Agrammatic Primary Progressive Aphasia Research Articles

A - 87 A Neuropsychological Case Study of Primary Progressive Apraxia of Speech Versus Agrammatic Primary Progressive Aphasia.

Primary progressive apraxia of speech (PPAOS) is a lesser-known neurodegenerative disorder characterized by progressive speech production loss, affecting word articulation. Apraxic speech commonly occurs in primary progressive aphasias (PPAs) and as a result, is often misdiagnosed as agrammatic PPA (aPPA). The current case highlights the importance of neuropsychological evaluations and behavioral observations in delineating PPAOS from aPPA. The patient is a 71-year-old right-handed White female who presented with a 2-year history of language difficulties beginning with a lisp and progressing to an inability to produce words. MRI of the brain showed moderate white matter disease. Her neurocognitive profile was notable for primary deficits in expressive language, including oral/written production, verbal fluency, and repetition. Milder deficits were observed in aspects of executive functioning. Observed spontaneous speech was notable for impaired and effortful articulation with syllabically segmented prosodic speech patterns, some distortions and prosody alterations, and slow rate. All other cognitive domains were intact. Patients with PPAOS and aPPA typically score in the impaired range on tests that depend on rate and accuracy of speech. Apraxia was her most salient feature reported and observed on testing. We did not find learning and memory difficulties, which are more common in aPPA. Moreover, she had trial-and-error articulatory attempts, groping, and distorted substitutions, which are more commonly seen in PPAOS. Her speech was also devoid of grammatical errors which is another distinguishing feature. While subtle and confounded by her alcohol use and orthopedic injuries, her profile altogether appeared most consistent with PPAOS.

Evaluating the Association Between Genetically Proxied Neurodevelopmental Language Phenotypes and the Risk of Primary Progressive Aphasia.

Primary progressive aphasia (PPA) is a neurodegenerative syndrome of progressive language decline. PPA has 3 main subtypes: logopenic, semantic, and agrammatic. Observational studies suggested an association between language-related neurodevelopmental phenotypes and an increased risk of PPA. We sought to assess such relationships through Mendelian randomization (MR) approach, which can suggest potentially causal associations. Genome-wide significant single-nucleotide polymorphisms (SNPs) associated with dyslexia (42 SNPs), developmental speech disorders (29 SNPs), and left-handedness (41 SNPs) were used as genetic proxies for the exposures. Eighteen of 41 SNPs of left-handedness were associated with structural asymmetry of the cerebral cortex. Genome-wide association study summary statistics were obtained from publicly available databases for semantic (308 cases/616 controls) and agrammatic PPA (269 cases/538 controls). The logopenic PPA (324 cases/3,444 controls) was approximated by proxy through the rubric of clinically diagnosed Alzheimer disease with salient language impairment. Inverse-weighted variance MR was performed as the main analysis for testing the relationship between the exposures and outcomes. Sensitivity analyses were completed to test the robustness of the results. Dyslexia, developmental speech disorders, and left-handedness were not associated with any PPA subtype (p > 0.05). The genetic proxy of cortical asymmetry in left-handedness was significantly associated with agrammatic PPA (β = 4.3, p = 0.007), but not with other PPA subtypes. This association was driven by microtubule-related genes, primarily by a variant that is in complete linkage disequilibrium with MAPT gene. Sensitivity analyses were overall consistent with the primary analyses. Our results do not support a causal association between dyslexia, developmental speech disorders, and handedness with any of the PPA subtypes. Our data suggest a complex association between cortical asymmetry genes and agrammatic PPA. Whether the additional association with left-handedness is necessary remains to be determined but is unlikely, given the absence of association between left-handedness and PPA. Genetic proxy of brain asymmetry (regardless of handedness) was not tested as an exposure due to lack of suitable genetic proxy. Furthermore, the genes related to cortical asymmetry associated with agrammatic PPA are implicated in microtubule-related proteins (TUBA1B, TUBB, and MAPT), which is keeping with the association of tau-related neurodegeneration in this PPA variant.

Word picture verification performance reveals auditory comprehension deficits in primary progressive aphasia

Word/picture verification has been found to be a sensitive measure of lexical-semantic abilities in post-stroke aphasia and reveals information about disruptions in semantic and phonological processing. Exploration of the nature of auditory comprehension deficits using word/picture verification has not been replicated in primary progressive aphasia (PPA). We tested 108 individuals with PPA [logopenic variant PPA (lvPPA), n = 50; nonfluent agrammatic PPA (nfaPPA), n = 36; semantic variant PPA (svPPA), n = 22] on a spoken word/picture verification task and a spoken word/picture matching task. The spoken word/picture matching task identified 22 (20%) of individuals as impaired, whereas the spoken word/picture verification task identified 51 (47%) of individuals as impaired (two-tailed p < 0.001). Errors on spoken word/picture verification were due to semantic rather than phonologic foils in lvPPA (nouns, p < 0.001; verbs, p < 0.001), svPPA (nouns, p < 0.001; verbs, p < 0.001), and for nouns (p = 0.001) but not verbs in nfaPPA. Spoken word/picture verification was a more sensitive measure of single-word auditory comprehension deficits in PPA than word/picture matching. The error pattern, consistent with the distributed model of semantic knowledge, suggests that degradation of semantic representations for both nouns and verbs can occur in lvPPA, which may help to distinguish lvPPA versus nfaPPA and guide treatment for anomia. • We investigated picture verification and picture matching to assess auditory comprehension impairment in primary progressive aphasia (PPA). • Picture verification was a more sensitive measure of single-word auditory comprehension deficits in PPA than picture matching. • Errors on spoken word/picture verification were due to semantic rather than phonologic foils for nouns and verbs in logopenic variant and semantic variant PPA.

Clinical Spectrum of Tauopathies.

Tauopathies are both clinical and pathological heterogeneous disorders characterized by neuronal and/or glial accumulation of misfolded tau protein. It is now well understood that every pathologic tauopathy may present with various clinical phenotypes based on the primary site of involvement and the spread and distribution of the pathology in the nervous system making clinicopathological correlation more and more challenging. The clinical spectrum of tauopathies includes syndromes with a strong association with an underlying primary tauopathy, including Richardson syndrome (RS), corticobasal syndrome (CBS), non-fluent agrammatic primary progressive aphasia (nfaPPA)/apraxia of speech, pure akinesia with gait freezing (PAGF), and behavioral variant frontotemporal dementia (bvFTD), or weak association with an underlying primary tauopathy, including Parkinsonian syndrome, late-onset cerebellar ataxia, primary lateral sclerosis, semantic variant PPA (svPPA), and amnestic syndrome. Here, we discuss clinical syndromes associated with various primary tauopathies and their distinguishing clinical features and new biomarkers becoming available to improve in vivo diagnosis. Although the typical phenotypic clinical presentations lead us to suspect specific underlying pathologies, it is still challenging to differentiate pathology accurately based on clinical findings due to large phenotypic overlaps. Larger pathology-confirmed studies to validate the use of different biomarkers and prospective longitudinal cohorts evaluating detailed clinical, biofluid, and imaging protocols in subjects presenting with heterogenous phenotypes reflecting a variety of suspected underlying pathologies are fundamental for a better understanding of the clinicopathological correlations.

Sentence Comprehension in Primary Progressive Aphasia: A Study of the Application of the Brazilian Version of the Test for the Reception of Grammar (TROG2-Br).

Sentence-comprehension deficits have been described in patients with primary progressive aphasia (PPA). However, most instruments to address this domain in more detail and in a clinical context have not been adapted and translated into several languages, posing limitations to clinical practice and cross-language research.ObjectivesThe study aimed to (1) test the applicability of the Brazilian version of the Test for Reception of Grammar (TROG2-Br) to detect morphosyntactic deficits in patients with PPA; (2) investigate the association between performance in the test and sociodemographic and clinical variables (age, years of formal education, and disease duration); (3) characterize the performance of individuals presenting with the three more common variants of PPA (non-fluent, semantic, and logopenic) and mixed PPA (PPA-Mx) and analyze whether TROG-2 may assist in the distinction of these clinical profiles.MethodsA total of 74 cognitively healthy participants and 34 individuals diagnosed with PPA were assessed with TROG2-Br. Overall scores (correct items, passed blocks), types, and categories of errors were analyzed.ResultsIn controls, block scores were significantly correlated with years of formal education (Spearman's r = 0.33, p = 004) but not with age. In PPA, age, education, and disease duration were not significantly associated with performance in the test. Controls presented a significantly higher performance on TROG2-Br compared to PPA individuals and their errors pattern pointed to mild general cognitive processing difficulties (attention, working memory). PPA error types pointed to processing and morphosyntactic deficits in nonfluent or agrammatic PPA, (PPA-NF/A), logopenic PPA (PPA-L), and PPA-Mx. The semantic PPA (PPA-S) subgroup was qualitatively more similar to controls (processing difficulties and lower percentage of morphosyntactic errors). TROG2-Br presented good internal consistency and concurrent validity.DiscussionOur results corroborate findings with TROG-2 in other populations. The performance of typical older adults with heterogeneous levels of education is discussed along with recommendations for clinical use of the test and future directions of research.

Primary progressive aphasias: clinical and genetic heterogeneity and diagnostic difficulties

This systematic review describes primary progressive aphasia (PPA) variants and includes the authors' own clinical observations. Over 20 genes have now been identified, with mutations that are directly involved in the development of the behavioural variant of frontotemporal dementia, as well as other forms of PPA. Pathomorphological markers of Alzheimer's disease were identified in 76% of cases of logopenic PPA, while signs of frontotemporal dementia associated with TDP-43 were identified in 80% of cases of the semantic variant, and those associated with TDP-43/tau were identified in 64% of cases of agrammatic PPA. The clinical diagnosis of PPA is based on a history of long-term, progressive speech disturbances and identifying a particular variant: agrammatic, semantic or logopenic. The primary variant of the speech disorder cannot be identified in approximately 30% of cases. The focus should be on the main and additional clinical signs (presence of agrammatism, object naming, word comprehension, preserved repetition), as well as neuroimaging (presence of asymmetrical frontal and/or temporal lobe atrophy).&#x0D; The article also provides key aspects of differential diagnosis of the PPA variants, and puts forth a stepwise diagnostic algorithm. It examines features of PPA progression, with possible development of corticobasal syndrome, illustrated by a clinical case. A dissociation between neuroimaging findings and clinical disease variant is also demonstrated to be possible. Different neuropsychological assessments of patients with aphasia and methods of determining the severity of speech dysfunction are presented. Standardized aphasia assessment tools and the adapted PPA severity scale are provided.

Longitudinal decline in spoken word recognition and object knowledge in primary progressive aphasia.

The premise of this study is that spoken word recognition and object knowledge are impaired in semantic variant primary progressive aphasia (PPA) (svPPA) and are spared in logopenic variant (lvPPA) and nonfluent agrammatic primary progressive aphasia (nfaPPA) at disease onset. Over time, however, there may be heterogeneity in these abilities in lvPPA and nfaPPA. We hypothesized that individuals with svPPA would demonstrate poorer performance on baseline spoken word recognition and object knowledge than those with lvPPA and nfaPPA) as documented in the literature, but that rates of decline over time on spoken word recognition and object knowledge would be similar in all 3 PPA variants because these become less distinguishable with disease progression.The aim of this study was to investigate longitudinal patterns of decline in spoken word recognition and object knowledge across PPA variants.Ninety-five individuals with PPA completed the Semantic Word Picture Matching and Semantic Associates tests at baseline to establish expected performance in these areas. Thirty-five individuals completed follow-up testing.The distributions of trichotomized mean rates of decline in object knowledge were similar for lvPPA and svPPA (P = .05). There were weak negative correlations between symptom duration and baseline scores on Semantic Word Picture Matching (r[37] = −0.399, P = .01), and baseline scores on Semantic Associates (r[37] = −0.394, P = .01) in lvPPA.Degradation of spoken word recognition and object knowledge occurs over time in lvPPA. Further investigation of the receptive language deficits in PPA is warranted to characterize language changes that lessen the distinctions between PPA variants with disease progression.

A longitudinal study of automated analysis of acoustic speech markers in FTD and PPA

AbstractBackgroundSpeech is a complex activity requiring proper function and connectivity of multiple brain networks and as such is sensitive to focal neurodegeneration. We have previously reported on acoustic markers of dysprosody in speech samples of speakers with frontotemporal dementia (FTD) phenotypes. In the current study we explore the longitudinal changes in acoustic‐prosodic markers in FTD.MethodWe analyzed 102 speech samples of picture descriptions from 46 participants with FTD (Table 1): 8 with non‐fluent/agrammatic primary progressive aphasia (naPPA), 14 with semantic variant PPA (svPPA), 10 with logopenic aphasia (lvPPA) and 14 with behavioral FTD (bvFTD). We automatically segmented the acoustic signal into segments of continuous speech or silence, measured their durations, and derived other measures. We used linear mixed effects (lme) models to test changes over time for each acoustic measure, controlling for sex, education, and random intercepts. We also examined any interaction between phenotypes and disease duration.ResultbvFTD speakers increased their pause duration by 0.27 seconds per year and their pause rate by 3.9 pauses per minute (ppm) each year. Their speech segment duration shortened by 0.1 seconds per year (p=0.041), decreasing their total speech time by 6.6 seconds (p=0.003) per year. Thus, bvFTD patients reduced the proportion of speech in their samples by 5.16 percent per year (p=0.008). svPPA speakers increased their pause rate similarly, but in contrast, their pause duration decreased by 0.097 seconds per year and they increased their speech segment frequency by 8.32 per minute each year (p=0.054). naPPA and lvPPA speakers increased their pause rate over time and spent less total time (speech + pause) describing the picture (by 5.6 seconds per year; p=0.018). They did not differ from bvFTD and svPPA in these two acoustic measures.ConclusionIn our study all FTD speakers became more dysfluent and produced shorter descriptions with time, however, only bvFTD speakers actually exhibited reduced speech production. In contrast, svPPA speech had more frequent pauses and speech segments over time, rendering it “fragmented” and inefficient. These findings support the role of automated acoustic analysis in characterizing speech longitudinally in neurodegeneration.

Acoustic measures in natural speech of progressive supranuclear palsy and corticobasal spectrum disorders

AbstractBackgroundProgressive supranuclear palsy and corticobasal syndrome (PSP‐CBS) are neurodegenerative disorders involving motor and cognitive deficits. These patients may have slowed and dysfluent speech. However, few studies have investigated specific speech and language deficits in these disorders, although some patients may have non‐fluent/agrammatic primary progressive aphasia (naPPA). In our study, we used novel, automated speech analysis methods to quantify acoustic properties of natural speech in PSP‐CBS. We hypothesized patients would exhibit slowed speech and longer pauses, and predicted that prosodic changes would be related to underlying cognitive and motor impairments. Because PSP and CBS are tauopathies, we related their acoustic performance to cerebrospinal fluid (CSF) analytes associated with Tau pathology.MethodWe obtained digitized samples of natural speech with the Cookie Theft picture description task from PSP‐CBS patients (n = 95), naPPA patients (n = 25) and healthy controls (HC, n = 41). Eight PSP‐CBS patients had concomitant naPPA (PSP‐CBS+naPPA). The groups were matched for age, sex, education, and disease duration. A speech activity detector program automatically segmented the acoustic signal into speech and silent pause segments. We automatically calculated the pitch range by measuring fundamental frequency (f0, semitones), total speech duration, mean speech and pause segment durations, and pause rate (pauses per minute). In a subset of patients with available CSF analytes, we related acoustic markers with levels of phosphorylated tau (pTau).ResultPSP‐CBS without naPPA had shorter mean speech segments (1.42 ± 0.48 sec), shorter total speech durations (31.77 ± 14.66 sec), longer mean pause segments (1.82 ± 1.01 sec) and higher pause rates (45.10 ± 13.43 pauses per minute) compared to HC (2.00 ± 0.57 sec, p &lt; .001; 51.08 ± 21.30 sec, p &lt; .001; 0.93 ± 0.44 sec, p &lt; .001; 31.61 ± 9.51 ppm, p &lt; .001, respectively). PSP‐CBS only differed from naPPA for pause rate (PSP‐CBS, 45.10 ± 13.43 ppm; naPPA, 57.81 ± 19.95 ppm; p = .026). PSP‐CBS+naPPA patients were most impaired for f0 range (3.56 ± 1.21 ST) compared to HC (5.87 ± 1.94 ST, p = .021), paralleling naPPA patients, who had reduced f0 range compared to HC (4.30 ± 1.59 ST, p = .02). f0 range was associated with pTau levels in all patients (r = ‐0.43, p = .004).ConclusionPatients with PSP‐CBS have impaired speech as quantified by automated analysis of acoustic measures of speech. These measures are related to pTau, a marker of likely pathology.

Using narratives in differential diagnosis of neurodegenerative syndromes

PurposeLanguage decline has been associated with healthy aging and with various neurodegenerative conditions, making it challenging to differentiate among these conditions. This study examined the utility of linguistic measures derived from a short narrative language sample for 1) identifying language characteristics and cut-off scores to differentiate between healthy aging, Primary Progressive Aphasia (PPA), Mild Cognitive Impairment (MCI), and Alzheimer’s dementia (AD); and 2) differentiating among PPA variants in which language is the primary impairment. MethodParticipants were 25 neurologically healthy English speakers, 20 individuals with MCI, 20 with AD, and 26 with PPA (non-fluent/agrammatic N = 10, logopenic N = 9, semantic N = 7). Narrative language samples of the Cookie Theft Picture of persons with healthy aging, MCI and AD were retrospectively obtained from the DementiaBank database (https://talkbank.org/DementiaBank/) and PPA samples were obtained from an ongoing research study. The language samples were analyzed for fluency, word retrieval success, grammatical accuracy, and errors using automated and manual analysis methods. The sensitivity and specificity of various language measures was computed. ResultsParticipants with PPA scored lower than neurologically healthy and MCI groups on fluency (words per minute and disfluencies), word retrieval (Correct Information Units and number of errors), and sentence grammaticality. PPA and AD groups did not differ on language measures. Agrammatic PPA participants scored lower than logopenic and semantic PPA groups on several measures, while logopenic and semantic PPA did not differ on any measures. ConclusionMeasures derived from brief language samples and analyzed using mostly automated methods are clinically useful in differentiating PPA from healthy aging and MCI, and agrammatic PPA from other variants. The sensitivity and specificity of these measures is modest and can be improved when coupled with clinical presentation.

Classification of primary progressive aphasia: challenges and complexities.

Primary progressive aphasia (PPA) is classified into three variants, logopenic variant PPA (lvPPA), nonfluent agrammatic PPA (nfaPPA), and semantic variant PPA (svPPA), based on clinical (syndromic) characteristics with support from neuroimaging and/or underlying neuropathology. Classification of PPA variants provides information valuable to disease management. International consensus criteria are widely employed to identify PPA subtypes; however, classification is complex, and some individuals do not fit neatly into the subtyping scheme. In this review, diagnostic challenges and their implications are discussed, possible explanations for these challenges are explored, and approaches to address PPA classification are considered.

Taxonomic Interference Associated with Phonemic Paraphasias in Agrammatic Primary Progressive Aphasia.

Phonemic paraphasias are thought to reflect phonological (post-semantic) deficits in language production. Here we present evidence that phonemic paraphasias in non-semantic primary progressive aphasia (PPA) may be associated with taxonomic interference. Agrammatic and logopenic PPA patients and control participants performed a word-to-picture visual search task where they matched a stimulus noun to 1 of 16 object pictures as their eye movements were recorded. Participants were subsequently asked to name the same items. We measured taxonomic interference (ratio of time spent viewing related vs. unrelated foils) during the search task for each item. Target items that elicited a phonemic paraphasia during object naming elicited increased taxonomic interference during the search task in agrammatic but not logopenic PPA patients. These results could reflect either very subtle sub-clinical semantic distortions of word representations or partial degradation of specific phonological word forms in agrammatic PPA during both word-to-picture matching (input stage) and picture naming (output stage). The mechanism for phonemic paraphasias in logopenic patients seems to be different and to be operative at the pre-articulatory stage of phonological retrieval. Glucose metabolic imaging suggests that degeneration in the left posterior frontal lobe and left temporo-parietal junction, respectively, might underlie these different patterns of phonemic paraphasia.

Visuomotor figure construction and visual figure delayed recall and recognition in primary progressive aphasia

ABSTRACT Background: Individuals with primary progressive aphasia (PPA) develop visuospatial deficits over time, and those with logopenic variant (lvPPA) are at greatest risk of developing such deficits. However, not all previous studies of visuospatial deficits in PPA have ensured equivalent duration of disease across variants and few have measured deficits longitudinally. Aims: The aims of our study were to 1) investigate differences in baseline visuomotor figure construction, visual figure delayed recall, and figure recognition in PPA variants with similar symptom duration at baseline, and 2) explore patterns of decline in these areas. Methods & Procedures: 93 individuals with PPA [39 lvPPA, 24 nonfluent agrammatic PPA (nfaPPA), and 30 semantic variant PPA (svPPA)] were administered the Benson Complex Figure Copy, Benson Complex Figure Delay (Recall), and Benson Figure Recognition. Thirty individuals completed this testing 3 to 47 months post-baseline. Outcome & Results: Participants with lvPPA and svPPA showed lower mean scores than those with nfaPPA on visual figure delayed recall at baseline, even though there were no differences in estimated time from disease onset or correlation with disease severity as reflected by naming performance, F(2, 90) = 5.78, p < .004. Those with nfaPPA performed significantly better than those with lvPPA, Tukey HSD p < .05, and those with svPPA, Tukey HSD p < .01. There were no differences between variants in rate of decline in visuomotor figure construction, visual figure delayed recall, and figure recognition. Conclusions: These findings revealed relatively spared visuospatial memory in nfaPPA, which may aid in the differential diagnosis of PPA and contribute to designing therapy or compensatory strategies.

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

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. 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. 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. 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.

Tau uptake in agrammatic primary progressive aphasia with and without apraxia of speech.

The 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. Nine 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. The 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. This cross-sectional study suggests that [18F]AV-1451 uptake in the precentral gyrus is implicated in AOS in agPPA.

Patterns of decline in naming and semantic knowledge in primary progressive aphasia

ABSTRACTBackground: Individuals with primary progressive aphasia (PPA) and their caregivers want to know what to expect so that they can plan support appropriately. The ability to predict decline in naming and semantic knowledge, and advise individuals with PPA and their caregivers regarding future planning, would be invaluable clinically.Aims: The aims of this study were to investigate patterns of decline in naming and semantic knowledge in each of the clinical variants of PPA (logopenic variant PPA, lvPPA; nonfluent agrammatic PPA, nfaPPA; and semantic variant PPA, svPPA) and to examine the effects of other variables on rate of decline. We hypothesized that speech-language rehabilitation, higher education, and higher baseline test scores would be associated with slower decline, and older age with faster decline.Methods and Procedures: A total of 94 participants with PPA underwent language testing, including 36 participants with lvPPA, 31 participants with nfaPPA, and 27 participants with svPPA. All participant groups were similar in age and education. We focused on decline on three tests: the short form of the Boston Naming Test (BNT), the Hopkins Assessment of Naming Actions (HANA), and the short form of the Pyramids and Palm Trees Test (PPTT).Outcome and Results: Across language tests, the most precipitous rates of decline (loss of points per month) occurred in nfaPPA, followed by svPPA, then lvPPA. Female sex, longer symptom duration, higher baseline test score, and speech-language rehabilitation were associated with slower decline.Conclusions: PPA variants were distinguishable by rapidity of decline, with nfaPPA having the most precipitous decline. As hypothesized, higher baseline test scores and speech-language rehabilitation were associated with slower decline. Surprisingly, age and education were not important prognostically for individuals in this study. Further study of prognostically-relevant variables in PPA is indicated in this population.

Differentiating between subtypes of primary progressive aphasia and mild cognitive impairment on a modified version of the Frontal Behavioral Inventory.

Behavioral assessment has been investigated in frontotemporal lobar degeneration and Alzheimer’s disease, but has not been explored extensively in subtypes of primary progressive aphasia (PPA). We explored the ability of a modified version of the Frontal Behavioral Inventory (FBI-mod) to discriminate between patients with distinct subtypes of PPA and patients with mild cognitive impairment (MCI). We hypothesized that individuals with nonfluent agrammatic PPA (nfaPPA) would have higher negative behavior scores than other groups and that individuals with semantic variant PPA (svPPA) would have higher disinhibition scores than other groups. Family members and/or caregivers of 120 individuals with PPA and MCI (mean age 69.54+8.75 years; 65 (54%) female; education 16.06±2.68 years; disease duration 46.47±34.26 months) completed the FBI-mod [logopenic PPA (lvPPA) n = 40. nfaPPA n = 29, svPPA n = 27, MCI n = 24]. The groups were not significantly different in age, gender, education, or disease duration. There were no significant differences between the groups for negative behaviors (p = 0.72) and disinhibition scores (p = 0.14). When comparing negative and disinhibition scores (in percent), negative scores were significantly higher in all groups (p < 0.001). When comparing subtest items, there was a pairwise difference between lvPPA and svPPA for restlessness (lvPPA < svPPA, p = 0.02, after adjusting for multiple between-group comparisons). There was a significant difference in the proportion of severe neglect between the groups with lvPPA having a lower proportion than the other two variants (p = 0.05), and there was a significant difference in the proportion of severe poor judgment between the groups with lvPPA also having a lower proportion than nfaPPA (p = 0.04). This study reveals the greater negative behavioral disturbance than disinhibition in the PPA and MCI groups of similar age and duration since onset and identifies different profiles for some specific behaviors for the PPA groups. These findings may have clinical and practical implications.

Predicting Decline in Agrammatism, Apraxia of Speech and Parkinsonism in Agrammatic Primary Progressive Aphasia (P4.030)

Predicting Decline in Agrammatism, Apraxia of Speech and Parkinsonism in Agrammatic Primary Progressive Aphasia (P4.030)

The Brain Network of Naming: A Lesson from Primary Progressive Aphasia.

ObjectiveWord finding depends on the processing of semantic and lexical information, and it involves an intermediate level for mapping semantic-to-lexical information which also subserves lexical-to-semantic mapping during word comprehension. However, the brain regions implementing these components are still controversial and have not been clarified via a comprehensive lesion model encompassing the whole range of language-related cortices. Primary progressive aphasia (PPA), for which anomia is thought to be the most common sign, provides such a model, but the exploration of cortical areas impacting naming in its three main variants and the underlying processing mechanisms is still lacking.MethodsWe addressed this double issue, related to language structure and PPA, with thirty patients (11 semantic, 12 logopenic, 7 agrammatic variant) using a picture-naming task and voxel-based morphometry for anatomo-functional correlation. First, we analyzed correlations for each of the three variants to identify the regions impacting naming in PPA and to disentangle the core regions of word finding. We then combined the three variants and correlation analyses for naming (semantic-to-lexical mapping) and single-word comprehension (lexical-to-semantic mapping), predicting an overlap zone corresponding to a bidirectional lexical-semantic hub.Results and ConclusionsOur results showed that superior portions of the left temporal pole and left posterior temporal cortices impact semantic and lexical naming mechanisms in semantic and logopenic PPA, respectively. In agrammatic PPA naming deficits were rare, and did not correlate with any cortical region. Combined analyses revealed a cortical overlap zone in superior/middle mid-temporal cortices, distinct from the two former regions, impacting bidirectional binding of lexical and semantic information. Altogether, our findings indicate that lexical/semantic word processing depends on an anterior-posterior axis within lateral-temporal cortices, including an anatomically intermediate hub dedicated to lexical-semantic integration. Within this axis our data reveal the underpinnings of anomia in the PPA variants, which is of relevance for both diagnosis and future therapy strategies.

Asymmetric pathology in primary progressive aphasia with progranulin mutations and TDP inclusions.

To investigate quantitative regional distribution and hemispheric asymmetry of TDP-43 (TAR DNA-binding protein 43) inclusions, neurons, and activated microglia in primary progressive aphasia (PPA) with progranulin (GRN) mutations, and to determine concordance between distribution of pathology, clinical phenotype, and known atrophy patterns. Antibodies to phospho-TDP-43, NeuN (neuronal nuclei), and HLA-DR were used to visualize inclusions, neurons, and activated microglia in paraffin-embedded tissue sections from 4 participants with PPA: 2 of the agrammatic and 2 of the logopenic subtype. Unbiased stereological counting techniques were used for quantitation of immunoreactive profiles in language- and memory-related cortical areas bilaterally. Patterns of pathology across cortical areas and hemispheres were compared and their relationships with known patterns of atrophy investigated. Numerical densities of TDP-43 inclusions, and less so of activated microglia, were greater in language-related areas compared with memory-related areas. In language areas, neuronal density displayed a pattern opposite to inclusions and activated microglia. Densities of inclusions and microglia were greater (p < 0.05), and densities of neurons were lower (p < 0.005), in the left hemisphere compared with the right. In agrammatic PPA, the highest densities of TDP-43 inclusions were observed in left inferior or middle frontal gyri, and in logopenic participants, the highest density of inclusions was seen in left inferior parietal lobule. This distribution is consistent with subtype-specific peak atrophy sites. Distribution of TDP-43 inclusions and neurons, and to a smaller extent of activated microglia, show a regional and hemispheric pattern consistent with disease phenotype and known patterns of atrophy in PPA with GRN mutations.