Variant Primary Progressive Aphasia Research Articles

Investigating Verbal Repetition in Persian-speaking Patients with the Semantic Variant of Primary Progressive Aphasia Compared to Healthy Individuals

Introduction: Language deficit is regarded as one of the most important hallmarks of primary progressive aphasia. This study aims to analyze the nature of verbal repetition ability in a group of patients suffering from the semantic variant of primary progressive aphasia and investigate their cognitive capability.
 Materials and Methods: In this cross-sectional study, 12 patients of the semantic variant of primary progressive aphasia and 12 healthy individuals accomplished a set of tasks, including naming, word comprehension, digit span, repetition of multisyllabic single words, monosyllabic word span under similar or dissimilar phonological conditions, and sentence repetition
 Results: The patients exhibited some degree of impairment with diverse patterns in each task, although the accomplishment of the sentence repetition task was the most challenging activity for the primary progressive aphasic patients of the semantic variant. However, the healthy individuals performed well in all tasks.
 Conclusion: The recognition of the quantity and quality of the cognitive deficit in the semantic variant of primary progressive aphasics can illuminate the nature of this disease and contribute to a better diagnosis of this disease. Furthermore, it can assist speech therapists and neuropsychologist to recruit appropriate therapies and employ better techniques for the diagnosis and cure of these patients.

A - 66 Non-Fluent/Agrammatic Variant of Primary Progressive Aphasia (Nappa) in a Bilingual Chinese Speaker: a Single-Case Study.

The non-fluent/agrammatic variant of primary progressive aphasia (naPPA) is a neurodegenerative syndrome associated with agrammatism in language production and effortful speech (Gorno-Tempini et al., 2011). There is limited literature on PPA in non-English speakers and few clinical cases of bilingual naPPA have been described (Tee et al., 2022; Zanini et al., 2011). Characteristics of symptoms in orthographic languages, such as Chinese, are not well understood (Ting et al., 2017). This case describes the assessment of naPPA in a bilingual Mandarin Chinese speaker. A 66-year-old Asian male with 16years of education complained of worsening aphasia in both languages over two years with initial preferential sparing of Chinese. A comprehensive neuropsychological battery was administered mostly in Chinese with select subtests in English. Language functioning was assessed with the Bilingual Aphasia Screening Test (Paradis & Libben, 1987). Agrammatism and apraxia of speech was present in both languages. Single-word comprehension and object knowledge was preserved, while comprehension of complex commands was impaired. Lexical discrimination of real and nonsense words was preserved. Delayed memory was impaired with relative improvement upon recognition. Attention, processing speed, visuospatial skills, and motor functioning were preserved. Mood was euthymic. This case revealed deficits in both languages with slower decline of the dominant language, suggesting that the less proficient language in bilinguals is more vulnerable to degeneration in naPPA.

A - 9 The Progressive Supranuclear Palsy Rating Scale Identifies Early Motor Symptoms in Primary Progressive Aphasia.

This study examined cross-sectional differences in Progressive Supranuclear Palsy Rating Scale (PSPRS) scores among participants with behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA). We hypothesized that participants with nonfluent/agrammatic PPA (nfPPA) will show the highest (worst) PSPRS scores and greater gray matter atrophy in regions associated with progressive supranuclear palsy (PSP) pathology. Participants were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium (ALLFTD). Analyses were limited to first visit data. Ten anatomic regions of interest were pre-selected for analysis based on previously identified neuroanatomic correlates of PSPRS performance. Differences in participant characteristics and clinical outcomes were compared using pairwise comparison of means. Linear multivariable regression adjusting for age and total intracranial volume was used to examine associations between regional gray matter volumes and diagnosis. The analyses were stratified by disease severity. Participants with early-stage nfPPA had higher total PSPRS scores compared to those with bvFTD or semantic dementia (SD) and performed more poorly on domains of dysphagia, fine motor movements, falls, postural stability, dysarthria, saccadic eye movements, and motor rigidity. Participants with advanced-stage nfPPA showed greater atrophy in the left putamen, supplementary motor area, and precentral gyrus than those with bvFTD. Our study highlights the phenotypic complexity of PPA and the utility of the PSPRS in capturing early motor symptoms in nfPPA. These data suggest that the PSPRS may facilitate early intervention in identifying and facilitating treatment of early motor symptoms, decreasing disability and improving quality of life in PPA.

A - 127 Unveiling Discrepancies in Identifying Depression in Dementia: a Comparative Analysis of Caregiver and Patient Self-Report Measures.

Standard assessment of depression in research and clinical care with persons with dementia (PWD) relies on caregiver report, and views of PWD are typically not incorporated due to concerns that they lack insight into their own neuropsychiatric status. This study explored the discrepancies between self-reported and caregiver-reported depression among PWD. Participants included 373 PWD who met criteria for Alzheimer's disease, behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, and progressive supranuclear palsy. Each PWD self-reported depressive symptoms using the Geriatric Depression Scale (GDS), including subscales of dysphoria, withdrawal, worry, worthlessness, and cognitive concern. Caregivers described the PWD using the Neuropsychiatric Inventory (NPI) depression and apathy subscales. Of the total sample, 112 (30%) patients were positive for depression on both their self-report (GDS total > =13) and their informant report (NPI depression = yes). However, 226 (60.5%) patients self-reported depression on the GDS, including dysphoria and hopelessness, but their caregivers reported no depression. Additionally, 110 (49%) patients who self-reported depression but whose informants reported no depression were described as apathetic by their informants, compared to 43 (19%) of these depressed patients whose informants did not report depression or apathy. These results suggest that overreliance on caregivers' reports of depression may seriously underrepresent rates of depression in PWD and mischaracterize patients' experience. Difficulty distinguishing depression from apathy accounted for only part of this PWD-caregiver discrepancy. Prioritizing PWD self-report of mood, and broadening caregiver education about depression, may improve care and quality of life for PWD.

A - 44 Social Cognition and its Neuroanatomic Correlates in Frontotemporal Dementia.

Frontotemporal dementia (FTD) often presents with impaired social cognition in both the behavioral and language variants. Establishing reliable measures and neural correlates of social cognition may aid in staging and monitoring FTD subtypes. Here, we examined group differences in social cognitive measures between FTD subtypes and cortical thickness correlates of social cognition across groups. Participants with behavioral variant FTD (n = 53; bvFTD), semantic variant primary progressive aphasia (n = 32; svPPA) and non-fluent variant PPA (n = 32; nfPPA) were enrolled in the Frontotemporal Lobar Degeneration Neuroimaging Initiative (NIFD). In first-visit data, we examined group differences in social cognition measures [Interpersonal Reactivity Index (IRI), Revised Social-Monitoring Scale (RSMS), and Behavioral Inhibition/Activation (BIS/BAS) Scales]. We used multivariate regression adjusted for age, total intracranial volume, and CDR global score to explore associations between social cognition and cortical thickness in pre-specified regions. Reduced perspective-taking and sensitivity to socio-emotional expressiveness was observed in early-stage bvFTD and svPPA groups compared to the nfPPA group. Across FTD cohorts, increased perspective-taking was associated with reduced cortical thickness of regions within the salience and default mode networks. Increased empathic concern was associated with increased left inferior parietal cortical thickness. Increased behavioral inhibition was associated with reduced right posterior cingulate cortical thickness. Increased behavioral activation was associated with reduced right pars triangularis cortical thickness. Social cognition is affected in early-stage bvFTD and svPPA to a greater extent than nfPPA. Neural correlates of social cognition are varied and warrant additional study as our findings contrast with previous literature that has typically linked lower perspective-taking with atrophy.

Neural basis of speech and grammar symptoms in non-fluent variant primary progressive aphasia spectrum.

The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) is a neurodegenerative syndrome primarily defined by the presence of apraxia of speech (AoS) and/or expressive agrammatism. In addition, many patients exhibit dysarthria and/or receptive agrammatism. This leads to substantial phenotypic variation within the speech-language domain across individuals and time, in terms of both the specific combination of symptoms as well as their severity. How to resolve such phenotypic heterogeneity in nfvPPA is a matter of debate. 'Splitting' views propose separate clinical entities: 'primary progressive apraxia of speech' when AoS occurs in the absence of expressive agrammatism, 'progressive agrammatic aphasia' (PAA) in the opposite case, and 'AOS + PAA' when mixed motor speech and language symptoms are clearly present. While therapeutic interventions typically vary depending on the predominant symptom (e.g. AoS versus expressive agrammatism), the existence of behavioural, anatomical and pathological overlap across these phenotypes argues against drawing such clear-cut boundaries. In the current study, we contribute to this debate by mapping behaviour to brain in a large, prospective cohort of well characterized patients with nfvPPA (n = 104). We sought to advance scientific understanding of nfvPPA and the neural basis of speech-language by uncovering where in the brain the degree of MRI-based atrophy is associated with inter-patient variability in the presence and severity of AoS, dysarthria, expressive agrammatism or receptive agrammatism. Our cross-sectional examination of brain-behaviour relationships revealed three main observations. First, we found that the neural correlates of AoS and expressive agrammatism in nfvPPA lie side by side in the left posterior inferior frontal lobe, explaining their behavioural dissociation/association in previous reports. Second, we identified a 'left-right' and 'ventral-dorsal' neuroanatomical distinction between AoS versus dysarthria, highlighting (i) that dysarthria, but not AoS, is significantly influenced by tissue loss in right-hemisphere motor-speech regions; and (ii) that, within the left hemisphere, dysarthria and AoS map onto dorsally versus ventrally located motor-speech regions, respectively. Third, we confirmed that, within the large-scale grammar network, left frontal tissue loss is preferentially involved in expressive agrammatism and left temporal tissue loss in receptive agrammatism. Our findings thus contribute to define the function and location of the epicentres within the large-scale neural networks vulnerable to neurodegenerative changes in nfvPPA. We propose that nfvPPA be redefined as an umbrella term subsuming a spectrum of speech and/or language phenotypes that are closely linked by the underlying neuroanatomy and neuropathology.

Multimodal Semantic Knowledge Assessment –Standard and Preliminary Data in Semantic Variant Primary Progressive Aphasia and Alzheimer’s Disease in Comparison with Vascular Aphasia

Les troubles lexico-sémantiques sont connus pour être l’une des manifestations majeures de l’aphasie, qu’elle soit d’origine vasculaire (comme l’aphasie sémantique -AS-) ou dégénérative (comme l’aphasie sémantique progressive primaire -APPvs- et la maladie d’Alzheimer -MA-). En pratique clinique, ces troubles sont principalement évalués par des tests verbaux, alors que, selon la littérature, le déficit doit être observé dans plusieurs modalités. Le but de cette étude était de créer une batterie française d’évaluation sémantique multimodale appelée EMCS (Évaluation Multimodale des Connaissances Sémantiques), qui étudie, en un temps plus court que les outils existants, l’efficacité de la mémoire sémantique à travers plusieurs tâches multimodales. Quatre-vingt-sept participants témoins français ont été recrutés. Ils ont subi les 10 tâches de la batterie EMCS, à savoir les modalités verbales et non verbales. Pour explorer la sensibilité de la batterie, trois patients AS, deux APPvs et deux MA au stade débutant de la maladie ont réalisé l’EMCS. Analyses et résultats : Les analyses statistiques ont permis d’établir des données normatives, avec des scores en percentiles, et ont mis en évidence, pour les témoins, un effet du niveau d’éducation pour la majorité des tests, un effet d’âge pour plusieurs tâches, mais pas d’effet de sexe. Pour chaque patient, les résultats se sont montrés discriminants par rapport au groupe témoin de référence pour plusieurs tâches, à savoir la dénomination d’images, les connaissances sémantiques sur les célébrités et l’épreuve gustative (p < 0,05). Discussion / Conclusion : La batterie EMCS peut contribuer à identifier, en un temps relativement court, des troubles sémantiques multimodaux chez des patients souffrant d’aphasie vasculaire et dégénérative. Ainsi, cet outil peut être une aide au diagnostic clinique et offre au clinicien la possibilité de déterminer, à un stade précoce, la nature de l’atteinte sémantique (accès ou centrale).

Nonfluent Variant Primary Progressive Aphasia on FDG, 11 C-PIB, and 18 F-APN-1607 PET Imaging.

A 61-year-old right-handed man presented with decreased cognitive function, short-term memory, fluent speech disorders, and grammatical errors for 1 year. The patient underwent PET imaging with 11 C-PIB, 18 F-FDG, and 18 F-APN-1607. The 11 C-PIB PET showed no amyloid accumulation; the 18 F-FDG PET showed hypometabolism in the bilateral frontal lobe, temporal lobe, and midbrain; and the 18 F-APN-1607 PET showed tau accumulation in the brainstem, basal ganglia, and left inferior frontal gyrus. These findings suggested a diagnosis of nonfluent variant primary progressive aphasia. This case emphasizes the value of combined imaging of glucose metabolism, Aβ, and tau PET in the diagnosis of nonfluent variant primary progressive aphasia.

Racial Differences in Clinical Presentation in Individuals Diagnosed With Frontotemporal Dementia

Prior research suggests there are racial disparities in the presentation of dementia, but this has not been investigated in the context of frontotemporal dementia (FTD). To explore racial disparities in dementia severity, functional impairment, and neuropsychiatric symptoms in individuals with a diagnosis of FTD. This exploratory cross-sectional study of National Alzheimer's Coordinating Center (NACC) data collected between June 2005 to August 2021 evaluated Asian, Black, and White individuals with a diagnosis of FTD (behavioral variant FTD or primary progressive aphasia). Excluded were races with limited data, including American Indian or Alaska Native (n = 4), Native Hawaiian or other Pacific Islander (n = 3), other (n = 13), and unknown (n = 24), and participants with symptom duration more than 4 SDs above the mean. Racial differences at initial NACC visit were examined on Clinical Dementia Rating Dementia Staging Instrument plus NACC Frontotemporal Lobar Degeneration Behavior & Language Domains (FTLD-CDR), Functional Assessment Scale, and Neuropsychiatric Inventory using regression models. Matching was also performed to address the imbalance between racial groups. The final sample comprised 2478 individuals, of which 59 (2.4%) were Asian, 63 (2.5%) were Black, and 2356 (95.1%) were White. The mean (SD) age at initial visit was 65.3 (9.4) years and symptom duration at initial visit was 67.5 (35.6) months. Asian and Black individuals were considerably underrepresented, comprising a small percent of the sample. Black individuals had a higher degree of dementia severity on FTLD-CDR (β = 0.64; SE = 0.24; P = .006) and FTLD-CDR sum of boxes (β = 1.21; SE = 0.57; P = .03) and greater functional impairment (β = 3.83; SE = 1.49; P = .01). There were no differences on FTLD-CDR and Functional Assessment Scale between Asian and White individuals. Black individuals were found to exhibit a higher frequency of delusions, agitation, and depression (delusions: odds ratio [OR], 2.18; 95% CI, 1.15-3.93; P = .01; agitation: OR, 1.73; 95% CI, 1.03-2.93; P = .04; depression: OR, 1.75; 95% CI, 1.05-2.92; P = .03). Asian individuals were found to exhibit a higher frequency of apathy (OR, 1.89; 95% CI, 1.09-3.78; P = .03), nighttime behaviors (OR, 1.72; 95% CI, 1.01-2.91; P = .04), and appetite/eating (OR, 1.99; 95% CI, 1.17-3.47; P = .01) compared to White individuals. This exploratory study suggests there are racial disparities in dementia severity, functional impairment, and neuropsychiatric symptoms. Future work must address racial disparities and their underlying determinants as well as the lack of representation of racially minoritized individuals in nationally representative dementia registries.

The involvement of language-associated networks, tracts, and cortical regions in frontotemporal dementia and amyotrophic lateral sclerosis: Structural and functional alterations.

Language deficits are cardinal manifestations of some frontotemporal dementia (FTD) phenotypes and also increasingly recognized in sporadic and familial amyotrophic lateral sclerosis (ALS). They have considerable social and quality-of-life implications, and adaptive strategies are challenging to implement. While the neuropsychological profiles of ALS-FTD phenotypes are well characterized, the neuronal underpinnings of language deficits are less well studied. A multiparametric, quantitative neuroimaging study was conducted to characterize the involvement of language-associated networks, tracts, and cortical regions with a panel of structural, diffusivity, and functional magnetic resonance imaging (MRI) metrics. Seven study groups were evaluated along the ALS-FTD spectrum: healthy controls (HC), individuals with ALS without cognitive impairment (ALSnci), C9orf72-negative ALS-FTD, C9orf72-positive ALS-FTD, behavioral-variant FTD (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA). The integrity of the Broca's area, Wernicke's area, frontal aslant tract (FAT), arcuate fascicle (AF), inferior occipitofrontal fascicle (IFO), inferior longitudinal fascicle (ILF), superior longitudinal fascicle (SLF), and uncinate fascicle (UF) was quantitatively evaluated. The functional connectivity (FC) between Broca's and Wernicke' areas and FC along the FAT was also specifically assessed. Patients with nfvPPA and svPPA exhibit distinctive patterns of gray and white matter degeneration in language-associated brain regions. Individuals with bvFTD exhibit Broca's area, right FAT, right IFO, and UF degeneration. The ALSnci group exhibits Broca's area atrophy and decreased FC along the FAT. Both ALS-FTD cohorts, irrespective of C9orf72 status, show bilateral FAT, AF, and IFO pathology. Interestingly, only C9orf72-negative ALS-FTD patients exhibit bilateral uncinate and right ILF involvement, while C9orf72-positive ALS-FTD patients do not. Language-associated tracts and networks are not only affected in language-variant FTD phenotypes but also in ALS and bvFTD. Language domains should be routinely assessed in ALS irrespective of the genotype.

Jargonaphasia in logopenic variant primary progressive aphasia

BackgroundLogopenic variant primary progressive aphasia (lvPPA), which is most commonly an early onset variant of Alzheimer's disease (AD), is a progressive impairment in word retrieval and language expression. Clinicians often misdiagnose these patients when they present with severely unintelligible speech consistent with jargonaphasia. MethodsWe reviewed all patients presenting to a behavioral neurology program over a 23-year period who met criteria for lvPPA after completion of an evaluation extending to positron emission tomography (PET) of the brain. Among these lvPPA patients, we additionally identified and characterized those whose presentation involved incomprehensible yet fluent verbal output. ResultsOut of 95 patients with lvPPA, 9 (9.47%) had jargonaphasia on presentation. These patients differed from the remaining 86 patients in lacking awareness or concern for their impaired communication, having worse mental status scale scores, greater auditory comprehension difficulty, and more bilateral temporo-parietal hypometabolism. In addition, 44.4% of those with jargonaphasia, compared to 14% of those without, were bi/multilingual. ConclusionNearly 1 in 10 patients with lvPPA present with severely unintelligible speech. These patients have disease extending to bilateral temporoparietal areas affecting language comprehension and disease awareness. Jargonaphasia can be a confusing presentation of AD and must be differentiated from other progressive aphasias, Wernicke's aphasia, and the word salad of “schizoaphasia”.

The impact of phonological short-term memory impairment on verbal repetition in the logopenic variant of primary progressive aphasia

ABSTRACT The logopenic variant of primary progressive aphasia (lvPPA) is characterized mainly by anomia, production of phonological errors, and impairment in repetition of sentences. The functional origin of these language impairments is mainly attributed to the breakdown of phonological short-term memory. The present study examined the effects of phonological short-term memory impairment on language processing in lvPPA. In two studies, 11 participants with lvPPA and 11 healthy control participants were presented with repetition tasks in which the type and length of stimuli and the mode of administration were manipulated. Study 1 aimed to examine the influence of length and lexicality (words vs. pseudowords) on immediate and delayed repetition, whereas Study 2 aimed to examine the influence of length, syntactic complexity (nominalized vs. pronominalized sentences), and serial position on immediate sentence repetition. Study 1 showed that participants’ performance with lvPPA was impaired only on immediate repetition of five-syllable pseudowords and on delayed repetition of words and pseudowords. Study 2 showed that participants’ performance with lvPPA was impaired in the repetition of nominalized sentences where a recency effect was observed. Repetition of pronominalized sentences was also impaired in the lvPPA group. This study provides additional support for arguments regarding phonological short-term memory as a cause of language impairment in lvPPA. Clinically, the results of the study suggest that instruments for assessing repetition ability in lvPPA should include not only lists of short or long nominalized sentences, but also delayed repetition of words and pseudowords and pronominalized sentences.

Auditory phonological identification impairment in primary progressive aphasia

ObjectiveTo examine the audiological characteristics and neuroanatomical regions associated with auditory phonological identification impairment in primary progressive aphasia (PPA). MethodsTwenty-seven patients with PPA [13 non-fluent/agrammatic variant PPA (nfvPPA), three logopenic variant PPA (lvPPA), seven semantic variant PPA (svPPA), and four mixed type PPA] were included in the study. Neuropsychological, language, audiological, and neuroradiological examinations were also performed. Auditory function examinations consisted of a pure-tone threshold test, a phonological identification task, and temporal auditory acuity tests, such as click counting or fusion. As an evaluation value of phonological identification ability, we calculated the discrepancy scores, which were the smaller discrepancy (left or right ear) in phonological identification ability scores between measured and expected values from the pure-tone threshold. In the neuroradiological examination, we evaluated the regional cerebral blood flow using 123I-iodoamphetamine single-photon emission computed tomography. ResultsEight of the 27 patients were allocated to the impaired phonological identification group, and four were considered to have significant impairment on further analysis. Two of these patients, one with lvPPA and one with mixed type of lvPPA and nfvPPA, showed apparent phonological identification deficits that could be observed in daily life. The discrepancy scores were not significantly related to the results of neuropsychological, language, or any other auditory examinations, except for the click counting score in the left ear. Voxel-based correlation analyses revealed that regional cerebral blood flow in the bilateral superior temporal gyrus and bilateral primary auditory cortex was significantly and positively correlated with phonological identification ability. ConclusionsOur results suggest that progressive dysfunction of the bilateral superior temporal gyrus and bilateral primary auditory cortex due to neurodegenerative diseases leads to phonological identification impairment in PPA syndrome.

A heterozygous splicing variant IVS9-7A > T in intron 9 of the MAPT gene in a patient with right-temporal variant frontotemporal dementia with atypical 4 repeat tauopathy

Right temporal variant frontotemporal dementia, also called right-predominant semantic dementia, often has an unclear position within the framework of the updated diagnostic criteria for behavioral variant frontotemporal dementia or primary progressive aphasia. Recent studies have suggested that this population may be clinically, neuropathologically, and genetically distinct from those with behavioral variant frontotemporal dementia or left-predominant typical semantic variant primary progressive aphasia. Here we describe a Japanese case of right temporal variant frontotemporal dementia with novel heterozygous MAPT mutation Adenine to Thymidine in intervening sequence (IVS) 9 at position -7 from 3ʹ splicing site of intron 9/exon 10 boundary (MAPT IVS9-7A > T). Postmortem neuropathological analysis revealed a predominant accumulation of 4 repeat tau, especially in the temporal lobe, amygdala, and substantia nigra, but lacked astrocytic plaques or tufted astrocytes. Immunoelectron microscopy of the tau filaments extracted from the brain revealed a ribbon-like structure. Moreover, a cellular MAPT splicing assay confirmed that this novel variant promoted the inclusion of exon 10, resulting in the predominant production of 4 repeat tau. These data strongly suggest that the MAPT IVS9-7 A > T variant found in our case is a novel mutation that stimulates the inclusion of exon 10 through alternative splicing of MAPT transcript and causes predominant 4 repeat tauopathy which clinically presents as right temporal variant frontotemporal dementia.

Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia.

Here we set out to create a symptom-led staging system for the canonical semantic and non-fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias. An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed-methods sequential explanatory design. Both PPA syndromes were characterized by initial communication dysfunction and non-verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages. Milestone symptoms were distilled to create a prototypical progression and severity scale of functional impairment: the PPA Progression Planning Aid ("PPA-Squared"). This work introduces a symptom-led staging scheme and functional scale for semantic and non-fluent/agrammatic variants of PPA. Our findings have implications for diagnostic and care pathway guidelines, trial design, and personalized prognosis and treatment for PPA. We introduce new symptom-led perspectives on primary progressive aphasia (PPA). The focus is on non-fluent/agrammatic (nfvPPA) and semantic (svPPA) variants. Foregrounding of early and non-verbal features of PPA and clinical trajectories is featured. We introduce a symptom-led staging scheme for PPA. We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid.

Cortical signature of depressive symptoms in frontotemporal dementia: A surface-based analysis.

Depressive symptoms are frequently reported in patients affected by frontotemporal dementia (FTD). At structural MRI, cortical features of depressed FTD patients have been poorly described. Our objective was to investigate correlations between cortical measures and depression severity in FTD patients. Data were obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI) database. We included 98 controls and 92 FTD patients, n = 38 behavioral variant FTD (bvFTD), n = 26 non-fluent variant Primary Progressive Aphasia (nfvPPA), and n = 28 semantic variant Primary Progressive Aphasia (svPPA). Patients underwent clinical and cognitive evaluations, as well as a 3D T1-weighted MRI on a 3 Tesla scanner (Siemens, Trio Tim system). Depression was evaluated by means of Geriatric Depression Scale (GDS). Surface-based analysis was performed on T1-weighted images to evaluate cortical thickness, a measure of gray matter integrity, and local gyrification index (lGI), a quantitative metric of cortical folding. Patients affected by svPPA were more depressed than controls at NPI and depression severity at GDS was higher in svPPA and bvFTD. Severity of depression correlated with a decrease in lGI in left precentral and superior frontal gyrus, supramarginal and postcentral gyrus and right precentral, supramarginal, superior parietal and superior frontal gyri. Furthermore, depression severity correlated positively with cortical thickness in the left medial orbitofrontal cortex. We found that lGI was associated with depressive symptoms over brain regions involved in the pathophysiology of major depressive disorder. This finding provides novel insights into the mechanisms underlying psychiatric symptoms in FTD.

Distinct neurophysiology during nonword repetition in logopenic and non-fluent variants of primary progressive aphasia.

Overlapping clinical presentations in primary progressive aphasia (PPA) variants present challenges for diagnosis and understanding pathophysiology, particularly in the early stages of the disease when behavioral (speech) symptoms are not clearly evident. Divergent atrophy patterns (temporoparietal degeneration in logopenic variant lvPPA, frontal degeneration in nonfluent variant nfvPPA) can partially account for differential speech production errors in the two groups in the later stages of the disease. While the existing dogma states that neurodegeneration is the root cause of compromised behavior and cortical activity in PPA, the extent to which neurophysiological signatures of speech dysfunction manifest independent of their divergent atrophy patterns remain unknown. We test the hypothesis that nonword deficits in lvPPA and nfvPPA arise from distinct patterns of neural oscillations that are unrelated to atrophy. We use a novel structure-function imaging approach integrating magnetoencephalographic imaging of neural oscillations during a non-word repetition task with voxel-based morphometry-derived measures of gray matter volume to isolate neural oscillation abnormalities independent of atrophy. We find reduced beta band neural activity in left temporal regions associated with the late stages of auditory encoding unique to patients with lvPPA and reduced high-gamma neural activity over left frontal regions associated with the early stages of motor preparation in patients with nfvPPA. Neither of these patterns of reduced cortical oscillations was explained by cortical atrophy in our statistical model. These findings highlight the importance of structure-function imaging in revealing neurophysiological sequelae in early stages of dementia when neither structural atrophy nor behavioral deficits are clinically distinct.

Expressive Prosody in Patients With Focal Anterior Temporal Neurodegeneration.

Progressive focal anterior temporal lobe (ATL) neurodegeneration has been historically called semantic dementia. More recently, semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) have been linked with predominant left and right ATL neurodegeneration, respectively. Nonetheless, clinical tools for an accurate diagnosis of sbvFTD are still lacking. Expressive prosody refers to the modulation of pitch, loudness, tempo, and quality of voice used to convey emotional and linguistic information and has been linked to bilateral but right-predominant frontotemporal functioning. Changes in expressive prosody can be detected with semiautomated methods and could represent a useful diagnostic marker of socioemotional functioning in sbvFTD. Participants underwent a comprehensive neuropsychological and language evaluation and a 3T MRI at the University of California San Francisco. Each participant provided a verbal description of the picnic scene from the Western Aphasia Battery. The fundamental frequency (f0) range, an acoustic measure of pitch variability, was extracted for each participant. We compared the f0 range between groups and investigated associations with an informant-rated measure of empathy, a facial emotion labeling task, and gray matter (GM) volumes using voxel-based morphometry. Twenty-eight patients with svPPA, 18 with sbvFTD, and 18 healthy controls (HCs) were included. f0 range was significantly different across groups: patients with sbvFTD showed reduced f0 range in comparison with both patients with svPPA (mean difference of -1.4 ± 2.4 semitones; 95% CI -2.4 to -0.4]; p < 0.005) and HCs (mean difference of -1.9 ± 3.0 semitones; 95% CI -3.0 to -0.7]; p < 0.001). A higher f0 range was correlated with a greater informant-rated empathy (r = 0.355; p ≤ 0.05), but not facial emotion labeling. Finally, the lower f0 range was correlated with lower GM volume in the right superior temporal gyrus, encompassing anterior and posterior portions (p < 0.05 FWE cluster corrected). Expressive prosody may be a useful clinical marker of sbvFTD. Reduced empathy is a core symptom in sbvFTD; the present results extend this to prosody, a core component of social interaction, at the intersection of speech and emotion. They also inform the long-standing debate on the lateralization of expressive prosody in the brain, highlighting the critical role of the right superior temporal lobe.

Automated analysis of written language in the three variants of primary progressive aphasia.

Despite the important role of written language in everyday life, abnormalities in functional written communication have been sparsely investigated in primary progressive aphasia. Prior studies have analysed written language separately in each of the three variants of primary progressive aphasia-but have rarely compared them to each other or to spoken language. Manual analysis of written language can be a time-consuming process. We therefore developed a program that quantifies content units and total units in written or transcribed language samples. We analysed written and spoken descriptions of the Western Aphasia Battery picnic scene, based on a predefined content unit corpus. We calculated the ratio of content units to units as a measure of content density. Our cohort included 115 participants (20 controls for written, 20 controls for spoken, 28 participants with nonfluent variant primary progressive aphasia, 30 for logopenic variant and 17 for semantic variant). Our program identified content units with a validity of 99.7% (95%CI 99.5-99.8). All patients wrote fewer units than controls (P < 0.001). Patients with the logopenic variant (P = 0.013) and the semantic variant (0.004) wrote fewer content units than controls. The content unit-to-unit ratio was higher in the nonfluent and semantic variants than controls (P = 0.019), but no difference in the logopenic variant (P = 0.962). Participants with the logopenic (P < 0.001) and semantic (P = 0.04) variants produced fewer content units in written compared to spoken descriptions. All variants produced fewer units in written samples compared to spoken (P < 0.001). However, due to a relatively smaller decrease in written content units, we observed a larger content unit-to-unit ratio in writing over speech (P < 0.001). Written and spoken content units (r = 0.5, P = 0.009) and total units (r = 0.64, P < 0.001) were significantly correlated in patients with nonfluent variant, but this was not the case for logopenic or semantic. Considering all patients with primary progressive aphasia, fewer content units were produced in those with greater aphasia severity (Progressive Aphasia Severity Scale Sum of Boxes, r = -0.24, P = 0.04) and dementia severity (Clinical Dementia Rating scale Sum of Boxes, r = -0.34, P = 0.004). In conclusion, we observed reduced written content in patients with primary progressive aphasia compared to controls, with a preference for content over non-content units in patients with the nonfluent and semantic variants. We observed a similar 'telegraphic' style in both language modalities in patients with the nonfluent variant. Lastly, we show how our program provides a time-efficient tool, which could enable feedback and tracking of writing as an important feature of language and cognition.

Composite Indices of the Color-Picture Version of Boston Naming Test Have Better Discriminatory Power: Reliability and Validity in a Chinese Sample with Diverse Neurodegenerative Diseases.

The Boston Naming Test (BNT) is the most widely used measure to assess anomia. However, it has been criticized for failing to differentiate the underlying cognitive process of anomia. We validated the color-picture version of BNT (CP-BNT) in a sample with diverse neurodegenerative dementia diseases (NDDs). We also verified the differential ability of the composite indices of CP-BNT across NDDs groups. The present study included Alzheimer's disease (n = 132), semantic variant primary progressive aphasia (svPPA, n = 53), non-svPPA (n = 33), posterior cortical atrophy (PCA, n = 35), and normal controls (n = 110). We evaluated psychometric properties of CP-BNT for the spontaneous naming (SN), the percentage of correct responses on semantic cuing and word recognition cuing (% SC, % WR). Receiver operating characteristic analysis was used to examine the discriminatory power of SN alone and the composite indices (SN, % SC, and % WR). The CP-BNT had sufficient internal consistency, good convergent, divergent validity, and criterion validity. Different indices of CP-BNT demonstrated distinct cognitive underpinnings. Category fluency was the strongest predictor of SN (β= 0.46, p < 0.001). Auditory comprehension tests highly associated with % WR (Sentence comprehension: β= 0.22, p = 0.001; Word comprehension: β= 0.20, p = 0.001), whereas a lower visuospatial score predicted % SC (β= -0.2, p = 0.001). Composite indices had better predictability than the SN alone when differentiating between NDDs, especially for PCA versus non-svPPA (area under the curve increased from 63.9% to 81.2%). The CP-BNT is a highly linguistically relevant test with sufficient reliability and validity. Composite indices could provide more differential information beyond SN and should be used in clinical practice.