dominant patterns of hypometabolism.

Dynamic Aphasia as a Variant of Frontotemporal Dementia.

We describe two individuals with progressive verbal difficulty who exhibited impairment of propositional language, with relatively well-preserved auditory comprehension, naming, and repetition-a profile that is consistent with dynamic aphasia. By providing a brief review of pertinent literature and the results from our neurologic, speech and language, neuropsychological, and neuroimaging testing, this report sheds light on the infrequently reported dynamic aphasia in the context of frontotemporal dementia. Our patients' insights into their verbal difficulty tend to support the notion that dynamic aphasia results from interference at the stage where thoughts are converted into verbal messages-that is, the thought-verbal interface.

Progressive agrammatic aphasia without apraxia of speech as a distinct syndrome.

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.

Dysphagia in Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is the most common Parkinson-Plus syndrome and is associated with early onset of dysphagia relative to Parkinson Disease. The current study contributes to the growing understanding of swallowing dysfunction in PSP by describing oropharyngeal swallowing characteristics in a large prospective cohort of participants with PSP employing a nationally standardized videofluoroscopy protocol and a disease severity scale developed expressly for PSP. Participants were 51 adults diagnosed with PSP. Each participant underwent a clinical interview and standardized videofluorographic assessment. Swallowing function was characterized with the Modified Barium Swallow Impairment Scale (MBSImP) and Penetration-Aspiration Scale (PAS). Variables of interest were participant-reported difficulties with liquids and/or solids; overall impression score for each of the 17 individual MBSImP components, as well as Oral Total Sum and Pharyngeal Total Sum; and PAS. Data were described with median interquartile range, counts, and proportions. Spearman's rank correlations were calculated between MBSImP scores and participant-reported indices, FOIS, and PSP Rating Scale. Approximately two-thirds of participants reported difficulties with liquids, solids, or both, although fewer than 15% reported modifying consistencies. Videofluorographic findings included predominant oral phase impairments, including back and forth rocking motion of the tongue, delayed initiation of the pharyngeal swallow, and oral residue. Pharyngeal phase impairments were relatively infrequent and comparatively mild, with the exception of reduced tongue base retraction contributing to pharyngeal residue, and mildly disrupted laryngeal vestibule closure. Disease severity correlated significantly with oral (r = .0.42, p = .0.002) and pharyngeal (r = 0.41, p = .0.003) total sum scores as well as with the oral phase components of oral transport (r = .0.33, p = .0.02) and initiation of the pharyngeal swallow (r = .0.38, p = .0.007), and PAS for thin liquids (r = .0.44, p = .0.001). The PSP Rating Scale was not more strongly correlated with swallowing impairment than has been reported for other disease severity rating scales. Dysphagia is a common complaint of patients with PSP. The current findings corroborate and expand upon those reported in the literature, detailing relatively more frequent and more severe oral phase impairments and relatively spared hyolaryngeal excursion. Further research is needed to characterize the progression of dysphagia in PSP and to determine whether dysphagia varies in character or in rate of progression across variants of PSP.

[18 F]AV-1451 tau-PET and primary progressive aphasia.

OBJECTIVES: To assess [18 F]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 [18 F]AV-1451 independent of clinical diagnosis, and compare the diagnostic utility of [18 F]AV-1451, [18 F]-fluorodeoxygluclose (FDG)-PET and MRI (magnetic resonance imaging) to differentiate the PPA variants. METHODS: We performed statistical parametric mapping of [18 F]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 [18 F]AV-1451 tau-PET standard uptake value ratio was performed to understand underlying patterns of [18 F]AV-1451 uptake independent of clinical diagnosis. Penalized multinomial regression analyses were utilized to assess diagnostic utility. RESULTS: Logopenic-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 [18 F]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 [18 F]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 [18 F]AV-1451was superior to MRI and at least equal to FDG-PET. INTERPRETATION: [18 F]AV-1451binding characteristics differ across the PPA variants and were excellent at distinguishing between the variants. [18 F]AV-1451binding characteristics were as good or better than other brain imaging modalities utilized in clinical practice, suggesting that [18 F]AV-1451 may have clinical diagnostic utility in PPA. Ann Neurol 2018 Ann Neurol 2018;83:599-611.

Longitudinal structural and molecular neuroimaging in agrammatic primary progressive aphasia.

The agrammatic variant of primary progressive aphasia affects normal grammatical language production, often occurs with apraxia of speech, and is associated with left frontal abnormalities on cross-sectional neuroimaging studies. We aimed to perform a detailed assessment of longitudinal change on structural and molecular neuroimaging to provide a complete picture of neurodegeneration in these patients, and to determine how patterns of progression compare to patients with isolated apraxia of speech (primary progressive apraxia of speech). We assessed longitudinal structural MRI, diffusion tensor imaging and 18F-fluorodeoxyglucose PET in 11 agrammatic aphasia subjects, 20 primary progressive apraxia of speech subjects, and 62 age and gender-matched controls with two serial assessments. Rates of change in grey matter volume and hypometabolism, and white matter fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity were assessed at the voxel-level and for numerous regions of interest. The greatest rates of grey matter atrophy in agrammatic aphasia were observed in inferior, middle, and superior frontal gyri, premotor and motor cortices, as well as medial temporal lobe, insula, basal ganglia, and brainstem compared to controls. Longitudinal decline in metabolism was observed in the same regions, with additional findings in medial and lateral parietal lobe. Diffusion tensor imaging changes were prominent bilaterally in inferior and middle frontal white matter and superior longitudinal fasciculus, as well as right inferior fronto-occipital fasciculus, superior frontal and precentral white matter. More focal patterns of degeneration of motor and premotor cortex were observed in primary progressive apraxia of speech. Agrammatic aphasia showed greater rates of grey matter atrophy, decline in metabolism, and white matter degeneration compared to primary progressive apraxia of speech in the left frontal lobe, predominantly inferior and middle frontal grey and white matter. Correlations were also assessed between rates of change on neuroimaging and rates of clinical decline. Progression of aphasia correlated with rates of degeneration in frontal and temporal regions within the language network, while progression of parkinsonism and limb apraxia correlated with degeneration of motor cortex and brainstem. These findings demonstrate that disease progression in agrammatic aphasia is associated with widespread neurodegeneration throughout regions of the language network, as well as connecting white matter tracts, but also with progression to regions outside of the language network that are responsible for the development of motor symptoms. The fact that patterns of progression differed from primary progressive apraxia of speech supports the clinical distinction of these syndromes.

Rapid rate on quasi-speech tasks in the semantic variant of primary progressive aphasia: A non-motor phenomenon?

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.

Training effects of the effortful swallow under three exercise conditions.

The effortful swallow achieves overload through high effort. It was predicted that both immediate effects on biomechanics and long-term neuromuscular adaptations would be facilitated by maximal overload during this exercise. This study examined how high-effort sips from small-diameter straws influenced linguapalatal swallow pressures. Additionally, training effects of effortful swallows preceded by high-effort sips were compared to two other exercise conditions: effortful swallows preceded by maximum effort lingual elevation and effortful swallows performed in isolation. Training outcomes included linguapalatal pressures produced during effortful and noneffortful swallows, and maximum isometric pressure (MIP) produced during tongue elevation and interlabial compression. Forty healthy adults participated in the experiment. Lingual-palatal swallowing pressure during non effortful and effortful swallows and MIPs were measured prior to and after 4 weeks of training. Prior to training, anterior linguapalatal pressures were significantly higher during effortful compared to noneffortful swallows. Anterior linguapalatal pressures did not significantly differ during swallows preceded by sips from high-resistance straws. Weak correlations were observed between tongue MIP and linguapalatal pressures during effortful swallows. After training, anterior linguapalatal pressures significantly increased, with training effects more dramatic for effortful swallows. Anterior tongue MIP also significantly increased. Gains in anterior linguapalatal pressure were not correlated with gains in tongue MIP. Training effects did not vary across exercise condition. The study failed to find a training advantage of pairing the effortful swallow with a precursor movement. The results demonstrated specificity of training, with more dramatic benefits observed for effortful swallows relative to noneffortful swallows. Further investigation is needed to characterize training effects in older adults and patients with dysphagia.

Influences of motor speech impairments on the presentation of dysphagia in progressive supranuclear palsy.

PURPOSE: The purpose of this study was to examine whether differences in motor speech features are related to presentations of dysphagia in progressive supranuclear palsy (PSP) given the sparsity of data examining this relationship. METHOD: Motor speech disorder (MSD) type and severity along with specific swallowing variables were analysed to obtain insights among these relationships in 73 participants with PSP. RESULT: Results revealed that most participants (93%) had dysarthria, with 19% having co-occurring apraxia of speech (AOS). Greater MSD severity was related to more severe pharyngeal phase impairments (95% CI [-0.917, -0.146], p = 0.008). While certain motor speech and swallowing scores varied minimally across participants, incremental changes in these functions were more likely to occur when specific MSD features were present. A trend for participants with spastic dysarthria and/or AOS to exhibit more severe dysphagia was observed. CONCLUSION: This study points to the need for thorough neurological evaluation, with inclusion of speech-language pathology consultation, in the standard of care for PSP. Comprehensive assessment of both motor speech and swallowing functions can inform differential diagnosis and assist patients/families facing decisions regarding modalities for communication and nutrition in the setting of neurodegenerative disease. Additional research may yield greater insights about relevant assessment and intervention considerations in PSP.