Nonfluent Variant Research Articles

Hodges’ Frontotemporal Dementia, Second Edition

Hodges’ Frontotemporal Dementia, Second Edition

White Matter Disruption and Connected Speech in Non-Fluent and Semantic Variants of Primary Progressive Aphasia

Differential patterns of white matter disruption have recently been reported in the non-fluent (nfvPPA) and semantic (svPPA) variants of primary progressive aphasia (PPA). No single measure is sufficient to distinguish between the PPA variants, but connected speech allows for the quantification of multiple measures. The aim of the present study was to further investigate the white matter correlates associated with connected speech features in PPA. We examined the relationship between white matter metrics and connected speech deficits using an automated analysis of transcriptions of connected speech and diffusion tensor imaging in language-related tracts. Syntactic, lexical, and semantic features were automatically extracted from transcriptions of topic-directed interviews conducted with groups of individuals with nfvPPA or svPPA as well as with a group of healthy controls. A principal component analysis was performed in order to reduce the number of language measures and yielded a five-factor solution. The results indicated that nfvPPA patients differed from healthy controls on a syntactic factor, and svPPA patients differed from controls on two semantic factors. However, the patient groups did not differ on any factor. Moreover, a correlational analysis revealed that the lexical richness factor was significantly correlated with radial diffusivity in the left inferior longitudinal fasciculus, which suggests that semantic deficits in connected speech reflect a disruption of this ventral pathway, and which is largely consistent with the results of previous studies. Using an automated approach for the analysis of connected speech combined with probabilistic tractography, the present findings demonstrate that nfvPPA patients are impaired relative to healthy controls on syntactic measures and have increased radial diffusivity in the left superior longitudinal fasciculus, whereas the svPPA group was impaired on lexico-semantic measures relative to controls and showed increased radial diffusivity in the uncinate and inferior longitudinal fasciculus bilaterally.

Generalization and maintenance of treatment gains in primary progressive aphasia (PPA): a systematic review.

Cognitive-linguistic treatments and interventions targeting communication have been developed within the context of primary progressive aphasia (PPA), however knowledge about the scope of generalization and maintenance of therapy gains considering PPA subtypes remains scarce and awaits systematic investigation. To analyse the effects of semantic therapy on generalization and maintenance of treatment outcomes in individuals with PPA, considering its different subtypes. Central, PubMed, Medline, Web of Knowledge and Scopus were used to retrieve articles of interest. A total of 25 non-randomized studies published between 2000 and 2016 met the eligibility criteria and therefore were included in this study. This systematic review provides evidence-based information for clinical practice in PPA. Generalization and maintenance effects post-treatment for each PPA variant are analysed and discussed. Several factors are described as important to maximize the scope for generalization and maintenance of treatment gains. Generalization is particularly hard to achieve in the semantic variant, as in the face of degraded semantic knowledge learning is rigid and context dependent. In contrast, non-fluent and logopenic variants offer better scope for generalization. Maintenance patterns do not seem to be influenced by PPA subtype, but rather by other factors such as continued practice, treatment length and frequency of sessions. In the future, clinicians should consider the PPA subtype when planning the treatment protocol.

Determining efficacy of a treatment strategy in patients with non-fluent variant of primary progressive aphasia and apraxia of speech

Determining efficacy of a treatment strategy in patients with non-fluent variant of primary progressive aphasia and apraxia of speech

(Dis)fluency markers in dementia: how much can errors tell us?

(Dis)fluency markers in dementia: how much can errors tell us?

Cholinergic depletion and basal forebrain volume in primary progressive aphasia.

Primary progressive aphasia (PPA) is a heterogeneous syndrome with various neuropathological causes for which no medical treatment with proven efficacy exists. Basal forebrain (BF) volume loss has been reported in PPA but its relation to cholinergic depletion is still unclear. The primary objective of this study was to investigate whether cholinergic alterations occur in PPA variants and how this relates to BF volume loss. An academic memory clinic based consecutive series of 11 PPA patients (five with the semantic variant (SV), four with the logopenic variant (LV) and two with the nonfluent variant (NFV)) participated in this cross-sectional in vivo PET imaging study together with 10 healthy control subjects. Acetylcholinesterase (AChE) activity was quantitatively measured in the neo- and allocortex using N-[11C]-Methylpiperidin-4-yl propionate (PMP)-PET with arterial sampling and metabolite correction. Whole brain and BF volumes were quantified using voxel-based morphometry on high-resolution magnetic resonance imaging (MRI) scans.In the PPA group, only LV cases showed decreases in AChE activity levels compared to controls. Surprisingly, a substantial number of SV cases showed significant AChE activity increases compared to controls. BF volume did not correlate with AChE activity levels in PPA. To conclude, in our sample of PPA patients, LV but not SV was associated with cholinergic depletion. BF atrophy in PPA does not imply cholinergic depletion.

Lack of Frank Agrammatism in the Nonfluent Agrammatic Variant of Primary Progressive Aphasia

Background/Aims: Frank agrammatism, defined as the omission and/or substitution of grammatical morphemes with associated grammatical errors, is variably reported in patients with nonfluent variant primary progressive aphasia (nfPPA). This study addressed whether frank agrammatism is typical in agrammatic nfPPA patients when this feature is not required for diagnosis. Method: We assessed grammatical production in 9 patients who satisfied current diagnostic criteria. Although the focus was agrammatism, motor speech skills were also evaluated to determine whether dysfluency arose primarily from apraxia of speech (AOS), instead of, or in addition to, agrammatism. Volumetric MRI analyses provided impartial imaging-supported diagnosis. Results: The majority of cases exhibited neither frank agrammatism nor AOS. Conclusion: There are nfPPA patients with imaging-supported diagnosis and preserved motor speech skills who do not exhibit frank agrammatism, and this may persist beyond the earliest stages of the illness. Because absence of frank agrammatism is a subsidiary diagnostic feature in the logopenic variant of PPA, this result has implications for differentiation of the nonfluent and logopenic variants, and indicates that PPA patients with nonfluent speech in the absence of frank agrammatism or AOS do not necessarily have the logopenic variant.

Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia.

Objective:To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease.Methods:Serum samples were collected from 74 participants (34 with behavioral variant FTD [bvFTD], 3 with FTD and motor neuron disease and 37 with primary progressive aphasia [PPA]) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau (MAPT; 11), or progranulin (GRN; 4). Serum NfL concentrations were determined with the NF-Light kit transferred onto the single-molecule array platform and compared between FTD and healthy controls and between the FTD clinical and genetic subtypes. We also assessed the relationship between NfL concentrations and measures of cognition and brain volume.Results:Serum NfL concentrations were higher in patients with FTD overall (mean 77.9 pg/mL [SD 51.3 pg/mL]) than controls (19.6 pg/mL [SD 8.2 pg/mL]; p < 0.001). Concentrations were also significantly higher in bvFTD (57.8 pg/mL [SD 33.1 pg/mL]) and both the semantic and nonfluent variants of PPA (95.9 and 82.5 pg/mL [SD 33.0 and 33.8 pg/mL], respectively) compared with controls and in semantic variant PPA compared with logopenic variant PPA. Concentrations were significantly higher than controls in both the C9orf72 and MAPT subgroups (79.2 and 40.5 pg/mL [SD 48.2 and 20.9 pg/mL], respectively) with a trend to a higher level in the GRN subgroup (138.5 pg/mL [SD 103.3 pg/mL). However, there was variability within all groups. Serum concentrations correlated particularly with frontal lobe atrophy rate (r = 0.53, p = 0.003).Conclusions:Increased serum NfL concentrations are seen in FTD but show wide variability within each clinical and genetic group. Higher concentrations may reflect the intensity of the disease in FTD and are associated with more rapid atrophy of the frontal lobes.

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.

Profiles of cognitive and language impairment of logopenic and non-fluent variant of primary progressive aphasia

To decipher the cognitive and linguistic feature of logopenic variant primary progressive aphasia (lv-PPA) and nonfluent variant primary progressive aphasia (nfv-PPA) and to explore the extent to which cognitive and language impairment contribute to the dysfunction of activity of daily living(ADL). Seven lv-PPA and five nfv-PPA were enrolled in memory clinic of Xuanwu Hospital, Capital Medical University from January 2015 to January 2016 accordig to the international consensus criteria for PPA and its three subtypes. 20 age-matched normal controls (NC) were included. Both the patients and the NC completed a battery of neuropsychological test, lingusitic test and brain magnetic resonance imaging. All the patients conducted (11)C Pittsburgh compound B (PiB) PET imaging. Lv-PPA patients were characterized by deficits in lexical retrieval and long sentenses repetition, while nfv-PPA were with motor speech apraxia and phonetic distortion. Compared with nfv-PPA, lv-PPA patient displayed more severe cognitive deficit with younger onset of age (56±5 vs 61±5, P<0.05) , rapid decline of MMSE score within 1.5 years and pariental cortex dysfunctions such as ideomotor praxis, Gerstmann syndrome and contructional apraxia. Correlation analysis indicated that there was more significant association between pariental cortex dysfunction and ADL/mini-mental state examination(MMSE) than that of language deficit(r=-0.868, r=-0.922; r=0.312, r=-0.257). All seven lv-PPA were PiB-PET positive and five nfv-PPA were negative. This study enriched the chinical and linguistic characterization of lv-PPA and nfv-PPA, which has implication for diagnosis, disease management and treatment for clinicians.

Atrophy and structural covariance of the cholinergic basal forebrain in primary progressive aphasia

Primary progressive aphasia (PPA) is characterized by profound destruction of cortical language areas. Anatomical studies suggest an involvement of cholinergic basal forebrain (BF) in PPA syndromes, particularly in the area of the nucleus subputaminalis (NSP). Here we aimed to determine the pattern of atrophy and structural covariance as a proxy of structural connectivity of BF nuclei in PPA variants. We studied 62 prospectively recruited cases with the clinical diagnosis of PPA and 31 healthy older control participants from the cohort study of the German consortium for frontotemporal lobar degeneration (FTLD). We determined cortical and BF atrophy based on high-resolution magnetic resonance imaging (MRI) scans. Patterns of structural covariance of BF with cortical regions were determined using voxel-based partial least square analysis. We found significant atrophy of total BF and BF subregions in PPA patients compared with controls [F(1, 82) = 20.2, p < .001]. Atrophy was most pronounced in the NSP and the posterior BF, and most severe in the semantic variant and the nonfluent variant of PPA. Structural covariance analysis in healthy controls revealed associations of the BF nuclei, particularly the NSP, with left hemispheric predominant prefrontal, lateral temporal, and parietal cortical areas, including Broca's speech area (p < .001, permutation test). In contrast, the PPA patients showed preserved structural covariance of the BF nuclei mostly with right but not with left hemispheric cortical areas (p < .001, permutation test). Our findings agree with the neuroanatomically proposed involvement of the cholinergic BF, particularly the NSP, in PPA syndromes. We found a shift from a structural covariance of the BF with left hemispheric cortical areas in healthy aging towards right hemispheric cortical areas in PPA, possibly reflecting a consequence of the profound and early destruction of cortical language areas in PPA.

Neurochemical biomarkers in the diagnosis of frontotemporal lobar degeneration: an update.

Frontotemporal lobar degeneration (FTLD) is a spectrum of rare neurodegenerative diseases with overlapping symptoms and neuropathology. It includes the behavioral variant of frontotemporal dementia (bvFTD), the semantic and non-fluent variant of primary progressive aphasia (svPPA and nfvPPA), FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy, and corticobasal syndrome. The diagnosis of the FTLD spectrum of diseases is based on clinical symptoms which hampers the differentiation of the diseases among each other and with other disorders that show a similar clinical appearance resulting in a high rate of misdiagnoses. This highlights the need for objective and selective measures in the diagnostic criteria and there is extensive research on neurochemical biomarkers in FTLD as one option to address this unmet clinical need. Here, we review the advances in CSF biomarker research in FTLD in the last 2years with regard to the validation of previously suggested and identification of new biomarker candidates for the differential diagnosis of FTLD. New biomarkers for frontotemporal lobar degeneration (FTLD) are urgently needed to support differential diagnosis within the disease spectrum and with related neurodegenerative diseases such as Alzheimer disease (AD). Here, we review the advances in cerebrospinal fluid biomarker research in FTLD and provide a list of promising candidate markers.

Defining the spectrum of frontotemporal dementias associated with TARDBP mutations.

Objectives:We describe the largest series of patients with TARDBP mutations presenting with frontotemporal dementia (FTD) and review the cases in the literature to precisely characterize FTD diseases associated with this genotype.Methods:The phenotypic characteristics of 29 TARDBP patients, including 10 new French and Dutch cases and 19 reviewed from the literature, were evaluated.Results:The most frequent phenotype was a behavioral variant frontotemporal dementia (bvFTD), but a significant proportion (40%) of our patients had semantic (svFTD) or nonfluent variants (nfvFTD) at onset; and svFTD was significantly more frequent in TARDBP carriers than in other FTD genotypes (p < 0.001). Remarkably, only a minority (40%) of our patients secondarily developed amyotrophic lateral sclerosis (ALS). Two patients carried a homozygous mutation but strikingly different phenotypes (bvFTD and ALS) indicating that homozygosity does not result in a specific phenotype. Earlier age at onset in children than parent's generations, mimicking an apparent “anticipation” (21.8 ± 9.3 years, p = 0.001), and possible reduced penetrance were present in most families.Conclusions:This study enlarges the phenotypic spectrum of TARDBP and will have important clinical implications: (1) FTD can be the only clinical manifestation of TARDBP mutations; (2) Initial language or semantic disorders might be indicative of a specific genotype; (3) Mutations should be searched in all FTD phenotypes after exclusion of major genes, even in the absence of ALS in the proband or in family history; (4) reduced penetrance and clinical variability should be considered to deliver appropriate genetic counseling.

Core auditory processing deficits in primary progressive aphasia

The extent to which non-linguistic auditory processing deficits may contribute to the phenomenology of primary progressive aphasia is not established. Using non-linguistic stimuli devoid of meaning we assessed three key domains of auditory processing (pitch, timing and timbre) in a consecutive series of 18 patients with primary progressive aphasia (eight with semantic variant, six with non-fluent/agrammatic variant, and four with logopenic variant), as well as 28 age-matched healthy controls. We further examined whether performance on the psychoacoustic tasks in the three domains related to the patients' speech and language and neuropsychological profile. At the group level, patients were significantly impaired in the three domains. Patients had the most marked deficits within the rhythm domain for the processing of short sequences of up to seven tones. Patients with the non-fluent variant showed the most pronounced deficits at the group and the individual level. A subset of patients with the semantic variant were also impaired, though less severely. The patients with the logopenic variant did not show any significant impairments. Significant deficits in the non-fluent and the semantic variant remained after partialling out effects of executive dysfunction. Performance on a subset of the psychoacoustic tests correlated with conventional verbal repetition tests. In sum, a core central auditory impairment exists in primary progressive aphasia for non-linguistic stimuli. While the non-fluent variant is clinically characterized by a motor speech deficit (output problem), perceptual processing of tone sequences is clearly deficient. This may indicate the co-occurrence in the non-fluent variant of a deficit in working memory for auditory objects. Parsimoniously we propose that auditory timing pathways are altered, which are used in common for processing acoustic sequence structure in both speech output and acoustic input.

Initiation and suppression of verbal responses in Primary Progressive Aphasia

Initiation and suppression of verbal responses in Primary Progressive Aphasia

Semantic and nonfluent aphasic variants, secondarily associated with amyotrophic lateral sclerosis, are predominant frontotemporal lobar degeneration phenotypes in TBK1 carriers

IntroductionTBK1 mutations represent a rare novel genetic cause of amyotrophic lateral sclerosis (ALS) without or with dementia. The full spectrum of TBK1 phenotypes has not been completely defined so far. MethodsWe describe the clinical and neuroimaging characteristics of loss-of-function mutation carriers initially presenting with frontotemporal lobar degeneration (FTLD) phenotypes. ResultsTwo carriers initially presented semantic variant of FTLD (svFTLD); two other developed nonfluent variant of FTLD (nfvFTLD) and corticobasal syndrome (CBS), associated with severe anterior temporal and opercular atrophy. All secondarily developed ALS. DiscussionThis study enlarges the phenotypic spectrum of TBK1 mutations, including svFTLD and nfvFTLD/CBS, not reported so far. Aphasic presentations seem to be more evocative of TBK1 genotype than behavioral variant of FTLD, and TBK1 should be analyzed in patients with isolated FTLD at onset, particularly in rare aphasic cases secondarily associated with ALS.

Genetics of frontotemporal dementia in Asia: Advancing knowledge through collaboration.

Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder characterized by selective involvement of the frontal and temporal lobes, where non-Alzheimer disease (AD) pathology is expected. FTD encompasses 3 distinct clinical syndromes including behavioral variant FTD (bvFTD) characterized by prominent behavioral abnormalities, and 2 language variants (semantic variant and nonfluent variant) collectively known as primary progressive aphasia (PPA). The most common FTD subtype, bvFTD, may manifest with disinhibition, compulsive/perseverative behavior, overeating, apathy, and emotional blunting. FTD is known in Western populations to be the second most common cause of dementia in those younger than 65 years.1 In Asian populations, FTD appears to be far less common, being the third most common cause of young-onset dementia in some cohorts behind AD and vascular dementia.2 The proportion of Asian patients with FTD who have a positive family history ranges from 9.5% to 20%,2–4 considerably lower than the 30% to 50% seen in Caucasian populations.5

18F-FDG PET Improves Diagnosis in Patients with Focal-Onset Dementias.

Alzheimer disease is the cause of up to one-third of cases of primary progressive aphasia or corticobasal syndrome. The primary objective of this study was to determine the accuracy of 18F-FDG PET metabolic imaging for the detection of Alzheimer disease in patients with primary progressive aphasia or corticobasal syndrome. A cohort of patients (n=94), including those with an expert clinical diagnosis of logopenic (n=19), nonfluent (n=16), or semantic (n=13) variants of primary progressive aphasia, corticobasal syndrome (n=14), or Alzheimer disease (n=24), underwent 18F-FDG metabolic and 11C-labeled Pittsburgh compound B (11C-PiB) amyloid PET brain imaging. 18F-FDG PET scans interpreted with Neurostat and 3D-SSP displays were classified as revealing Alzheimer disease or "other" by interpreters who were unaware of the clinical assessments and 11C-PiB PET results. 11C-PiB PET imaging was considered to be the diagnostic reference standard, with a threshold standardized uptake value ratio of 1.5 being indicative of Alzheimer disease pathology. To address possible bias from subgroup selection for the Alzheimer disease binary classifier, we calculated both conventional and balanced accuracies. Diagnoses of Alzheimer disease based on 18F-FDG PET resulted in 84% accuracy (both conventional and balanced). In comparison, diagnoses based on clinical assessments resulted in 65% conventional accuracy and 67% balanced accuracy. Brain 18F-FDG PET scans interpreted with Neurostat and 3D-SSP displays accurately detected Alzheimer disease in patients with primary progressive aphasia or corticobasal syndrome as focal-onset dementias. In such diagnostically challenging cohorts, (18)F-FDG PET imaging can provide more accurate diagnoses, enabling more appropriate therapy.

SECT and MAST: new tests to assess grammatical abilities in primary progressive aphasia

Background: The presence/absence of agrammatism is critical for the classification of the different subtypes of primary progressive aphasia (PPA). Its quantitative evaluation is, however, a challenge in clinical practice because there are few brief, reliable, and easy-to-administer tests. Linguistic analysis of connected speech is the gold standard but is impractical outside the research setting.Aims: To tackle the need for brief grammatical tests, we developed the SEntence Comprehension Test (with auditory and visual versions, SECT A and V) and the Make A Sentence Test (MAST).Methods & Procedures: The tests were given to 92 participants (41 PPA patients, 21 Alzheimer’s disease patients, and 30 controls) from the Cambridge Longitudinal Study of PPA. Classification of the different subtypes of PPA was made purely on clinical assessment to avoid circularity from using the tests for diagnostic purposes. In addition, speech samples were recorded during a face-to-face semi-structured interview and all participants completed a standard neuropsychological battery as well as the three new tests.Outcomes & Results: All patients were impaired relative to controls on the SECT A and V. After controlling for semantic impairment, only the mixed variant of PPA (mPPA) and the non-fluent variant of PPA were impaired on the MAST. When controlling for working memory in SECT A, the mPPA only remained impaired. Regression analyses demonstrated that performance on the SECT A and V, and the MAST, was strongly related to measures of the patients’ spontaneous speech, particularly the number of grammatical errors and the percentage of abandoned and elliptical sentences. Performance on the SECT A was also significantly predicted by speech rate.Conclusion: The SECT and the MAST are brief tests capable of reflecting grammatical difficulty in spontaneous speech.

Connected speech production in the nonfluent variant of primary progressive aphasia and its relationship with white matter damage (P1.228)

Connected speech production in the nonfluent variant of primary progressive aphasia and its relationship with white matter damage (P1.228)