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.

Phonological Errors in Posterior Cortical Atrophy.

BACKGROUND: Posterior cortical atrophy (PCA) is an atypical variant of Alzheimer's disease (AD) that presents with visuospatial/perceptual deficits. PCA is characterized by atrophy in posterior brain regions, which overlaps with atrophy occurring in logopenic variant of primary progressive aphasia (lvPPA), another atypical AD variant characterized by language difficulties, including phonological errors. Language abnormalities have been observed in PCA, although the prevalence of phonological errors is unknown. We aimed to compare the frequency and severity of phonological errors in PCA and lvPPA and determine the neuroanatomical correlates of phonological errors and language abnormalities in PCA. METHODS: The presence and number of phonological errors were recorded during the Boston Naming Test and Western Aphasia Battery repetition subtest in 27 PCA patients and 27 age- and disease duration-matched lvPPA patients. Number of phonological errors and scores from language tests were correlated with regional gray matter volumes using Spearman correlations. RESULTS: Phonological errors were evident in 55% of PCA patients and 70% of lvPPA patients, with lvPPA having higher average number of errors. Phonological errors in PCA correlated with decreased left inferior parietal and lateral temporal volume. Naming and fluency were also associated with decreased left lateral temporal lobe volume. CONCLUSIONS: Phonological errors are common in PCA, although they are not as prevalent or severe as in lvPPA, and they are related to involvement of left temporoparietal cortex. This highlights the broad spectrum of clinical symptoms associated with AD and overlap between PCA and lvPPA.

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.

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.

Clinical and imaging progression over 10 years in a patient with primary progressive apraxia of speech and autopsy-confirmed corticobasal degeneration.

Primary progressive apraxia of speech (PPAOS) is a neurodegenerative disorder in which AOS is the sole presenting complaint. We report clinical and neuroimaging data spanning 10 years from disease onset-to-death in a 49 year-old male PPAOS patient, DY, who died with corticobasal degeneration. He presented with AOS with normal neuroimaging. Abnormalities in the caudate nucleus, supplementary motor area, cingulate, insula, and Broca's area were observed after five years, with involvement of motor cortex and development of agrammatism, Parkinsonism, and dysarthria three years later. Cognitive impairment and temporoparietal atrophy were late features. This data provides important insight into disease progression of corticobasal degeneration when presenting as PPAOS.

Characterizing Speech Errors Across Primary Progressive Apraxia of Speech Subtypes.

PURPOSE: Apraxia of speech (AOS) is a motor speech disorder affecting articulatory planning and speech programming. When AOS is the sole manifestation of neurodegeneration, it is termed primary progressive apraxia of speech (PPAOS). Recent work has shown that there are distinct PPAOS subtypes: phonetic, prosodic, and those that do not clearly align with either (mixed). PPAOS subtypes differ with respect to the predominating motor speech difficulties, as well as disease progression and underlying pathology. Because past studies have determined PPAOS subtype based on clinical impression, the goal of the present study was to quantitatively determine the distribution of speech error types across PPAOS subtypes in a word repetition task and to investigate how word complexity affects the type and number of speech errors across PPAOS subtypes. METHOD: Forty-five patients with PPAOS (13 phonetic, 23 prosodic, and nine mixed) and 45 healthy controls produced multiple repetitions of words that varied in phonetic complexity. Sound additions, deletions, and substitutions/distortions (phonetic errors) and within-word segmentations (prosodic errors) were calculated. RESULTS: All three PPAOS groups produced significantly more errors than controls, but the total number of errors was comparable among subtypes. The phonetic group produced more phonetic-type errors compared to the prosodic group but comparable to the mixed group. The prosodic group produced more segmentations compared to the phonetic and mixed PPAOS groups. As word complexity increased, the total number of errors increased for PPAOS patients. The phonetic and prosodic groups were more likely to produce phonetic- and prosodic-type errors, respectively, as word complexity increased. CONCLUSIONS: This study provides novel quantitative data showing that PPAOS subtype can be supported by the type and distribution of speech errors in a word repetition task. This may facilitate earlier, more reliable differential diagnosis and aid in disease prognosis, as PPAOS subtypes have distinct disease trajectories.

Amyloid and Tau PET Positivity in Progressive Agrammatic Aphasia and Apraxia of Speech.

BACKGROUND: The agrammatic variant of primary progressive aphasia (PAA), primary progressive apraxia of speech (PPAOS), or a combination of both (AOS-PAA) are neurodegenerative disorders characterized by speech-language impairments and together compose the AOS-PAA spectrum disorders. These patients typically have an underlying 4-repeat tauopathy, although they sometimes show evidence of amyloid-ß and tau deposition on PET, suggesting Alzheimer's disease (AD). Given the growing number of pharmacologic treatment options for AD, it is important to better understand the incidence of AD pathology in these patients. OBJECTIVE: This study aimed to evaluate the frequency of amyloid-ß and tau positivity in AOS-PAA spectrum disorders. Sixty-five patients with AOS-PAA underwent a clinical speech-language battery and PiB PET and flortaucipir PET imaging. METHODS: Global PiB PET standardized uptake value ratios (SUVRs) and flortaucipir PET SUVRs from the temporal meta region of interest were compared between patient groups. For 19 patients who had died and undergone autopsy, their PET and pathology findings were also compared. RESULTS: The results showed that although roughly half of the patients are positive for at least one biomarker, their clinical symptoms and biomarker status were not related, suggesting that AD is not the primary cause of their neurodegeneration. All but one patient in the autopsy subset had a Braak stage of IV or less, despite four being positive on tau PET imaging. CONCLUSIONS: Inclusion criteria for clinical trials should specify clinical presentation or adjust the evaluation of such treatments to be specific to disease diagnosis beyond the presence of certain imaging biomarkers.

Quantitative assessment of grammar in amyloid-negative logopenic aphasia.

Logopenic primary progressive aphasia (lvPPA) typically results from underlying Alzheimer's disease, but subjects have been reported that do not show beta-amyloid (Aß) deposition. These subjects do not differ on neurological and speech-language testing from Aß-positive lvPPA, but they impressionistically show increased grammatical deficits. We performed a quantitative linguistic analysis of grammatical characteristics in Aß-negative lvPPA compared to Aß-positive lvPPA and agrammatic PPA, which is characterized by increased grammatical difficulties. Aß-negative lvPPA used fewer function words and correct verbs but more syntactic and semantic errors compared to Aß-positive lvPPA. These measures did not differ between Aß-negative lvPPA and agPPA. Both lvPPA cohorts showed a higher mean length of utterance, more complex sentences, and fewer nouns than agPPA. Aß-negative lvPPA subjects appear unique and share linguistic features with both agPPA and Aß-positive lvPPA. Quantitative language analysis in lvPPA may be able to distinguish those with and without Aß deposition.

Quantitative Analysis of Agrammatism in Agrammatic Primary Progressive Aphasia and Dominant Apraxia of Speech.

Purpose: The aims of the study were to assess and compare grammatical deficits in written and spoken language production in subjects with agrammatic primary progressive aphasia (agPPA) and in subjects with agrammatism in the context of dominant apraxia of speech (DAOS) and to investigate neuroanatomical correlates. Method: Eight agPPA and 21 DAOS subjects performed the picture description task of the Western Aphasia Battery (WAB) both in writing and orally. Responses were transcribed and coded for linguistic analysis. agPPA and DAOS were compared to 13 subjects with primary progressive apraxia of speech (PPAOS) who did not have agrammatism. Spearman correlations were performed between the written and spoken variables. Patterns of atrophy in each group were compared, and relationships between the different linguistic measures and integrity of Broca's area were assessed. Results: agPPA and DAOS both showed lower mean length of utterance, fewer grammatical utterances, more nonutterances, more syntactic and semantic errors, and fewer complex utterances than PPAOS in writing and speech, as well as fewer correct verbs and nouns in speech. Only verb ratio and proportion of grammatical utterances correlated between modalities. agPPA and DAOS both showed greater involvement of Broca's area than PPAOS, and atrophy of Broca's area correlated with proportion of grammatical and ungrammatical utterances and semantic errors in writing and speech. Conclusions: agPPA and DAOS subjects showed similar patterns of agrammatism, although subjects performed differently when speaking versus writing. Integrity of Broca's area correlates with agrammatism.

Regional Distribution, Asymmetry, and Clinical Correlates of Tau Uptake on [18F]AV-1451 PET in Atypical Alzheimer's Disease.

BACKGROUND: Despite common pathology, Alzheimer's disease (AD) can have multiple clinical presentations which pathological studies suggest result from differences in the regional distribution of tau pathology. Positron emission tomography (PET) ligands are now available that can detect tau proteins in vivo and hence can be used to investigate the biological mechanisms underlying atypical AD. OBJECTIVE: To assess regional patterns of tau uptake on PET imaging in two atypical AD variants, posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA). METHODS: Eighteen PCA and 19 lvPPA subjects that showed amyloid-ß deposition on PET underwent tau-PET imaging with [18F]AV-1451. Group comparisons of tau uptake in PCA and lvPPA were performed using voxel-level and regional-level analyses. We also assessed the degree of lobar tau asymmetry and correlated regional tau uptake to age and performance on clinical evaluations. RESULTS: Both syndromes showed diffuse tau uptake throughout all cortical regions, although PCA showed greater uptake in occipital regions compared to lvPPA, and lvPPA showed greater uptake in left frontal and temporal regions compared to PCA. While lvPPA showed predominant left-asymmetric tau deposition, PCA was more bilateral. Younger subjects showed greater tau uptake bilaterally in frontal and parietal lobes than older subjects, and sentence repetition, Boston naming test, simultanagnosia, and visuoperceptual function showed specific regional tau correlates. CONCLUSION: Tau deposition is closely related to clinical presentation in atypical AD with age playing a role in determining the degree of cortical tau deposition.