Primary Progressive Aphasia Subtypes Research Articles

The production of adjectives in narratives by individuals with primary progressive aphasia

Adjectives (e.g., hungry) are an important part of language, but have been little studied in individuals with impaired language. Adjectives are used in two different ways in English: attributively, to modify a noun (the hungry dog); or predicatively, after a verb (the dog is hungry). Attributive adjectives have a more complex grammatical structure than predicative adjectives, and may therefore be particularly prone to disruption in individuals with grammatical impairments. We investigated adjective production in three subtypes of primary progressive aphasia (PPA: agrammatic, semantic, logopenic), as well as in agrammatic stroke aphasia and a group of healthy control participants. Participants produced narratives based on picture books, and we coded every adjective they produced for its syntactic structure. Compared to healthy controls, the two agrammatic groups, but not the other two patient groups, produced significantly fewer attributive adjectives per sentence. All four patient groups were similar to controls for their rate of predicative adjective production. In addition, we found a significant correlation in the agrammatic PPA participants between their rate of producing attributive adjectives and impaired production of sentences with complex syntactic structure (subject cleft sentences like It was the boy that chased the girl); no such correlation was found for predicative adjectives. Irrespective of structure, we examined the lexical characteristics of the adjectives that were produced, including length, frequency, semantic diversity and neighborhood density. Overall, the lexical characteristics of the produced adjectives were largely consistent with the language profile of each group. In sum, the results suggest that attributive adjectives present a particular challenge for individuals with agrammatic language production, and add a new dimension to the description of agrammatism. Our results further suggest that attributive adjectives may be a fruitful target for improved treatment and recovery of agrammatic language.

Asymmetry of radiomics features in the white matter of patients with Primary Progressive Aphasia (P6-12.005)

<h3>Objective:</h3> Primary Progressive Aphasia (PPA) is a neurological disease characterized by linguistic deficits. Semantic (svPPA) and non-fluent/agrammatic (nfvPPA) variants are the two main subtypes of PPA. <h3>Background:</h3> Several studies have investigated brain morphometric changes in PPA patients documenting patterns of asymmetry in gray and white matter (WM) properties. We applied a novel radiomics framework to investigate WM asymmetry. Moreover, we examined whether WM asymmetry in specific brain regions could be associated with verbal fluency impairments. <h3>Design/Methods:</h3> Analyses were performed on 3 Tesla T1-MRI. We included 31 svPPA, 25 nfvPPA and 53 age- and sex-matched controls. Asymmetry Index (AI) was computed for 86 radiomics features in 34 WM regions. Between-group comparisons in AIs were performed using analysis of variance. Correlation analyses investigated the relationships between performance at verbal fluency tasks (semantic and phonemic) and at Boston Naming Test and AIs. <h3>Results:</h3> Relative to controls, WM asymmetry in svPPA patients involved regions adjacent to middle temporal cortex as part of the inferior longitudinal (ILF), fronto-occipital (IFOF) and superior longitudinal (SLF) fasciculi. Conversely, nfvPPA patients showed an asymmetry of WM in lateral occipital brain regions (ILF/IFOF). A higher lateralization of radiomics features involving IFOF, cingulum and forceps minor was found in nfvPPA compared to svPPA patients. Correlation analysis highlighted a positive relationship between semantic fluency and AI in WM adjacent to the lateral occipital gyrus in nfvPPA patients. Performances at Boston Naming Test were significantly associated with AI in WM regions located close to the middle temporal and parahippocampal gyri in svPPA patients. <h3>Conclusions:</h3> Radiomics depicted distinct pathways of WM asymmetry in svPPA and nfvPPA involving damage of fiber tracts associated to linguistic functions. Assessing asymmetry of radiomics in PPA allows achieving a deeper insight into the neuroanatomical damage and a possible marker to evaluate the language severity changes related to drug therapy or rehabilitation speech treatments. <b>Disclosure:</b> Dr. Tafuri has nothing to disclose. Dr. Filardi has nothing to disclose. Dr. Urso has nothing to disclose. Dr. Gnoni has nothing to disclose. Dr. DE BLASI has nothing to disclose. Dr. Nigro has nothing to disclose. Dr. Logroscino has nothing to disclose.

Changes in motor activity level in individuals with frontotemporal dementia.

Changes in motor activity are common in individuals with Frontotemporal dementia (FTD). Yet, it remains unclear why some individuals become motorically hyperactive, while others hypoactive even in early stages of the disease. This study aimed to examine the relationship between motor activity level and (1) FTD clinical subtype, and (2) cortical thickness and subcortical volumes. Eighty-two charts were retrospectively reviewed from patients meeting consensus criteria for one of the three main clinical subtypes of FTD: probable bvFTD, semantic variant Primary Progressive Aphasia (PPA), or non-fluent variant PPA. Participants were assigned to one of three groups: (1) hyperactive, (2) hypoactive, or (3) no record of change. Hyperactivity was prevalent among bvFTD (58.5%) and semantic PPA (68.8%) subtypes while hypoactivity was less common in both subtypes (29.3% and 18.8%, respectively). The majority of patients with non-fluent PPA showed no record of change in motor activity (66.7%). The analysis of cortical thickness and subcortical volumes did not identify significant associations with motor activity levels. In conclusion, increased motor activity is highly prevalent among individuals with FTD, especially bvFTD and svPPA subtypes. These findings may inform prognosis and prediction of changes in motor activity, and allow planning for appropriate environmental and behavioural interventions. Future studies with prospective, standardized longitudinal collection of information regarding the type and level of change in motor activity, including wearable measures of actigraphy, may help to further delineate the onset and progression of abnormal motor behaviours and determine neuroanatomic associations in FTD.

Evaluating the Association Between Genetically Proxied Neurodevelopmental Language Phenotypes and the Risk of Primary Progressive Aphasia.

Primary progressive aphasia (PPA) is a neurodegenerative syndrome of progressive language decline. PPA has 3 main subtypes: logopenic, semantic, and agrammatic. Observational studies suggested an association between language-related neurodevelopmental phenotypes and an increased risk of PPA. We sought to assess such relationships through Mendelian randomization (MR) approach, which can suggest potentially causal associations. Genome-wide significant single-nucleotide polymorphisms (SNPs) associated with dyslexia (42 SNPs), developmental speech disorders (29 SNPs), and left-handedness (41 SNPs) were used as genetic proxies for the exposures. Eighteen of 41 SNPs of left-handedness were associated with structural asymmetry of the cerebral cortex. Genome-wide association study summary statistics were obtained from publicly available databases for semantic (308 cases/616 controls) and agrammatic PPA (269 cases/538 controls). The logopenic PPA (324 cases/3,444 controls) was approximated by proxy through the rubric of clinically diagnosed Alzheimer disease with salient language impairment. Inverse-weighted variance MR was performed as the main analysis for testing the relationship between the exposures and outcomes. Sensitivity analyses were completed to test the robustness of the results. Dyslexia, developmental speech disorders, and left-handedness were not associated with any PPA subtype (p > 0.05). The genetic proxy of cortical asymmetry in left-handedness was significantly associated with agrammatic PPA (β = 4.3, p = 0.007), but not with other PPA subtypes. This association was driven by microtubule-related genes, primarily by a variant that is in complete linkage disequilibrium with MAPT gene. Sensitivity analyses were overall consistent with the primary analyses. Our results do not support a causal association between dyslexia, developmental speech disorders, and handedness with any of the PPA subtypes. Our data suggest a complex association between cortical asymmetry genes and agrammatic PPA. Whether the additional association with left-handedness is necessary remains to be determined but is unlikely, given the absence of association between left-handedness and PPA. Genetic proxy of brain asymmetry (regardless of handedness) was not tested as an exposure due to lack of suitable genetic proxy. Furthermore, the genes related to cortical asymmetry associated with agrammatic PPA are implicated in microtubule-related proteins (TUBA1B, TUBB, and MAPT), which is keeping with the association of tau-related neurodegeneration in this PPA variant.

Multiclass prediction of different dementia syndromes based on multi-centric volumetric MRI imaging

IntroductionDementia syndromes can be difficult to diagnose. We aimed at building a classifier for multiple dementia syndromes using magnetic resonance imaging (MRI). MethodsAtlas-based volumetry was performed on T1-weighted MRI data of 426 patients and 51 controls from the multi-centric German Research Consortium of Frontotemporal Lobar Degeneration including patients with behavioral variant frontotemporal dementia, Alzheimer’s disease, the three subtypes of primary progressive aphasia, i.e., semantic, logopenic and nonfluent-agrammatic variant, and the atypical parkinsonian syndromes progressive supranuclear palsy and corticobasal syndrome. Support vector machine classification was used to classify each patient group against controls (binary classification) and all seven diagnostic groups against each other in a multi-syndrome classifier (multiclass classification). ResultsThe binary classification models reached high prediction accuracies between 71 and 95% with a chance level of 50%. Feature importance reflected disease-specific atrophy patterns. The multi-syndrome model reached accuracies of more than three times higher than chance level but was far from 100%. Multi-syndrome model performance was not homogenous across dementia syndromes, with better performance in syndromes characterized by regionally specific atrophy patterns. Whereas diseases generally could be classified vs controls more correctly with increasing severity and duration, differentiation between diseases was optimal in disease-specific windows of severity and duration. DiscussionResults suggest that automated methods applied to MR imaging data can support physicians in diagnosis of dementia syndromes. It is particularly relevant for orphan diseases beside frequent syndromes such as Alzheimer’s disease.

Brain total creatine differs between primary progressive aphasia (PPA) subtypes and correlates with disease severity

Primary progressive aphasia (PPA) is comprised of three subtypes: logopenic (lvPPA), non-fluent (nfvPPA), and semantic (svPPA). We used magnetic resonance spectroscopy (MRS) to measure tissue-corrected metabolite levels in the left inferior frontal gyrus (IFG) and right sensorimotor cortex (SMC) from 61 PPA patients. We aimed to: (1) characterize subtype differences in metabolites; and (2) test for metabolite associations with symptom severity. tCr differed by subtype across the left IFG and right SMC. tCr levels were lowest in lvPPA and highest in svPPA. tCr levels predicted lvPPA versus svPPA diagnosis. Higher IFG tCr and lower Glx correlated with greater disease severity. As tCr is involved in brain energy metabolism, svPPA pathology might involve changes in specific cellular energy processes. Perturbations to cellular energy homeostasis in language areas may contribute to symptoms. Reduced cortical excitatory capacity (i.e. lower Glx) in language regions may also contribute to symptoms. Thus, tCr may be useful for differentiating between PPA subtypes, and both tCr and Glx might have utility in understanding PPA mechanisms and tracking progression.

Comorbid Neurodegeneration in Primary Progressive Aphasia: Clinicopathological Correlations in a Single-Center Study.

Introduction Primary progressive aphasia (PPA) is a clinically variable syndrome manifesting as slow progressive loss of speech and language with multiple underlying neurodegenerative pathologies. Materials and Methods We included data from nine PPA patients with available autopsies. We then retrospectively reviewed all available medical records, neuropsychology, and MRI results to confirm the corresponding subtypes of PPA and compared them with postmortem neuropathological results. Results Clinical presentations corresponded to the nonfluent/agrammatic variant in six cases, the semantic variant in one case, the logopenic variant in one case, and the mixed variant (concomitant nonfluent/agrammatic plus semantic variant) in one case. Patients with a broader clinical presentation, i.e., combining manifestations of one PPA subtype and symptoms of another PPA variant, had autopsy comorbidities showing multiple neurodegenerative disorders. Of the nine subjects enrolled in the study, Alzheimer's disease (AD) was found in eight cases; however, in only one case, AD was detected as an isolated neuropathological substrate of PPA. In eight brain samples, different comorbid neuropathologies were detected: three cases with comorbid AD and dementia with Lewy bodies, two cases with comorbid AD and TDP-43 pathology, one case with comorbid AD and complex tauopathies, and one case with comorbid AD with both tau and TDP-43 deposits. Finally, one case had comorbid tau and TDP-43 pathology but without comorbid AD pathology. Conclusions Our observation suggests that PPA cases could be more heterogeneous in their etiology than previously thought and underlying neurodegenerative comorbidities should be considered in routine practice, especially if the clinical presentation of PPA is atypical.

Multimodality Imaging in Primary Progressive Aphasia.

Primary progressive aphasia is a clinically and neuropathologically heterogeneous group of progressive neurodegenerative disorders, characterized by language-predominant impairment and commonly associated with atrophy of the dominant language hemisphere. While this clinical entity has been recognized dating back to the 19th century, important advances have been made in defining our current understanding of primary progressive aphasia, with 3 recognized subtypes to date: logopenic variant, semantic variant, and nonfluent/agrammatic variant. Given the ongoing progress in our understanding of the neurobiology and genomics of these rare neurodegenerative conditions, accurate imaging diagnoses are of the utmost importance and carry implications for future therapeutic triaging. This review covers the diverse spectrum of primary progressive aphasia and its multimodal imaging features, including structural, functional, and molecular neuroimaging findings; it also highlights currently recognized diagnostic criteria, clinical presentations, histopathologic biomarkers, and treatment options of these 3 primary progressive aphasia subtypes.

Neuropathological fingerprints of survival, atrophy and language in primary progressive aphasia.

Primary progressive aphasia is a neurodegenerative disease that selectively impairs language without equivalent impairment of speech, memory or comportment. In 118 consecutive autopsies on patients with primary progressive aphasia, primary diagnosis was Alzheimer's disease neuropathological changes (ADNC) in 42%, corticobasal degeneration or progressive supranuclear palsy neuropathology in 24%, Pick's disease neuropathology in 10%, transactive response DNA binding proteinopathy type A [TDP(A)] in 10%, TDP(C) in 11% and infrequent entities in 3%. Survival was longest in TDP(C) (13.2 ± 2.6 years) and shortest in TDP(A) (7.1 ± 2.4 years). A subset of 68 right-handed participants entered longitudinal investigations. They were classified as logopenic, agrammatic/non-fluent or semantic by quantitative algorithms. Each variant had a preferred but not invariant neuropathological correlate. Seventy-seven per cent of logopenics had ADNC, 56% of agrammatics had corticobasal degeneration/progressive supranuclear palsy or Pick's disease and 89% of semantics had TDP(C). Word comprehension impairments had strong predictive power for determining underlying neuropathology positively for TDP(C) and negatively for ADNC. Cortical atrophy was smallest in corticobasal degeneration/progressive supranuclear palsy and largest in TDP(A). Atrophy encompassed posterior frontal but not temporoparietal cortex in corticobasal degeneration/progressive supranuclear palsy, anterior temporal but not frontoparietal cortex in TDP(C), temporofrontal but not parietal cortex in Pick's disease and all three lobes with ADNC or TDP(A). There were individual deviations from these group patterns, accounting for less frequent clinicopathologic associations. The one common denominator was progressive asymmetric atrophy overwhelmingly favouring the left hemisphere language network. Comparisons of ADNC in typical amnestic versus atypical aphasic dementia and of TDP in type A versus type C revealed fundamental biological and clinical differences, suggesting that members of each pair may constitute distinct clinicopathologic entities despite identical downstream proteinopathies. Individual TDP(C) participants with unilateral left temporal atrophy displayed word comprehension impairments without additional object recognition deficits, helping to dissociate semantic primary progressive aphasia from semantic dementia. When common and uncommon associations were considered in the set of 68 participants, one neuropathology was found to cause multiple clinical subtypes, and one subtype of primary progressive aphasia to be caused by multiple neuropathologies, but with different probabilities. Occasionally, expected clinical manifestations of atrophy sites were absent, probably reflecting individual peculiarities of language organization. The hemispheric asymmetry of neurodegeneration and resultant language impairment in primary progressive aphasia reflect complex interactions among the cellular affinities of the degenerative disease, the constitutive biology of language cortex, familial or developmental vulnerabilities of this network and potential idiosyncrasies of functional anatomy in the affected individual.

Linguistic profiles of variants of primary progressive aphasia

BackgroundSeveral subtypes of primary progressive aphasia (PPA) have been proposed. Most reports use small samples, and few have included Spanish-speaking participants. AimTo analyze the language profile and nonlinguistic deficits in a large sample of PPA Spanish monolingual participants. Method177 individuals were diagnosed with PPA in a sample consisting of 69 men and 108 women (Mage = 66.40 years, SD = 9.30). The participants were assessed using the Spanish versions of the Western Aphasia Battery Revised (SWAB-R) and the Boston Diagnostic Aphasia Examination (SBDAE). Non-verbal reasoning was evaluated with the Raven's Colored Progressive Matrices. Results41.8% of the sample met the criteria for the logopenic variant (lvPPA), while 28.2% met the criteria for semantic (svPPA), 15.3% for lexical (lxvPPA), and 14.7% for nonfluent/agrammatic (nfvPPA) variants. Language difficulties were similar in all variants except for lxvPPA. Scores on Spontaneous Language, Auditory Comprehension, Repetition, and Naming were significantly higher for the lxvPPA group. Raven's Colored Progressive Matrices scores were significantly lower in lvPPA. Years of education correlated with all test scores, while age was negatively associated with naming. When the PPA variants were classified according to the traditional aphasia classification, discrepancies were evident. Furthermore, the most frequent type of aphasia was Amnesic, while the least frequent was Wernicke's aphasia. ConclusionThe SWAB-R is useful in describing the clinical characteristics of aphasia for each variant of PPA, but quantitative scores from this battery are not capable of distinguishing between variants of PPA, with the exception of lxvPPA.

Chapter 6 - Clinical and neuroimaging characteristics of primary progressive aphasia

The chapter covers the clinical syndrome of a primary progressive aphasia (PPA), the demographics of this rare neurodegenerative disease, defining clinical and neuroanatomic characteristics of each PPA variant, disease progression, and behavioral features. The chapter begins with a brief introduction that includes references to seminal papers that defined this clinical syndrome and its three variants. The classic PPA subtypes discussed in the chapter are semantic variant PPA (svPPA), nonfluent/agrammatic PPA (nfaPPA), and logopenic variant PPA (lvPPA). The key language and cognitive characteristics, and language tasks that can elicit these language impairments, are detailed. Overlap in the clinical profiles of the PPA variants, which make differential diagnosis challenging, are explained. Disease progression is described, revealing that the PPA variants become more similar over time. Although PPA is language-predominant dementia, there are behavioral manifestations, particularly in svPPA. Changes in behavior in this variant are addressed as well as behavioral changes in nfaPPA and lvPPA that are less well recognized. The patterns of atrophy in the left temporal, parietal, and/or frontal cortices unique to each PPA variant are described. The underlying neuropathologies of the PPA variants are discussed, specifically tauopathies and non-tauopathies associated with svPPA and nfaPPA and Alzheimer's disease pathology in lvPPA.

MicroRNA biomarkers in frontotemporal dementia and to distinguish from Alzheimer's disease and amyotrophic lateral sclerosis.

Frontotemporal lobar degeneration describes a group of progressive brain disorders that primarily are associated with atrophy of the prefrontal and anterior temporal lobes. Frontotemporal lobar degeneration is considered to be equivalent to frontotemporal dementia. Frontotemporal dementia is characterized by progressive impairments in behavior, executive function, and language. There are two main clinical subtypes: behavioral-variant frontotemporal dementia and primary progressive aphasia. The early diagnosis of frontotemporal dementia is critical for developing management strategies and interventions for these patients. Without validated biomarkers, the clinical diagnosis depends on recognizing all the core or necessary neuropsychiatric features, but misdiagnosis often occurs due to overlap with a range of neurologic and psychiatric disorders. In the studies reviewed a very large number of microRNAs were found to be dysregulated but with limited overlap between individual studies. Measurement of specific miRNAs singly or in combination, or as miRNA pairs (as a ratio) in blood plasma, serum, or cerebrospinal fluid enabled frontotemporal dementia to be discriminated from healthy controls, Alzheimer's disease, and amyotrophic lateral sclerosis. Furthermore, upregulation of miR-223-3p and downregulation of miR-15a-5p, which occurred both in blood serum and cerebrospinal fluid, distinguished behavioral-variant frontotemporal dementia from healthy controls. Downregulation of miR-132-3p in frontal and temporal cortical tissue distinguished frontotemporal lobar degeneration and frontotemporal dementia, respectively, from healthy controls. Possible strong miRNA biofluid biomarker contenders for behavioral-variant frontotemporal dementia are miR-223-3p, miR-15a-5p, miR-22-3p in blood serum and cerebrospinal fluid, and miR-124 in cerebrospinal fluid. No miRNAs were identified able to distinguish between behavioral-variant frontotemporal dementia and primary progressive aphasia subtypes. Further studies are warranted on investigating miRNA expression in biofluids and frontal/temporal cortical tissue to validate and extend these findings.

The Diagnostic Value of Language Screening in Primary Progressive Aphasia: Validation and Application of the Sydney Language Battery.

The three variants of primary progressive aphasia (PPA) differ in clinical presentation, underlying brain pathology, and clinical course, which stresses the need for early differentiation. However, brief cognitive tests that validly distinguish between all PPA variants are lacking. The Sydney Language Battery (SYDBAT) is a promising screening instrument that can be used as a first step in a comprehensive neuropsychological assessment to distinguish PPA subtypes, but evidence on its validity and reliability is to date limited. In the current study, the validation and diagnostic value of the SYDBAT are described for discriminating PPA subtypes as well as distinguishing PPA from mild cognitive impairment (MCI) or Alzheimer's dementia (AD). Forty-five patients with PPA (13 with semantic PPA, 20 with logopenic PPA, and 12 with nonfluent/agrammatic PPA), 25 MCI patients, 13 AD patients, and 50 cognitively unimpaired controls were included in this study. Both patients and controls completed the SYDBAT-NL (Dutch version). Performance on and predictive ability of the four subtests (i.e., Naming, Word Comprehension, Repetition, and Semantic Association) were assessed. In addition, construct validity and internal consistency were examined. Different SYDBAT performance patterns were found across PPA and non-PPA patient groups. While a discriminant function analysis based on SYDBAT subtest scores could predict PPA subtype with 78% accuracy, it was more difficult to disentangle PPA from non-PPA patients based on SYDBAT scores alone. For assisting in clinical interpretation, simple rules were set up and translated into a diagnostic decision tree for subtyping PPA, which was capable of diagnosing a large proportion of the cases. Satisfying validity and reliability measures were found. The SYDBAT is an easy-to-use and promising screen for assessing single-word language processes, which may contribute to the differential diagnostic process of PPA and the assessment of language impairment in MCI and AD. It can be easily implemented for initial screening of patients in a memory clinic.

Language profile of primary progressive aphasia in a linguistically diverse cohort in India

AbstractBackgroundThe accurate characterization of language and semantic memory deficits is crucial for diagnosis of primary progressive aphasia (PPA). In a linguistically diverse society like India, assessment with linguistically appropriate and culturally relevant tools is essential but challenging. This study aimed at developing language and culture specific tests to diagnose PPA and profile cognitive‐linguistic characteristics of a diverse cohort of PPA in India.MethodBased on typical characteristics of Indian languages: free‐word order, rich system of morphology and case‐marking that are features that differentiate Indian languages from English, a language‐specific assessment battery was developed in seven languages: Hindi, Bengali (Indo‐Aryan languages) and Kannada, Telugu, Malayalam and Tamil (Dravidian languages). In the background of the importance of case‐markers in the syntax of Indian languages, a unique syntax assessment test was specifically developed. To evaluate semantic memory, the Indian Semantic Memory battery was developed using stimuli appropriate for a pan‐Indian cultural context. All patients underwent assessment of language proficiency and comprehensive cognitive evaluation by examiners proficient in the language of testing.Result36 patients with PPA: 22 with semantic variant (svPPA), 12 nonfluent variant (nfvPPA) and 2 logopenic variant (lvPPA) participated. The cohort consisted of proficient speakers of seven Indian languages. A particular difficulty in the appropriate use of case markers on the new test of syntax was revealed in nfvPPA compared to svPPA. Further, the core diagnostic feature of ‘agrammatism’ for PPA in English‐speaking nfvPPA was not as dramatic in Indian patients owing to the morphological richness of Indian languages, leading to reduced contrast between fluent versus non‐fluent aphasia. Consistent with diagnosis, a significant reduction in fluency was demonstrated in nfvPPA (p&lt; 0.006 on fluency tasks). Semantic memory was significantly affected in svPPA as revealed on non‐verbal tasks i.e., word‐picture matching (p&lt;0.02)and semantic association task(p&lt;0.01) of Indian Semantic Battery.ConclusionUsing language and culture specific assessment batteries tailored to the Indian context, a comprehensive clinical characteristics in PPA subtypes were identified. The need to re‐define agrammatism with respect to Indian languages with additional weightage to the use of case markers that assist in identifying the PPA subtype was a novel finding.

Neuroanatomical mapping of artificial intelligence‐based classification of language in PPA

AbstractBackgroundPatients with Primary Progressive Aphasia (PPA) are usually subtyped into one of the three canonical subtypes (nfvPPA, svPPA, lvPPA) based on a neurological and cognitive assessment including their language characteristics typically measured from a battery of confrontational tests. While widely used, this classification system has been criticized, and also the approach makes assumptions about the features of language that are important to measure. Here we use methods from Artificial Intelligence to measure features of speech from naturalistic connected speech samples with the goal of determining how well this data‐driven approach matches independent clinical subtypes and how its results relate to neuroanatomical abnormalities measured from MRI.MethodLanguage data was obtained from 78 PPA patients (28 nfvPPA, 26 lvPPA, 24 svPPA) describing the WAB Picnic Scene. A transformer model, RoBERTa, was used to measure similarities in language features, IVIS to perform dimensionality reduction, and nested k‐means to cluster language samples. We then examined the cortical atrophy patterns of these clusters of PPA patients versus healthy controls (N=25).ResultSeven PPA clusters were identified with 88% agreement with the classic classification system. Individuals in Clusters 1 and 2 (mainly nfvPPA) exhibited speech dysfluency and reduced clausal complexity with atrophy in the left pars opercularis, superior and caudal middle frontal gyri. Those in Clusters 3 and 4 (predominantly lvPPA) exhibited difficulties in subject‐verb agreement, demonstratives and tense and shared atrophy in the superior and middle temporal and inferior parietal gyri. Individuals in Clusters 5‐7 (mainly svPPA) exhibited deficits in nouns/verbs access with atrophy in the left temporal pole and inferior and middle temporal gyri.ConclusionData‐driven Artificial Intelligence methods applied to naturalistic speech samples from PPA patients identify clusters of patients that match well to clinical subtypes, and that exhibit cortical atrophy patterns typical of those subtypes. This suggests that PPA subtypes are natural kinds and that computational analysis of simple speech samples can be used to identify them.

Diagnosis of Alzheimer’s disease and frontotemporal dementia using FDG‐PET: Application of genetic algorithms

AbstractBackgroundGenetic algorithms are methods used in machine learning, which have a proven capability to explore a large space of solutions, deal with very large numbers of input features, and avoid local minima. Diagnosis of Alzheimer’s Disease (AD) and Frontotemporal dementia (FTD) is often challenging, and thorough costly assessments are often needed. We hypothesised that the application of machine learning, and specifically genetic algorithms, to 18F‐Fluorodeoxyglucose Positron Emission Tomography (FDG‐PET) may help in diagnosis by selecting the most meaningful features and automating diagnosis. In this study, we aimed to develop algorithms for three common situations: discrimination between patients with AD or FTD and healthy controls (HC), differential diagnosis between behavioural FTD (bvFTD) and AD, and differential diagnosis between primary progressive aphasia (PPA) variants.MethodEighty‐one patients with bvFTD, 88 patients with AD, 68 patients with PPA, and 39 HC were enrolled. Patients underwent a comprehensive clinical and neuropsychological protocol, and FDG‐PET imaging. Genetic algorithms, customised with K‐Nearest Neighbor and BayesNet Naives as the fitness function, were developed applied to the PET imaging and compared with Principal Component Analysis. The highest accuracy rate and most relevant features were identified. K‐fold cross validation within the same sample and external validation with ADNI samples were performed.ResultDiscrimination accuracy of FDG‐PET was 92‐95% for AD vs HCs, 95‐96% for bvFTD vs HCs, 89‐90% for AD vs bvFTD, and 90‐91% for classification of PPA subtypes. A reduced number of features was achieved, with cutting rates from 62% to 95.69% regarding the total number of variables, and several key brain regions were selected. External validation with ADNI obtained an accuracy of 82.93% for BayesNet Naives algorithm for the differentiation between AD and HC.ConclusionGenetic algorithms identified the most meaningful features with the minimum set of features, which may be relevant for automated assessment of brain FDG‐PET images. Overall, our study contributes to the development of an automated, and optimised diagnosis of neurodegenerative disorders using brain metabolism.

Metabolic positron-emission tomography/magnetic resonance imaging in primary progressive aphasia and frontotemporal lobar degeneration subtypes: Reassessment of expected [18F]-fluorodeoxyglucose uptake patterns.

Clinical assessment of frontotemporal lobar degeneration (FTLD)/primary progressive aphasia (PPA) patients is challenging, given that common cognitive assessments rely extensively on language. Since asymmetry in neuroimaging biomarkers is often described as a central finding in these patients, our study evaluated [18F]-fluorodeoxyglucose (FDG) uptake patterns in patients meeting clinical and imaging criteria for FTLD, with emphasis on PPA. Fifty-one subjects underwent brain [18F]-FDG positron-emission tomography/magnetic resonance imaging (PET/MRI) as part of their routine clinical workup for dementia and neurodegenerative disease. Images were obtained using a Siemens Biograph mMR integrated 3T PET/MRI scanner. PET surface maps and fusion fluid-attenuated inversion recovery-PET images were generated utilizing MIMneuro software. Two board-certified neuroradiologists and one nuclear medicine physician blinded to patient history classified each FTLD/PPA subtype and assessed for left- versus right-side dominant hypometabolism. Qualitative and semiquantitative assessment demonstrated 18 cases of PPA, 16 behavioral variant frontotemporal dementia (bvFTD), 12 corticobasal degeneration, and 5 progressive supranuclear palsy. Among the 18 PPA subjects (11 svPPA, 5 lvPPA, and 2 agPPA), 12 (67%) demonstrated left-dominant hypometabolism and 6 (33%) right-dominant hypometabolism. While existing literature stresses left-dominant hypometabolism as a key imaging feature in the PPA subtypes, a third of our cases demonstrated right-dominant hypometabolism, suggesting that emphasis should be placed on the functionality of specific brain regions affected, rather than left versus right sidedness of hypometabolism patterns.

Motor speech disorders in the nonfluent, semantic and logopenic variants of primary progressive aphasia

ObjectiveMotor speech disorders (MSDs) are characteristic for nonfluent primary progressive aphasia (nfvPPA). In primary progressive aphasia (PPA) of the semantic (svPPA) and of the logopenic type (lvPPA), speech motor function is considered typically intact. However, knowledge on the prevalence of MSDs in svPPA and lvPPA is mainly based on studies with a priori knowledge of PPA syndrome diagnosis. This fully blinded retrospective study aims to provide data on the prevalence of all types of MSDs in a large sample of German-speaking patients with different subtypes of PPA. MethodTwo raters, blinded for PPA subtype, independently evaluated connected speech samples for MSD syndrome and severity from 161 patients diagnosed with nfvPPA, svPPA or lvPPA in the database of the German Consortium of Frontotemporal Lobar Degeneration (FTLDc). In case of disagreement, a third experienced rater re-evaluated the speech samples, followed by a consensus procedure. Consensus was reached for 160 patients (74 nfvPPA, 49 svPPA, 37 lvPPA). Main resultsAcross all PPA syndromes, 43.8% of the patients showed MSDs. Patients with nfvPPA demonstrated the highest proportion of MSDs (62.2%), but MSDs were also identified in svPPA (26.5%) and lvPPA (29.7%), respectively. Overall, dysarthria was the most common class of MSDs, followed by apraxia of speech. In addition, we identified speech abnormalities presenting as “syllabic speech”, “dysfluent speech”, and “adynamic speech”. DiscussionOur study confirmed MSDs as frequently occurring in PPA. The study also confirmed MSDs to be most common in patients with nfvPPA. However, MSDs were also found in substantial proportions of patients with svPPA and lvPPA. Furthermore, our study identified speech motor deficits that have not received attention in previous studies on PPA. The results are discussed against the background of the existing literature on MSDs in PPA, including theoretical considerations of the neuroanatomical conditions described for each of the different subtypes of PPA.

Beyond language impairment: Profiles of apathy in primary progressive aphasia

Primary progressive aphasia (PPA) is characterised by predominant language and communication impairment. However, behavioural changes, such as apathy, are increasingly recognised. Apathy is defined as a reduction in motivation and goal-directed behaviour. Recent theoretical models have suggested that apathy can be delineated into multiple dimensions: executive apathy (i.e., deficits in maintaining goals and organisation), emotional apathy (i.e., emotional blunting and indifference) and initiation apathy (i.e., reduced self-initiation). Whether the nature of apathy differs between clinical variants of PPA, and across early and late disease stages, remains to be established. Here, carers/informants of 20 semantic variant PPA (svPPA), 15 non-fluent variant PPA (nfvPPA), 16 logopenic variant PPA (lvPPA) and 25 healthy older controls completed the Dimensional Apathy Scale to quantify executive, emotional and initiation apathy. Voxel-based morphometry was used to identify associations between dimensions of apathy and regions of grey matter intensity decrease. Our behavioural results showed greater executive and initiation apathy in late svPPA than in late nfvPPA patients, while late svPPA had greater emotional apathy than both late nfvPPA and late lvPPA groups. Executive and initiation apathy were significantly higher than premorbid levels in all PPA subtypes, while elevated emotional apathy was only seen in early and late svPPA. Distinct neural correlates were identified across apathy dimensions. Executive apathy correlated with grey matter intensity of the left dorsolateral prefrontal and inferior parietal cortices; emotional apathy with the left medial prefrontal, insular and cerebellar regions; and initiation apathy with right parietal areas. Our findings are the first to reveal evidence of the dimensional nature of apathy in PPA, with different clinical signatures observed for each subtype. From a clinical standpoint, these results will inform the development of targeted interventions for specific aspects of apathy which emerge in PPA.

Thematic Integration Impairments in Primary Progressive Aphasia: Evidence From Eye-Tracking.

Primary progressive aphasia (PPA) is a degenerative disease affecting language while leaving other cognitive facilities relatively unscathed. The agrammatic subtype of PPA (PPA-G) is characterized by agrammatic language production with impaired comprehension of noncanonical filler-gap syntactic structures, such as object-relatives [e.g., The sandwich that the girl ate (gap) was tasty], in which the filler (the sandwich) is displaced from the object position within the relative clause to a position preceding both the verb and the agent (the girl) and is replaced by a gap linked with the filler. One hypothesis suggests that the observed deficits of these structures reflect impaired thematic integration, including impaired prediction of the thematic role of the filler and impaired thematic integration at the gap, but spared structure building (i.e., creation of the gap). In the current study, we examined the on-line comprehension of object-relative and subject-relative clauses in healthy controls and individuals with agrammatic and logopenic PPA using eye-tracking. Eye-movement patterns in canonical subject-relative clause structures were essentially spared in both PPA groups. In contrast, eye-movement patterns in noncanonical object-relative clauses revealed delayed thematic prediction in both agrammatic and logopenic PPA, on-time structure building (i.e., gap-filling) in both groups, and abnormal thematic integration in agrammatic, but not logopenic, PPA. We argue that these results are consistent with the hypothesis that agrammatic comprehension deficits reflect impaired thematic integration.