Baseline structural imaging correlates of treatment outcomes in semantic variant primary progressive aphasia.

Semantic variant primary progressive aphasia (svPPA) is a neurodegenerative disorder characterized by a loss of semantic knowledge in the context of anterior temporal lobe atrophy (left > right). Core features of svPPA include anomia and single-word comprehension impairment. Despite growing evidence supporting treatment for anomia in svPPA, there is a paucity of research investigating neural mechanisms supporting treatment-induced gains and generalization to untrained items. In the current study, we examined the relation between the structural integrity of brain parenchyma (tissue inclusive of gray and white matter) at pre-treatment and treatment outcomes for trained and untrained items in a group of 19 individuals with svPPA who completed lexical retrieval treatment. Two structural neuroimaging approaches were used: an exploratory, whole-brain, voxel-wise approach and an a priori region of interest (ROI) approach. Based on previous research, bilateral temporal (inferior, middle, and superior temporal gyri), parietal (supramarginal and angular gyri), frontal (inferior and middle frontal gyri) and medial temporal (hippocampus and parahippocampal gyri) ROIs were selected from the Automated Anatomical Labeling (AAL) atlas. Analyses revealed improved naming of trained items and generalization to untrained items following treatment, providing converging evidence that individuals with svPPA can benefit from treatment for anomia. Better post-treatment naming accuracy was associated with the structural integrity of inferior parietal cortex and the hippocampus. Specifically, improved naming of trained items was related to the left supramarginal (phonological processing) and angular gyri (phonological and semantic processing), and improved naming of trained and untrained items was related to the left hippocampus (episodic, context-based memory). Future research should examine treatment outcomes in relation to pre-treatment functional and structural connectivity as well as changes in network dynamics following speech-language intervention to further elucidate the neural mechanisms underlying treatment response in svPPA and related disorders.

Verbal Semantics and the Left Dorsolateral Anterior Temporal Lobe: A Longitudinal Case of Bilateral Temporal Degeneration.

BACKGROUND: Semantic variant primary progressive aphasia (svPPA), a clinical syndrome characterized by loss of semantic knowledge, is associated with neurodegeneration that starts in the anterior temporal lobe (ATL) and gradually spreads towards posterior temporal and medial frontal areas. At the earliest stages, atrophy may be predominantly lateralized to either the left or right ATL, leading to different clinical profiles with greatest impairment of word comprehension or visual/social semantics, respectively. METHODS & PROCEDURES: We report the in-depth longitudinal investigation of cognitive and neuroanatomical features of JB, an unusual case of ATL neurodegeneration with relative sparing of left lateral ATL regions. OUTCOMES & RESULTS: Over the course of nine years, neurodegeneration progressed to involve bilateral temporo-lateral and frontal regions, resulting in a relatively symmetric and diffuse frontotemporal atrophy pattern. In parallel, JB developed greater behavioral, cognitive, and language impairments, as well as signs of motor neuron disease at her last evaluation. Episodic memory and socio-emotional processing deficits arose, likely secondary to semantic verbal deficits, while visuospatial processing, executive function, and non-semantic language abilities remained largely unaffected throughout the course of the disease. CONCLUSIONS: The details of this rare case of early medial more than lateral ATL degeneration are consistent with a bilateral organization of the semantic system and, crucially, with a functional dissociation between medial paralimbic and lateral neocortical temporal regions. Cases of frontotemporal dementia (FTD) such as JB, who initially do not meet current clinical criteria for svPPA and instead present with some features of behavioral variant FTD, highlight the need for specific criteria for the right temporal variant of FTD that we propose could be called semantic variant FTD.

Speech production differences in English and Italian speakers with nonfluent variant PPA.

OBJECTIVE: To understand whether the clinical phenotype of nonfluent/agrammatic primary progressive aphasia (nfvPPA) could present differences depending on the patient's native language. METHODS: In this cross-sectional study, we analyzed connected speech samples in monolingual English (nfvPPA-E) and Italian speakers (nfvPPA-I) who were diagnosed with nfvPPA and matched for age, sex, and Mini-Mental State Examination scores. Patients also received a comprehensive neuropsychological battery. All patients and 2 groups of age-matched healthy controls underwent an MRI scan with 3D T1-weighted sequences. Connected speech measures and the other cognitive features were compared between patient groups. MRI variables, in terms of gray matter volume, were compared between each patient group and the corresponding controls. RESULTS: Compared to nfvPPA-E, nfvPPA-I had fewer years of education and shorter reported disease duration. The 2 groups showed similar regional atrophy compatible with clinical diagnosis. Patients did not differ in nonlanguage domains, comprising executive scores. Connected speech sample analysis showed that nfvPPA-E had significantly more distortions than nfvPPA-I, while nfvPPA-I showed reduced scores in some measures of syntactic complexity. On language measures, Italian speakers performed more poorly on syntactic comprehension. CONCLUSIONS: nfvPPA-E showed greater motor speech impairment than nfvPPA-I despite higher level of education and comparable disease severity and atrophy changes. The data also suggest greater grammatical impairment in nfvPPA-I. This study illustrates the need to take into account the possible effect of the individual's spoken language on the phenotype and clinical presentation of primary progressive aphasia variants.

Moving Toward Non-transcription based Discourse Analysis in Stable and Progressive Aphasia.

Measurement of communication ability at the discourse level holds promise for predicting how well persons with stable (e.g., stroke-induced), or progressive aphasia navigate everyday communicative interactions. However, barriers to the clinical utilization of discourse measures have persisted. Recent advancements in the standardization of elicitation protocols and the existence of large databases for development of normative references have begun to address some of these barriers. Still, time remains a consistently reported barrier by clinicians. Non-transcription based discourse measurement would reduce the time required for discourse analysis, making clinical utilization a reality. The purpose of this article is to present evidence regarding discourse measures (main concept analysis, core lexicon, and derived efficiency scores) that are well suited to non-transcription based analysis. Combined with previous research, our results suggest that these measures are sensitive to changes following stroke or neurodegenerative disease. Given the evidence, further research specifically assessing the reliability of these measures in clinical implementation is warranted.

Can Script Training Improve Narrative and Conversation in Aphasia across Etiology?

Script training is an effective treatment of stable (e.g., stroke-induced) and progressive aphasia of varying severities and subtypes. The theoretical underpinnings of script training are discussed and include fluency-inducing conditions, speech shadowing, principles of neuroplasticity, and automatization. Script training outcomes are reviewed, with a focus on discourse in persons with stable aphasia (PWSAs) and in persons with primary progressive aphasia (PWPPAs). PWSAs and PWPPAs are able to acquire and maintain short scripted monologues or conversational dialogues, with some evidence of generalization to untrained topics and settings. Advances in both technology and access have enriched script training protocols, so they now range from no-tech written script approaches to high-tech audiovisual support and avatars. Advances in audio and/or visual support promote large amounts of practice of less errorful whole-message language processing during a fluent language inducing condition. With enough practice, users decrease reliance on supports and independently produce scripted content. Script training can be delivered in a variety of settings (individual, group, telepractice), lends itself well to homework programs, and is in accordance with the principles of neuroplasticity for neurorehabilitation. Incorporating script training into therapy programming is advantageous throughout aphasia recovery following brain injuries such as stroke. It is also beneficial for persons with progressive disease for prophylaxis, remediation, and compensation. Recommendations for implementing script training in clinical practice and future research directions are presented.

Semantic and lexical features of words dissimilarly affected by non-fluent, logopenic, and semantic primary progressive aphasia.

OBJECTIVE: To determine the effect of three psycholinguistic variables-lexical frequency, age of acquisition (AoA), and neighborhood density (ND)-on lexical-semantic processing in individuals with non-fluent (nfvPPA), logopenic (lvPPA), and semantic primary progressive aphasia (svPPA). Identifying the scope and independence of these features can provide valuable information about the organization of words in our mind and brain. METHOD: We administered a lexical decision task-with words carefully selected to permit distinguishing lexical frequency, AoA, and orthographic ND effects-to 41 individuals with PPA (13 nfvPPA, 14 lvPPA, 14 svPPA) and 25 controls. RESULTS: Of the psycholinguistic variables studied, lexical frequency had the largest influence on lexical-semantic processing, but AoA and ND also played an independent role. The results reflect a brain-language relationship with different proportional effects of frequency, AoA, and ND in the PPA variants, in a pattern that is consistent with the organization of the mental lexicon. Individuals with nfvPPA and lvPPA experienced an ND effect consistent with the role of inferior frontal and temporoparietal regions in lexical analysis and word form processing. By contrast, individuals with svPPA experienced an AoA effect consistent with the role of the anterior temporal lobe in semantic processing. CONCLUSIONS: The findings are in line with a hierarchical mental lexicon structure with a conceptual (semantic) and a lexeme (word-form) level, such that a selective deficit at one of these levels of the mental lexicon manifests differently in lexical-semantic processing performance, consistent with the affected language-specific brain region in each PPA variant.

Treatment for Word Retrieval in Semantic and Logopenic Variants of Primary Progressive Aphasia: Immediate and Long-Term Outcomes.

Purpose Recent studies confirm the utility of speech-language intervention in primary progressive aphasia (PPA); however, long-term outcomes, ideal dosage parameters, and relative benefits of intervention across clinical variants warrant additional investigation. The purpose of this study was to determine whether naming treatment affords significant, lasting, and generalized improvement for individuals with semantic and logopenic PPA and whether dosage manipulations significantly affect treatment outcomes. Method Eighteen individuals with PPA (9 semantic and 9 logopenic variant) underwent lexical retrieval treatment designed to leverage spared cognitive-linguistic domains and develop self-cueing strategies to promote naming. One group (n = 10) underwent once-weekly treatment sessions, and the other group (n = 8) received the same treatment with 2 sessions per week and an additional "booster" treatment phase at 3 months post-treatment. Performance on trained and untrained targets/tasks was measured immediately after treatment and at 3, 6, and 12 months post-treatment. Results Outcomes from the full cohort of individuals with PPA showed significantly improved naming of trained items immediately post-treatment and at all follow-up assessments through 1 year. Generalized improvement on untrained items was significant up to 6 months post-treatment. The positive response to treatment was comparable regardless of session frequency or inclusion of a booster phase. Outcomes were comparable across PPA subtypes, as was maintenance of gains over the post-treatment period. Conclusion This study documents positive naming treatment outcomes for a group of individuals with PPA, demonstrating strong direct treatment effects, maintenance of gains up to 1 year post-treatment, and generalization to untrained items. Lexical retrieval treatment, in conjunction with daily home practice, had a strong positive effect that did not require more than 1 clinician-directed treatment session per week. Findings confirm that strategic training designed to capitalize on spared cognitive-linguistic abilities results in significant and lasting improvement, despite ongoing disease progression, in PPA.

Aprosodia and prosoplegia with right frontal neurodegeneration.

Affective prosody and facial expression are essential components of human communication. Aprosodic syndromes are associated with focal right cerebral lesions that impair the affective-prosodic aspects of language, but are rarely identified because affective prosody is not routinely assessed by clinicians. Inability to produce emotional faces (affective prosoplegia) is a related and important aspect of affective communication has overlapping neuroanatomic substrates with affective prosody. We describe a patient with progressive aprosodia and prosoplegia who had right greater than left perisylvian and temporal atrophy with an anterior predominance. We discuss the importance of assessing affective prosody and facial expression to arrive at an accurate clinical diagnosis.

Neurocognitive basis of repetition deficits in primary progressive aphasia.

Previous studies indicate that repetition is affected in primary progressive aphasia (PPA), particularly in the logopenic variant, due to limited auditory-verbal short-term memory (avSTM). We tested repetition of phrases varied by length (short, long) and meaning (meaningful, non-meaningful) in 58 participants (22 logopenic, 19 nonfluent, and 17 semantic variants) and 21 healthy controls using a modified Bayles repetition test. We evaluated the relation between cortical thickness and repetition performance and whether sub-scores could discriminate PPA variants. Logopenic participants showed impaired repetition across all phrases, specifically in repeating long phrases and any phrases that were non-meaningful. Nonfluent, semantic, and healthy control participants only had difficulty repeating long, non-meaningful phrases. Poor repetition of long phrases was associated with cortical thinning in left temporo-parietal areas across all variants, highlighting the importance of these areas in avSTM. Finally, Bayles repetition phrases can assist classification in PPA, discriminating logopenic from nonfluent/semantic participants with 89% accuracy.

Investigating the utility of teletherapy in individuals with primary progressive aphasia.

INTRODUCTION: Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by progressive deterioration of speech and language. A growing body of research supports the utility of speech and language intervention in individuals with PPA, although access to these services remains limited. One potential means of increasing treatment accessibility is the delivery of treatment via telemedicine. Evidence supports the use of teletherapy in stroke-induced aphasia, but research examining the application of teletherapy in PPA is limited. In the current study, a non-randomized group comparison design was used to evaluate the feasibility and utility of treatment delivered via teletherapy relative to treatment administered in person for individuals with PPA. METHODS: Two treatment protocols were administered as part of a larger study investigating treatment for speech and language deficits in PPA. Participants with semantic (n=10) and logopenic (n=11) PPA received lexical retrieval treatment and individuals with nonfluent/agrammatic PPA (n=10) received video-implemented script training for aphasia designed to promote speech production and fluency. Treatment was administered via teletherapy for approximately half of the participants receiving each intervention. Treatment outcomes and performance on standardized tests were assessed at pre-treatment and post-treatment, as well as 3, 6, and 12 months post-treatment. RESULTS: Overall, both treatment approaches resulted in significant gains for primary outcome measures. Critically, comparison of in-person and teletherapy groups revealed comparable outcomes. Generalization to untrained targets and tasks and maintenance of treatment-induced gains were also comparable for traditional vs teletherapy participants. CONCLUSION: Overall, treatment outcomes were largely equivalent for individuals receiving treatment via teletherapy vs traditional, in-person delivery. Results support the application of teletherapy for administering restitutive interventions to individuals with mild-to-moderate PPA. Potential implications for using teletherapy in the treatment of cognitive-linguistic and motoric impairments in other disorders and suggestions for administering treatment via telemedicine are discussed.

Primary progressive aphasia and the FTD-MND spectrum disorders: clinical, pathological, and neuroimaging correlates.

Objective: Behavioral variant frontotemporal dementia (bvFTD), is commonly considered the cognitive presentation of the frontotemporal dementia-motor neuron disease (FTD-MND) spectrum disorder. We evaluated the prevalence of primary progressive aphasia in a series of pathologically confirmed cases of FTD-MND spectrum. Methods: Pathologically confirmed cases of frontotemporal lobar degeneration-motor neuron disease (FTLD-MND) were obtained from the UCSF brain bank. Cases were analyzed for presence of language impairment via retrospective chart review of research visits that include neurologic exam, in-depth cognitive testing and magnetic resonance imaging (MRI) imaging. Forty one cases were included. Thirty two were diagnosed with FTD-MND, while nine cases were diagnosed as MND-only from clinical evaluation. Results: Ten FTLD-MND cases (31%) presented with prominent or isolated language involvement consistent with a diagnosis of primary progressive aphasia (PPA), which we called progressive aphasia with motor neuron disease (PA-MND). Of these, three cases that mirrored the non-fluent variant of PPA (nfvPPA) were named nfvPA-MND. The imaging pattern of these nfvPA-MND showed atrophy strictly confined to the frontal and anterior temporal language cortical areas. Another group of seven cases that resembled patients with the semantic variant PPA (svPPA) were named svPA-MND. The group of svPPA-MND on imaging analysis showed selective atrophy of the temporal lobe and orbitofrontal cortex. Conclusions: Language impairment was a frequent phenotype of FTD-MND associated with focal atrophy patterns within the language networks. This data suggest patients with FTD-MND can present quite often with language phenotype of nfvPPA and svPPA, as opposed to exclusive bvFTD symptoms.

Dementia and Hearing Loss: Interrelationships and Treatment Considerations.

Hearing loss is common among typically aging older adults and those with dementia. In recent years, there has been a renewed interest in the relationship between hearing and cognition among older adults, and in hearing loss as a modifiable risk factor for dementia. However, relatively less attention has been focused on the management of hearing loss among individuals with dementia and the key roles of speech-language pathologists and audiologists in providing such care. In this article, the authors review the literature on hearing loss and dementia, and analyze the research evidence for treatment of hearing loss in the context of major neurocognitive disorders, such as Alzheimer's disease. This article provides an up-to-date review of research evidence for hearing interventions, as well as recommendations for speech-language pathologists and audiologists to work together to ensure access to hearing health care and increased opportunities for meaningful life engagement for people with dementia and hearing loss.

The Impact of Aphasia Camp Participation on Quality of Life: A Primary Progressive Aphasia Perspective.

Individuals with primary progressive aphasia (PPA) and their caregivers are at risk for decreased quality of life (QoL) due to their progressive condition. Aphasia camps are an intervention that can improve QoL, yet individuals with PPA are underrepresented at aphasia camps relative to those with poststroke aphasia. The purpose of this exploratory case study was to examine the effect of participation in aphasia camp on the QoL of a couple impacted by PPA. The Living with Aphasia: Framework for Outcome Measurement (A-FROM) was used to guide a semistructured interview with an individual with PPA and her spouse, both of whom had attended the Alberta Aphasia Camp for 4 years. Conventional content analysis with an inductive approach was used to analyze results. Concepts that emerged from the interview were organized into pre-camp, during, and post-camp categories. Aspects of camp that had an effect on post-camp QoL for this couple with PPA included expanding social connections and introduction to new activities. Personal characteristics exhibited by the couple had an impact on their experience of aphasia camp and how they incorporated their experiences into their everyday lives post-camp. Aphasia camps are a participation-based service approach that can benefit people with aphasia regardless of etiology. A consideration of personal factors of potential campers with PPA, and the provision of PPA-specific resources, is recommended for programs such as aphasia camps that incorporate participants with mixed etiologies.

Retraining speech production and fluency in non-fluent/agrammatic primary progressive aphasia.

The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) presents with a gradual decline in grammar and motor speech resulting from selective degeneration of speech-language regions in the brain. There has been considerable progress in identifying treatment approaches to remediate language deficits in other primary progressive aphasia variants; however, interventions for the core deficits in nfvPPA have yet to be systematically investigated. Further, the neural mechanisms that support behavioural restitution in the context of neurodegeneration are not well understood. We examined the immediate and long-term benefits of video implemented script training for aphasia (VISTA) in 10 individuals with nfvPPA. The treatment approach involved repeated rehearsal of individualized scripts via structured treatment with a clinician as well as intensive home practice with an audiovisual model using 'speech entrainment'. We evaluated accuracy of script production as well as overall intelligibility and grammaticality for trained and untrained scripts. These measures and standardized test scores were collected at post-treatment and 3-, 6-, and 12-month follow-up visits. Treatment resulted in significant improvement in production of correct, intelligible scripted words for trained topics, a reduction in grammatical errors for trained topics, and an overall increase in intelligibility for trained as well as untrained topics at post-treatment. Follow-up testing revealed maintenance of gains for trained scripts up to 1 year post-treatment on the primary outcome measure. Performance on untrained scripts and standardized tests remained relatively stable during the follow-up period, indicating that treatment helped to stabilize speech and language despite disease progression. To identify neural predictors of responsiveness to intervention, we examined treatment effect sizes relative to grey matter volumes in regions of interest derived from a previously identified speech production network. Regions of significant atrophy within this network included bilateral inferior frontal cortices and supplementary motor area as well as left striatum. Volumes in a left middle/inferior temporal region of interest were significantly correlated with the magnitude of treatment effects. This region, which was relatively spared anatomically in nfvPPA patients, has been implicated in syntactic production as well as visuo-motor facilitation of speech. This is the first group study to document the benefits of behavioural intervention that targets both linguistic and motoric deficits in nfvPPA. Findings indicate that behavioural intervention may result in lasting and generalized improvement of communicative function in individuals with neurodegenerative disease and that the integrity of spared regions within the speech-language network may be an important predictor of treatment response.

Prevalence of Mathematical and Visuospatial Learning Disabilities in Patients With Posterior Cortical Atrophy.

Importance: Increased prevalence of language-based learning disabilities (LDs) has been previously reported in patients with primary progressive aphasia (PPA). This study hypothesized that patients with focal neurodegenerative syndromes outside the language network, such as posterior cortical atrophy (PCA), would have a higher rate of nonlanguage LDs, congruent with their mainly visuospatial presentation. Objective: To investigate the prevalence and type of LD (language and/or mathematical and visuospatial) in a large cohort of patients with PCA compared with patients with logopenic variant PPA (lvPPA) and amnestic Alzheimer disease (AD). Design, Setting, and Participants: This case-control study reviewed 279 medical records from a university-based clinic and research center for patients with neurodegenerative diseases for LD history, including patients with PCA (n = 95), patients with lvPPA (n = 84), and a matched cohort with amnestic AD (n = 100). No records were excluded. The study compared cognitive and neuroimaging features of patients with PCA with and without LDs. A review of the records of patients presenting from March 1, 1999, to August 31, 2014, revealed 95 PCA cases and 84 lvPPA cases. Then 100 patients with amnestic AD from this same period were chosen for comparison, matching against the groups for age, sex, and disease severity. Data analysis was performed from September 8, 2013, to November 6, 2017. Main Outcomes and Measures: Prevalence of total LD history and prevalence of language and mathematical or visuospatial LD history across all cohorts. Results: A total of 179 atypical AD cases (95 with PCA and 84 with lvPPA) and 100 disease control cases (amnestic AD) were included in the study. The groups were not statistically different for mean (SD) age at first visit (PCA, 61.9 [7.0] years; lvPPA, 65.1 [8.7] years; amnestic AD, 64.0 [12.6] years; P = .08), mean (SD) age at first symptom (PCA, 57.5 [7.0] years; lvPPA, 61.1 [9.0] years; amnestic AD, 59.6 [13.7] years; P = .06), or sex (PCA, 66.3% female; lvPPA, 56.0% female; amnestic AD, 57.0% female; P = .30) but differed on non-right-hand preference (PCA, 18.3%; lvPPA, 20.2%; amnestic AD, 7.7%; P = .04), race/ethnicity (PCA, 88.3% white; lvPPA, 99.0% white; amnestic AD, 80.0% white; P < .001), and mean (SD) educational level (PCA, 15.7 [3.2] years; lvPPA, 16.2 [3.3] years; amnestic AD, 14.8 [3.5] years; P = .02). A total of 18 of the 95 patients with PCA (18.9%) reported a history of LD, which is greater than the 3 of 100 patients (3.0%) in the amnestic AD cohort (P < .001) and the 10.0% expected rate in the general population (P = .007). In the PCA cohort, 13 of 95 patients (13.7%) had a nonlanguage mathematical and/or visuospatial LD; this rate was greater than that in the amnestic AD (1 of 100 [1.0%]; P < .001) and lvPPA (2 of 84 [2.4%]; P = .006) cohorts and greater than the 6.0% expected general population rate of mathematical LD (P = .003). Compared with the patients with PCA without LDs, the group with LDs had greater preservation of global cognition and a more right-lateralized pattern of atrophy. Conclusions and Relevance: Nonlanguage mathematical and visuospatial LDs were associated with focal, visuospatial predominant neurodegenerative clinical syndromes. This finding supports the hypothesis that neurodevelopmental differences in specific brain networks are associated with phenotypic manifestation of later-life neurodegenerative disease.

Visuospatial Functioning in the Primary Progressive Aphasias.

OBJECTIVES: The aim of this study was to identify whether the three main primary progressive aphasia (PPA) variants would show differential profiles on measures of visuospatial cognition. We hypothesized that the logopenic variant would have the most difficulty across tasks requiring visuospatial and visual memory abilities. METHODS: PPA patients (n=156), diagnosed using current criteria, and controls were tested on a battery of tests tapping different aspects of visuospatial cognition. We compared the groups on an overall visuospatial factor; construction, immediate recall, delayed recall, and executive functioning composites; and on individual tests. Cross-sectional and longitudinal comparisons were made, adjusted for disease severity, age, and education. RESULTS: The logopenic variant had significantly lower scores on the visuospatial factor and the most impaired scores on all composites. The nonfluent variant had significant difficulty on all visuospatial composites except the delayed recall, which differentiated them from the logopenic variant. In contrast, the semantic variants performed poorly only on delayed recall of visual information. The logopenic and nonfluent variants showed decline in figure copying performance over time, whereas in the semantic variant, this skill was remarkably preserved. CONCLUSIONS: This extensive examination of performance on visuospatial tasks in the PPA variants solidifies some previous findings, for example, delayed recall of visual stimuli adds value in differential diagnosis between logopenic variant PPA and nonfluent variant PPA variants, and illuminates the possibility of common mechanisms that underlie both linguistic and non-linguistic deficits in the variants. Furthermore, this is the first study that has investigated visuospatial functioning over time in the PPA variants. (JINS, 2018, 24, 259-268).

Healthy brain connectivity predicts atrophy progression in non-fluent variant of primary progressive aphasia.

Neurodegeneration has been hypothesized to follow predetermined large-scale networks through the trans-synaptic spread of toxic proteins from a syndrome-specific epicentre. To date, no longitudinal neuroimaging study has tested this hypothesis in vivo in frontotemporal dementia spectrum disorders. The aim of this study was to demonstrate that longitudinal progression of atrophy in non-fluent/agrammatic variant primary progressive aphasia spreads over time from a syndrome-specific epicentre to additional regions, based on their connectivity to the epicentre in healthy control subjects. The syndrome-specific epicentre of the non-fluent/agrammatic variant of primary progressive aphasia was derived in a group of 10 mildly affected patients (clinical dementia rating equal to 0) using voxel-based morphometry. From this region, the inferior frontal gyrus (pars opercularis), we derived functional and structural connectivity maps in healthy controls (n = 30) using functional magnetic resonance imaging at rest and diffusion-weighted imaging tractography. Graph theory analysis was applied to derive functional network features. Atrophy progression was calculated using voxel-based morphometry longitudinal analysis on 34 non-fluent/agrammatic patients. Correlation analyses were performed to compare volume changes in patients with connectivity measures of the healthy functional and structural speech/language network. The default mode network was used as a control network. From the epicentre, the healthy functional connectivity network included the left supplementary motor area and the prefrontal, inferior parietal and temporal regions, which were connected through the aslant, superior longitudinal and arcuate fasciculi. Longitudinal grey and white matter changes were found in the left language-related regions and in the right inferior frontal gyrus. Functional connectivity strength in the healthy speech/language network, but not in the default network, correlated with longitudinal grey matter changes in the non-fluent/agrammatic variant of primary progressive aphasia. Graph theoretical analysis of the speech/language network showed that regions with shorter functional paths to the epicentre exhibited greater longitudinal atrophy. The network contained three modules, including a left inferior frontal gyrus/supplementary motor area, which was most strongly connected with the epicentre. The aslant tract was the white matter pathway connecting these two regions and showed the most significant correlation between fractional anisotropy and white matter longitudinal atrophy changes. This study showed that the pattern of longitudinal atrophy progression in the non-fluent/agrammatic variant of primary progressive aphasia relates to the strength of connectivity in pre-determined functional and structural large-scale speech production networks. These findings support the hypothesis that the spread of neurodegeneration occurs by following specific anatomical and functional neuronal network architectures.

Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration.

IMPORTANCE: We provide novel evidence of specific clinical and neuroimaging features that may help for the in vivo prediction of underlying pathology in patients with nonfluent/agrammatic primary progressive aphasia (nfvPPA) and progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) proved by autopsy. OBJECTIVE: To characterize the neurological, cognitive, and neuroimaging features of patients with nfvPPA-in whom either PSP or CBD was eventually confirmed at autopsy-at initial presentation and at 1-year follow-up. DESIGN, SETTING, AND PARTICIPANTS: A prospective longitudinal clinical-pathological study was conducted in a tertiary research clinic that specialized in cognitive disorders. Fourteen patients were evaluated between January 2002 and December 2014. Inclusion criteria for the study were a clinical diagnosis of nfvPPA; the availability of speech, language, and cognitive testing for at least 1 evaluation; magnetic resonance imaging within 6 months of initial evaluation; and a postmortem pathological diagnosis of PSP or CBD. Ten matched healthy control participants were also included. MAIN OUTCOMES AND MEASURES: Clinical, cognitive, and neuroimaging longitudinal data were analyzed to characterize the whole nfvPPA-4-repeat-tau group and identify differences between nfvPPA-PSP and nfvPPA-CBD both at presentation and longitudinally. RESULTS: Patient groups did not differ significantly in age, sex, or handedness (nfvPPA-PSP group: median [interquartile range (IQR)] age, 74 [67-76] years; 1 of 5 male [20%]; 1 of 5 left-handed [20%]; and nfvPPA-CBD group: mean [IQR] age, 65 [54-81] years; 3 of 9 male [33%]; 0 left-handed). Motor speech impairment and left frontal white matter atrophy were the most prominent common features. At presentation, dysarthria (Motor Speech Examination median [IQR] score: nfvPPA-PSP, 4 [2-7]; nfvPPA-CBD, 0 [0-4]; P = .02), depression (Geriatric Depression Scale median [IQR] score: nfvPPA-PSP, 19 [3-28]; nfvPPA-CBD, 4 [0-16]; P = .04), and relatively selective white matter atrophy were typical of the nfvPPA-PSP group, while greater gray matter atrophy and a trend toward greater sentence comprehension deficits (median [IQR] sentence comprehension correct: nfvPPA-PSP, 98% [80-100]; nfvPPA-CBD, 81% [65-98]; P = .08) were found in the nfvPPA-CBD group. At follow-up after 1 year, we observed no significant differences in any speech or language measures. Furthermore, atrophy in patients with PSP progressed within the subcortical/brainstem motor system generating greater oculomotors deficits and swallowing difficulty; atrophy in patients with CBD spread anteriorly in prefrontal regions consistent with their greater working memory impairment and development of behavioral symptoms. CONCLUSIONS AND RELEVANCE: In patients presenting with nfvPPA, presence of early severe dysarthria, relatively selective white matter atrophy at presentation, and a greater rate of change in the brainstem measured by longitudinal imaging may be useful for differentiating underlying PSP from CBD pathology during life.

The effects of measurement error and vowel selection on the locus equation measure of coarticulation.

Effects on the slope of introducing error in the F2 Hz values in locus equations (LEs) and of using fewer than ten vowels were investigated. For each of the initial consonants /b, d, g/, 2000 simulated sets were generated using Monte Carlo techniques. The sets were altered with 50, 100, or 200 Hz error being randomly applied to each F2 value within a set. Selected vowels were then removed from the sets and the effects on the slopes were measured. Results suggest that the LE slopes are generally resistant to error and reduced number of vowels. Effects of adding 50 Hz of random error to the F2 values in sets using eight or ten vowels were minimal, yielding a mean absolute change in slope less than 0.07.

Speech entrainment enables patients with Broca's aphasia to produce fluent speech.

A distinguishing feature of Broca's aphasia is non-fluent halting speech typically involving one to three words per utterance. Yet, despite such profound impairments, some patients can mimic audio-visual speech stimuli enabling them to produce fluent speech in real time. We call this effect 'speech entrainment' and reveal its neural mechanism as well as explore its usefulness as a treatment for speech production in Broca's aphasia. In Experiment 1, 13 patients with Broca's aphasia were tested in three conditions: (i) speech entrainment with audio-visual feedback where they attempted to mimic a speaker whose mouth was seen on an iPod screen; (ii) speech entrainment with audio-only feedback where patients mimicked heard speech; and (iii) spontaneous speech where patients spoke freely about assigned topics. The patients produced a greater variety of words using audio-visual feedback compared with audio-only feedback and spontaneous speech. No difference was found between audio-only feedback and spontaneous speech. In Experiment 2, 10 of the 13 patients included in Experiment 1 and 20 control subjects underwent functional magnetic resonance imaging to determine the neural mechanism that supports speech entrainment. Group results with patients and controls revealed greater bilateral cortical activation for speech produced during speech entrainment compared with spontaneous speech at the junction of the anterior insula and Brodmann area 47, in Brodmann area 37, and unilaterally in the left middle temporal gyrus and the dorsal portion of Broca's area. Probabilistic white matter tracts constructed for these regions in the normal subjects revealed a structural network connected via the corpus callosum and ventral fibres through the extreme capsule. Unilateral areas were connected via the arcuate fasciculus. In Experiment 3, all patients included in Experiment 1 participated in a 6-week treatment phase using speech entrainment to improve speech production. Behavioural and functional magnetic resonance imaging data were collected before and after the treatment phase. Patients were able to produce a greater variety of words with and without speech entrainment at 1 and 6 weeks after training. Treatment-related decrease in cortical activation associated with speech entrainment was found in areas of the left posterior-inferior parietal lobe. We conclude that speech entrainment allows patients with Broca's aphasia to double their speech output compared with spontaneous speech. Neuroimaging results suggest that speech entrainment allows patients to produce fluent speech by providing an external gating mechanism that yokes a ventral language network that encodes conceptual aspects of speech. Preliminary results suggest that training with speech entrainment improves speech production in Broca's aphasia providing a potential therapeutic method for a disorder that has been shown to be particularly resistant to treatment.