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The non-fluent/agrammatic variant of primary progressive aphasia (naPPA) is a young-onset neurodegenerative disorder characterised by poor grammatical comprehension and expression and a disorder of speech sound production. In an era of disease-modifying treatments, the identification of naPPA might be an important step in establishing a specific cause of neurodegenerative disease. However, difficulties in defining the characteristic language deficits and heterogeneity in the anatomical distribution of disease in naPPA have led to controversy. Findings from imaging studies have linked an impairment of this uniquely human language capacity with disruption of large-scale neural networks centred in left inferior frontal and anterior superior temporal regions. Accordingly, the pathological burden of disease in naPPA is anatomically focused in these regions. Most cases of naPPA are associated with the spectrum of pathological changes found in frontotemporal lobar degeneration involving the microtubule-associated protein tau. Knowledge of these unique clinical-pathological associations should advance care for patients with this important class of neurodegenerative diseases while supplementing our knowledge of human cognitive neuroscience.

Background and objectives Nonfluent variant primary progressive aphasia (nfvPPA) and primary progressive apraxia of speech (PPAOS) can be precursors to corticobasal syndrome (CBS). Details on their progression remain unclear. We aimed to examine the clinical and neuroimaging evolution of nfvPPA and PPAOS into CBS. Methods We conducted a retrospective longitudinal study in 140 nfvPPA or PPAOS patients and applied the consensus criteria for possible and probable CBS for every visit, evaluating limb rigidity, akinesia, limb dystonia, myoclonus, ideomotor apraxia, alien limb phenomenon, and nonverbal oral apraxia (NVOA). Given the association of NVOA with AOS, we also modified the CBS criteria by excluding NVOA and assigned every patient to either a progressors or non-progressors group. We evaluated the frequency of every CBS feature by year from disease onset, and assessed gray and white matter volume loss using SPM12. Results Asymmetric akinesia, NVOA, and limb apraxia were the most common CBS features that developed; while limb dystonia, myoclonus, and alien limb were rare. Eighty-two patients progressed to possible CBS; only four to probable CBS. nfvPPA and PPAOS had a similar proportion of progressors, although nfvPPA progressed to CBS earlier ( p -value = 0.046), driven by an early appearance of limb apraxia ( p -value = 0.0041). The non-progressors and progressors both showed premotor/motor cortex involvement at baseline, with spread into prefrontal cortex over time. Discussion An important proportion of patients with nfvPPA and PPAOS progress to possible CBS, while they rarely develop features of probable CBS even after long follow-up.

Accurate processing of emotional information is a critical component of appropriate social interactions and interpersonal relationships. Disturbance of emotion processing is present in frontotemporal dementia (FTD) and is a clinical feature in two of the three subtypes: behavioural-variant FTD and semantic dementia. Emotion processing in progressive nonfluent aphasia, the third FTD subtype, is thought to be mostly preserved, although current evidence is scant. This paper reviews the literature on emotion recognition, reactivity and expression in FTD subtypes, although most studies focus on emotion recognition. The relationship between patterns of emotion processing deficits and patterns of neural atrophy are considered, by integrating evidence from recent neuroimaging studies. The review findings are discussed in the context of three contemporary theories of emotion processing: the limbic system model, the right hemisphere model and a multimodal system of emotion. Results across subtypes of FTD are most consistent with the multimodal system model, and support the presence of somewhat dissociable neural correlates for basic emotions, with strongest evidence for the emotions anger and sadness. Poor emotion processing is evident in all three subtypes, although deficits are more widespread than what would be predicted based on studies in healthy cohorts. Studies that include behavioural and imaging data are limited. Future investigations combining these approaches will help improve the understanding of the neural network underlying emotion processing. Presently, longitudinal investigations of emotion processing in FTD are lacking, and studies investigating emotion processing over time are critical to understand the clinical manifestations of disease progression in FTD.

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception. The role of frontal lobes in speech perception is controversial. Here, the authors show that neurodegeneration of frontal speech regions delays prediction reconciliation in temporal cortex and results in inflexible prior expectations, indicating that fronto-temporal interactions determine predictive processes in speech.

This study examines reading aloud in patients with amyotrophic lateral sclerosis (ALS) and those with frontotemporal dementia (FTD) in order to determine whether differences in patterns of speaking and pausing exist between patients with primary motor vs. primary cognitive-linguistic deficits, and in contrast to healthy controls. 136 participants were included in the study: 33 controls, 85 patients with ALS, and 18 patients with either the behavioural variant of FTD (FTD-BV) or progressive nonfluent aphasia (FTD-PNFA). Participants with ALS were further divided into 4 non-overlapping subgroups--mild, respiratory, bulbar (with oral-motor deficit) and bulbar-respiratory--based on the presence and severity of motor bulbar or respiratory signs. All participants read a passage aloud. Custom-made software was used to perform speech and pause analyses, and this provided measures of speaking and articulatory rates, duration of speech, and number and duration of pauses. These measures were statistically compared in different subgroups of patients. The results revealed clear differences between patient groups and healthy controls on the passage reading task. A speech-based motor function measure (i.e., articulatory rate) was able to distinguish patients with bulbar ALS or FTD-PNFA from those with respiratory ALS or FTD-BV. Distinguishing the disordered groups proved challenging based on the pausing measures. This study demonstrated the use of speech measures in the identification of those with an oral-motor deficit, and showed the usefulness of performing a relatively simple reading test to assess speech versus pause behaviors across the ALS-FTD disease continuum. The findings also suggest that motor speech assessment should be performed as part of the diagnostic workup for patients with FTD.

Purpose: The International Consensus Criteria for the diagnosis of primary progressive aphasia (PPA; Gorno-Tempini et al., 2011) propose apraxia of speech (AOS) as 1 of 2 core features of nonfluent/agrammatic PPA and propose phonological errors or absence of motor speech disorder as features of logopenic PPA. We investigated the sensitivity and specificity of AOS and phonological errors as markers for these variants and also investigated the relationship between AOS, phonological errors, and findings on C-labeled Pittsburgh Compound B (PiB)-positron emission tomography (PET) imaging associated with putative Alzheimer-type pathology. Method: Connected speech and word repetition in 23 people with PPA who underwent PiB-PET imaging were rated for apraxic versus phonological disruption by 1 rater who was blind to diagnosis and by 2 raters who were blind to PiB-PET results. Results: Apraxic characteristics had high sensitivity for nonfluent/agrammatic PPA, and phonological errors had high sensitivity for logopenic PPA; however, phonological errors showed lower specificity for logopenic PPA. On PiB imaging, 8 of 9 people with predominant AOS returned negative results, whereas participants with no or questionable AOS with and without phonological errors returned positive results. Conclusions: Attention to AOS and phonological errors may help counter some of the inherent limitations of diagnosis-by-exclusion in the current International Consensus Criteria for diagnosing PPA.

Crossed aphasia has been reported mainly as post-stroke aphasia resulting from brain damage ipsilateral to the dominant right hand. Here, we described a case of a crossed nonfluent/agrammatic primary progressive aphasia (nfvPPA), who developed a corticobasal syndrome (CBS). We collected clinical, cognitive, and neuroimaging data for four consecutive years from a 55-year-old right-handed lady (JV) presenting with speech disturbances. 18-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) and DaT-scan with 123 I-Ioflupane were obtained. Functional MRI (fMRI) during a verb naming task was acquired to characterize patterns of language lateralization. Diffusion tensor MRI was used to evaluate white matter damage within the language network. At onset, JV presented with prominent speech output impairment and right frontal atrophy. After 3 years, language deficits worsened, with the occurrence of a mild agrammatism. The patient also developed a left-sided mild extrapyramidal bradykinetic-rigid syndrome. The clinical picture was suggestive of nfvPPA with mild left-sided extrapyramidal syndrome. At this time, voxel-wise SPM analyses of 18 F-FDG PET and structural MRI showed right greater than left frontal hypometabolism and damage, which included the Broca’s area. DaT-scan showed a reduced uptake in the right striatum. FMRI during naming task demonstrated bilateral language activations, and tractography showed right superior longitudinal fasciculus (SLF) involvement. Over the following year, JV became mute and developed frank left-sided motor signs and symptoms, evolving into a CBS clinical picture. Brain atrophy worsened in frontal areas bilaterally, and extended to temporo-parietal regions, still with a right-sided asymmetry. Tractography showed an extension of damage to the left SLF and right inferior longitudinal fasciculus. We report a case of crossed nfvPPA followed longitudinally and studied with advanced neuroimaging techniques. The results highlight a complex interaction between individual premorbid developmental differences and the clinical phenotype.

Background/Aims: The longitudinal course of three primary progressive aphasia (PPA) variants was examined using Addenbrooke’s Cognitive Examination-Revised (ACE-R) and the Frontotemporal dementia Rating Scale (FRS). Methods: Cases with two assessments on the ACE-R and FRS were selected. A total of 220 assessments were obtained on 55 patients: 17 Alzheimer’s disease (AD) and 38 PPA [17 semantic variant (svPPA), 12 non-fluent/agrammatic (naPPA) and 9 logopenic variant (lvPPA) cases]. Results: The annualized rate of change was greater in all PPA variants in comparison with the AD group on the ACE-R whereas only the svPPA and naPPA groups differed from AD on the FRS. Conclusions: The longitudinal profile differs across PPA syndromes on cognitive and functional measures. Findings have theoretical implications and are relevant to the care of patients with dementia.

Background: Frontotemporal dementia (FTD) causes progressive change in activities of daily living (ADLs) and little is known about their rate of decline. This study aimed to examine changes in ADLs, including subcomponents of initiation, planning or execution. Methods: A total of 72 ADL and general cognitive assessments were analysed. The patients were subdivided into behavioural variant FTD (bvFTD) pathological and phenocopy subgroups, semantic dementia (SemDem) and progressive non-fluent aphasia (PNFA). Results: Pathological bvFTD, SemDem and PNFA groups showed significant decline on ADLs after 12 months, while the phenocopy subgroup did not. In terms of subcomponents of ADLs, each variant showed different profiles of decline. The decline in ADL and cognitive scores were significantly correlated. Conclusions: FTD variants show differential annual rates of functional decline. The rate of decline should be taken into consideration when discussing prognosis.

Background/Aims: This study examined functional changes in progressive non-fluent aphasia (PNFA) and logopenic progressive aphasia (LPA) and Alzheimer’s disease (AD) and the association between function, cognition and behaviour. Methods: 59 patients were assessed with the Disability Assessment of Dementia (DAD), Addenbrooke’s Cognitive Examination Revised (ACE-R) and the Cambridge Behavioural Inventory Revised (CBI-R). Results: No differences between groups in basic and instrumental activities of daily living (ADLs), and total ACE-R scores were found; there were correlations between total DAD and ACE-R scores for PNFA and LPA. Over 12 months, PNFA showed the marked decline of basic ADLs, whereas all three groups showed marked decline of instrumental ADLs. Conclusion: PNFA, LPA and AD appear functionally similar when matched for disease duration. The rate of decline of ADLs depends, however, on disease diagnosis.