Naming treatment in semantic and logopenic variant PPA

Primary progressive aphasia (PPA) is an acquired impairment of language caused by neurodegenerative disease affecting language regions in the brain. Unlike aphasia caused by stroke, the language impairments in PPA gradually worsen over time as atrophy spreads. Current consensus criteria for diagnosis identify three clinical variants, each of which is associated with a different pathological entity: a semantic variant, with verbal and nonverbal semantic deficits; a logopenic variant, with anomia and phonological working memory problems; and a nonfluent variant, with agrammatism and/or apraxia of speech (Gorno-Tempini et al., 2011; Gorno-Tempini et al., 2004)

Phonological processing in primary progressive aphasia

Primary progressive aphasia (PPA) is a debilitating condition wherein speech and language deteriorate as a result of neurodegenerative disease. Three variants of PPA are now recognized, each of which shows a unique constellation of speech-language deficits and pattern of underlying atrophy in the brain (Gorno-Tempini et al., 2011). The variants include a nonfluent/agrammatic type (nfvPPA), characterized by syntactic and motor speech deficits and fronto-insular atrophy in the left hemisphere. The semantic variant (svPPA) shows degradation of semantic knowledge in the context of anterior and inferior temporal lobe atrophy (left hemisphere greater than right). Finally, the more recently characterized logopenic variant (lvPPA) shows impairments in naming and repetition that are thought to be phonological in nature. This variant, associated with atrophy of temporoparietal regions in the left hemisphere, has also been referred to as the “phonological” variant of PPA due to observed deficits on tasks that require phonological storage (i.e., the “phonological loop”) and to the presence of phonological paraphasias in connected speech (Gorno-Tempini et al., 2008). Impaired phonological processing has been considered a unique feature of the logopenic variant of PPA, however, phonological skills have not been thoroughly characterized across the three variants. Recent models of the functional neuroanatomy of language propose two pathways by which speech is processed in the brain (Hickok & Poeppel, 2007). A dorsal pathway involving temporoparietal and posterior frontal structures is thought to be involved in mapping phonological representations onto articulatory representations. A ventral pathway located in the middle and inferior temporal lobes is considered crucial for mapping phonological representations onto lexical-semantic representations. Both the dorsal and ventral streams emanate from a common cortical region in posterior, superior temporal cortex/sulcus that appears critical to the mental representation of phonology. We investigated phonological processing in PPA, with the goal of identifying whether patterns of performance in the different variants support this functional-anatomical framework. Based on our knowledge of the locus of anatomical damage in the subtypes of PPA, we hypothesized that patients with damage to dorsal route structures (nonfluent and logopenic variants) would show greater impairment on phonological processing tasks, whereas patients with damage to ventral route structures (semantic variant) would show relative preservation of phonological abilities

COS-PPA: protocol to develop a core outcome set for primary progressive aphasia

Introduction: The term primary progressive aphasia (PPA) describes a group of language-led dementias. Disease-modifying treatments that delay, slow or reverse progression of PPA are currently lacking, though a number of interventions to manage the symptoms of PPA have been developed in recent years. Unfortunately, studies exploring the effectiveness of these interventions have used a variety of different outcome measures, limiting comparability. There are more constructs, apart from word retrieval, that are important for people with PPA that have not received much attention in the research literature. Existing core outcome sets (COS) for dementia and non-progressive aphasia do not meet the needs of people with PPA, highlighting a need to develop a specific COS for PPA. // Methods and analysis: This protocol describes a three-stage study to identify a COS for PPA interventions in research and clinical practice. The stage 1 systematic review will identify existing speech, language and communication measures used to examine the effectiveness of interventions for PPA in the research literature. Employing a nominal group technique, stage 2 will identify the most important outcomes for people with PPA and their families. The data collected in stages 1 and 2 will be jointly analysed with the project PPI group and will inform the stage 2 modified Delphi consensus study to identify a core outcome measurement set for PPA among a range of research disciplines undertaking intervention studies for people with PPA. // Ethics and dissemination: Ethical approval for stage 2 of the study has been sought individually in each country at collaborating institutions and is stated in detail in the manuscript. Stage 3 has been granted ethical approval by the Chairs of UCL Language and Cognition Department Ethics, Project ID LCD-2023-06. Work undertaken at stages 1, 2 and 3 will be published in open-access peer-reviewed journal articles and presented at international scientific conferences. // PROSPERO registration number: CRD42022367565

Neuropsychological, Behavioral, and Anatomical Evolution in Right Temporal Variant Frontotemporal Dementia: A Longitudinal Single Case Analysis

We examine longitudinal clinical and anatomical data for a patient with the right temporal variant of frontotemporal dementia. The patient received comprehensive clinical evaluations and structural MRI scans over three years. She presented with early behavioral deficits and ultimately developed semantic impairments consistent with the semantic variant of primary progressive aphasia. Imaging revealed early atrophy of the right temporal lobe, with later involvement of the left, and pathology confirmed bilateral temporal involvement. Findings support the view that right and left temporal variants reflect early asymmetry of atrophy that may become more bilateral over time, resulting in a mixed clinical picture

Examining the relation between bilingualism and age of symptom onset in frontotemporal dementia.

Bilingualism is thought to confer advantages in executive functioning, thereby contributing to cognitive reserve and a later age of dementia symptom onset. While the relation between bilingualism and age of onset has been explored in Alzheimer's dementia, there are few studies examining bilingualism as a contributor to cognitive reserve in frontotemporal dementia (FTD). In line with previous findings, we hypothesized that bilinguals with behavioral variant FTD would be older at symptom onset compared to monolinguals, but that no such effect would be found in patients with nonfluent/agrammatic variant primary progressive aphasia (PPA) or semantic variant PPA. Contrary to our hypothesis, we found no significant difference in age at symptom onset between monolingual and bilingual speakers within any of the FTD variants, and there were no notable differences on neuropsychological measures. Overall, our results do not support a protective effect of bilingualism in patients with FTD-spectrum disease in a U.S. based cohort

The relationship between non-orthographic language abilities and reading performance in chronic aphasia : an exploration of the primary systems hypothesis

PURPOSE : This study investigated the relationship between non-orthographic language abilities and reading in order to examine assumptions of the primary systems hypothesis and further our understanding of language processing poststroke. METHOD : Performance on non-orthographic semantic, phonologic, and syntactic tasks, as well as oral reading and reading comprehension tasks, was assessed in 43 individuals with aphasia. Correlation and regression analyses were conducted to determine the relationship between these measures. In addition, analyses of variance examined differences within and between reading groups (within normal limits, phonological, deep, or global alexia). RESULTS : Results showed that non-orthographic language abilities were significantly related to reading abilities. Semantics was most predictive of regular and irregular word reading, whereas phonology was most predictive of pseudohomophone and nonword reading. Written word and paragraph comprehension were primarily supported by semantics, whereas written sentence comprehension was related to semantic, phonologic, and syntactic performance. Finally, severity of alexia was found to reflect severity of semantic and phonologic impairment. CONCLUSIONS : Findings support the primary systems view of language by showing that non-orthographic language abilities and reading abilities are closely linked. This preliminary work requires replication and extension; however, current results highlight the importance of routine, integrated assessment and treatment of spoken and written language in aphasia.The first author was supported by the American Speech-Language-Hearing Foundation New Century Scholars Doctoral Scholarship and the University of Washington Research Training in Speech & Hearing Sciences National Institute on Deafness and Other Communication Disorders training grant (T32000033).https://pubs.asha.org/journal/jslhrhj2019Speech-Language Pathology and Audiolog

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

Network anatomy in logopenic variant of primary progressive aphasia

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis

Altered topology of the functional speech production network in non-fluent/agrammatic variant of PPA

Non-fluent/agrammatic primary progressive aphasia (nfvPPA) is caused by neuro-degeneration within the left fronto-insular speech and language production network (SPN). Graph theory is a branch of mathematics that studies network architecture (topology) by quantifying features based on its elements (nodes and connections). This approach has been recently applied to neuroimaging data to explore the complex architecture of the brain connectome, though few studies have exploited this technique in PPA. Here, we used graph theory on functional MRI resting state data from a group of 20 nfvPPA patients and 20 matched controls to investigate topological changes in response to focal neuro-degeneration. We hypothesized that changes in the network architecture would be specific to the affected SPN in nfvPPA, while preserved in the spared default mode network (DMN). Topological configuration was quantified by hub location and global network metrics. Our findings showed a less efficiently wired and less optimally clustered SPN, while no changes were detected in the DMN. The SPN in the nfvPPA group showed a loss of hubs in the left fronto-parietal-temporal area and new critical nodes in the anterior left inferior-frontal and right frontal regions. Behaviorally, speech production score and rule violation errors correlated with the strength of functional connectivity of the left (lost) and right (new) regions respectively. This study shows that focal neurodegeneration within the SPN in nfvPPA is associated with network-specific topological alterations, with the loss and gain of crucial hubs and decreased global efficiency that were better accounted for through functional rather than structural changes. These findings support the hypothesis of selective network vulnerability in nfvPPA and may offer biomarkers for future behavioral intervention

Rates Of Amyloid Imaging Positivity In Patients With Primary Progressive Aphasia

IMPORTANCE The ability to predict the pathology underlying different neurodegenerative syndromes is of critical importance owing to the advent of molecule-specific therapies. OBJECTIVE To determine the rates of positron emission tomography (PET) amyloid positivity in the main clinical variants of primary progressive aphasia (PPA). DESIGN, SETTING, AND PARTICIPANTS This prospective clinical-pathologic case series was conducted at a tertiary research clinic specialized in cognitive disorders. Patients were evaluated as part of a prospective, longitudinal research study between January 2002 and December 2015. Inclusion criteria included clinical diagnosis of PPA; availability of complete speech, language, and cognitive testing; magnetic resonance imaging performed within 6 months of the cognitive evaluation; and PET carbon 11-labeled Pittsburgh Compound-B or florbetapir F 18 brain scan results. Of 109 patients referred for evaluation of language symptoms who underwent amyloid brain imaging, 3 were excluded because of incomplete language evaluations, 5 for absence of significant aphasia, and 12 for presenting with significant initial symptoms outside of the language domain, leaving a cohort of 89 patients with PPA. MAIN OUTCOMES AND MEASURES Clinical, cognitive, neuroimaging, and pathology results. RESULTS Twenty-eight cases were classified as imaging-supported semantic variant PPA (11 women [39.3%]; mean [SD] age, 64 [7] years), 31 nonfluent/agrammatic variant PPA (22 women [71.0%]; mean [SD] age, 68 [7] years), 26 logopenic variant PPA (17 women [65.4%]; mean [SD] age, 63 [8] years), and 4 mixed PPA cases. Twenty-four of 28 patients with semantic variant PPA (86%) and 28 of 31 patients with nonfluent/agrammatic variant PPA (90%) had negative amyloid PET scan results, while 25 of 26 patients with logopenic variant PPA (96%) and 3 of 4 mixed PPA cases (75%) had positive scan results. The amyloid positive semantic variant PPA and nonfluent/agrammatic variant PPA cases with available autopsy data (2 of 4 and 2 of 3, respectively) all had a primary frontotemporal lobar degeneration and secondary Alzheimer disease pathologic diagnoses, whereas autopsy of 2 patients with amyloid PET-positive logopenic variant PPA confirmed Alzheimer disease. One mixed PPA patient with a negative amyloid PET scan had Pick disease at autopsy. CONCLUSIONS AND RELEVANCE Primary progressive aphasia variant diagnosis according to the current classification scheme is associated with Alzheimer disease biomarker status, with the logopenic variant being associated with carbon 11-labeled Pittsburgh Compound-B positivity in more than 95% of cases. Furthermore, in the presence of a clinical syndrome highly predictive of frontotemporal lobar degeneration pathology, biomarker positivity for Alzheimer disease may be associated more with mixed pathology rather than primary Alzheimer disease