Cognitive and Neurobiological Degeneration of the Mental Lexicon in Primary Progressive Aphasia

The ease with which we use the thousands of words in our vocabulary stands in stark contrast to our difficulty establishing how they are organized in our mind and brain. The breakdown of language due to cortical atrophy in primary progressive aphasia (PPA) creates conditions to study this organization at a cognitive and neurobiological level in that the three variants of this disease, namely non-fluent, logopenic, and semantic PPA, each bear their own signature of language-specific decline and cortical atrophy. As the impaired regions in each variant are linked to different lexical and semantic attributes of words, lexical decision performance of individuals with the distinct variants can reveal the conceptual and neural architecture of the lexicon through an anatomical-behavioral relationship. This dissertation investigated which lexical and semantic factors influence the structural degeneration of word processing in individuals with each variant of PPA through three studies that focused on the role of general semantic knowledge, psycholinguistic variables, and sensory-perceptual features, respectively. In Study 1, 41 individuals with PPA (13 non-fluent, 14 logopenic, and 14 semantic) as well as healthy controls (N = 25) performed a lexical decision task that consisted of 355 real words, carefully controlled on a broad range of psycholinguistic and semantic variables, and 175 pseudowords matched with the real words on the psycholinguistic variables. Two additional non-verbal semantic tasks (Pyramids and Palm Trees test and Over-regular Object Test) were administered to assess semantic ability and its relation with lexical decision performance. Results showed that—contrary to diagnostic expectations for the PPA variants—all three groups of individuals with PPA scored below the performance of matched control participants. The lexical-decision performance across all individuals with PPA correlated with semantic ability, but this correlation was not significant when separately analyzed per diagnosis. These findings suggest that semantic ability plays an active role in word recognition, but is not essential to lexical-semantic processing. In Study 2, the performance of the same participants was analyzed on a selected subset of the 355 words to examine the differential influence of the psycholinguistic factors lexical frequency, age of acquisition, and neighborhood density on lexical-semantic processing across the three diagnostic groups. The results demonstrated that lexical frequency has the largest influence on lexical-semantic processing, but that independent of that, age of acquisition and neighborhood density also play a role. The effect of these two variables becomes more salient dependent on the variant of PPA, accordant to the patterns of atrophy. That is, individuals with non-fluent and logopenic PPA experienced a neighborhood density effect consistent with atrophy in the inferior frontal and temporoparietal cortices, associated with lexical analysis and word form processing. By contrast, individuals with semantic PPA experienced an age of acquisition effect consistent with atrophy in the anterior temporal lobe which has been associated with semantic processing in previous literature. These findings suggest that the degeneration of lexical-semantic processing is affected by lexical factors—which relate to language-specific brain regions—in line with a hierarchical mental lexicon structure, such that a selective deficit at one of the levels of the mental lexicon results in distinctively expressed effects among psycholinguistic variables. Study 3 employed voxel-based morphometry (VBM) to identify the association between cortical volume—measured through T1-weighted magnetic resonance images (MRI)—and lexical decision performance related to sensory-perceptual features in 37 of the individuals with PPA and 17 of the controls on a second subset of the 355 words. Results showed that at both behavioral and neurobiological levels, semantic sensory-perceptual features of words (a strong association with, e.g., sound or action) influence lexical decision performance across all three groups with PPA. The results highlight the roles of the right hemisphere, the cerebellum, and the anterior temporal lobe in processing various sensory-perceptual features of concepts. The anterior temporal lobe has been proposed to be a semantic hub which processes various sensory-perceptual features (‘spokes’) into a conceptual representation in the hub-and-spoke model. The current results confirm this hub-role of the anterior temporal lobe, as well as the link of the ‘spokes’ to sensory-perceptual brain regions, as proposed by the hypothesis of embodied cognition. Most importantly, the results suggest that the intensity of semantic processing in the anterior temporal lobe is regulated by the degree of association with sensory-perceptual information. The current research presents novel evidence that lexical-semantic processing is influenced by a combination of lexical and semantic factors at both conceptual and neurobiological levels, which can become impaired in different ways in individuals with PPA based on a set of anatomical-behavioral relationships. In particular, this dissertation broke new ground in demonstrating that the intensity of semantic processing in the anterior temporal lobe depends on the degree of sensory-perceptual information of concepts, supporting both the hub-and-spoke model and the hypothesis of embodied cognition. As well, this dissertation established the independent effects of lexical frequency from age of acquisition and neighborhood density and their roles in lexical-semantic decline in PPA, supporting the theory of hierarchical distinctions between lexemes and their conceptual representations in the mental lexicon

Levels of Abstractness in Semantic Noun and Verb Processing:The Role of Sensory‑Perceptual and Sensory‑Motor Information

Effects of concreteness and grammatical class on lexical-semantic processing are well-documented, but the role of sensory-perceptual and sensory-motor features of concepts in underlying mechanisms producing these effects is relatively unknown. We hypothesized that processing dissimilarities in accuracy and response time performance in nouns versus verbs, concrete versus abstract words, and their interaction can be explained by differences in semantic weight—the combined amount of sensory-perceptual and sensory-motor information to conceptual representations—across those grammatical and semantic categories. We assessed performance on concrete and abstract subcategories of nouns and verbs with a semantic similarity judgment task. Results showed that when main effects of concreteness and grammatical class were analyzed in more detail, the grammatical-class effect, in which nouns are processed more accurately and quicker than verbs, was only present for concrete words, not for their abstract counterparts. Moreover, the concreteness effect, measured at different levels of abstract words, was present for both nouns and verbs, but it was less pronounced for verbs. The results do not support the grammatical-class hypothesis, in which nouns and verbs are separately organized, and instead provide evidence in favor of a unitary semantic space, in which lexical-semantic processing is influenced by the beneficial effect of sensory-perceptual and sensory-motor information of concepts

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

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

Midlife Vascular Factors and Prevalence of Mild Cognitive Impairment in Late-Life in Mexico

Objective: To estimate the prevalence of mild cognitive impairment (MCI) and its subtypes and investigate the impact of midlife cardiovascular risk factors on late-life MCI among the aging Mexican population. Method: Analyses included a sample of non-demented adults over the age of 55 living in both urban and rural areas of Mexico (N = 1807). MCI diagnosis was assigned based on a comprehensive cognitive assessment assessing the domains of memory, executive functioning, language, and visuospatial ability. The normative sample was selected by means of the robust norms approach. Cognitive impairment was defined by a 1.5-SD cut-off per cognitive domain using normative corrections for age, years of education, and sex. Risk factors included age, education, sex, rurality, depression, insurance status, workforce status, hypertension, diabetes, stroke, and heart disease. Results: The prevalence of amnestic MCI was 5.9%. Other MCI subtypes ranged from 4.2% to 7.7%. MCI with and without memory impairment was associated with older age (OR = 1.01 [1.01, 1.05]; OR = 1.03 [1.01, 1.04], respectively) and residing in rural areas (OR = 1.49 [1.08, 2.06]; OR = 1.35 [1.03, 1.77], respectively). Depression (OR = 1.07 [1.02, 1.12]), diabetes (OR = 1.37 [1.03, 1.82]), and years of education (OR = 0.94 [0.91, 0.97]) were associated with MCI without memory impairment. Midlife CVD increased the odds of MCI in late-life (OR = 1.76 [1.19, 2.59], which was driven by both midlife hypertension and diabetes (OR = 1.70 [1.18, 2.44]; OR = 1.88 [1.19, 2.97], respectively). Conclusions: Older age, depression, low education, rurality, and midlife hypertension and diabetes were associated with higher risk of late-life MCI among older adults in Mexico. Our findings suggest that the causes of cognitive impairment are multifactorial and vary by MCI subtype

Longitudinal decline in semantic versus letter fluency, but not their ratio, marks incident Alzheimer’s disease in Latinx Spanish-speaking older individuals

Objective: To compare longitudinal verbal fluency performance among Latinx Spanish speakers who develop Alzheimer’s disease to those who do not develop dementia in absolute number of words produced on each task and their ratio to combine both scores. Method: Participants included 833 Latinx Spanish-speaking older adults from a community-based prospective cohort in Manhattan. We performed growth curve modeling to investigate the trajectories of letter and semantic fluency, and their ratio (i.e., ‘semantic index’), between individuals who developed Alzheimer’s disease and those who did not (i.e., controls). The semantic index quantifies the proportion of words generated for semantic fluency in relation to the total verbal fluency performance. Results: Letter fluency performance did not decline in controls; we observed a linear decline in those who developed Alzheimer’s disease. Semantic fluency declined in both groups and showed an increased rate of change over time in the incident Alzheimer’s disease group; in comparison, the control group had a linear and slower decline. There were no group differences in the longitudinal trajectory (intercept and slope) of the semantic index. Conclusion: A decline in letter fluency and a more rapid and accelerating decline over time in semantic fluency distinguished people who developed Alzheimer’s disease from controls. Using the semantic index was not a superior marker of incident Alzheimer’s disease compared to examining the two fluency scores individually. Results suggest the differential decline in verbal fluency tasks, when evaluated appropriately, may be useful for early identification of Alzheimer’s disease in Latinx Spanish speakers, a historically understudied population. Keywords: category fluency, phonemic fluency, language, dementia, Hispani

Bear in mind: the role of personal background in semantic animal fluency – The SMART-MR study

ObjectivesSemantic fluency is a prominent neuropsychological task, typically administered within the category ‘animals’. With the increasing development of novel item-level metrics of semantic fluency, a concern around the validity of item-level analyses could be that personal background factors (e.g., hobbies like birdwatching or fishing) may disproportionally influence performance. We analyzed animal fluency performance at the item level and investigated the prevalence of individuals with abundant knowledge in specific classes of animals (e.g., birds, fish, insects) and the relationship of such knowledge with personal background factors and other cognitive tasks (episodic memory and executive functioning).MethodParticipants included 736 Dutch middle-aged to older adults from the SMART-MR cohort (mean age 58 ± 9.4 years, 18% women). Individuals were asked to name as many animals as possible for 2 min. Number of people with abundant animal class knowledge was calculated for the ability to recall a series of minimum ≥5 and up to ≥15 animals within a specific class with at most one interruption by an animal from another class. Subsequent analyses to investigate relationships of abundant class knowledge with sociodemographic characteristics (t-tests and chi-square tests) and cognitive performance (linear regressions) were performed for a cut-off of ≥10 animals within a specific class (90th percentile), with a sensitivity analysis for ≥7 animals (67th percentile).ResultsA total of 416 (56.2%) participants recalled a series of ≥5 animals from a specific class, 245 (33.3%) participants recalled ≥7, 78 (10.6%) participants recalled ≥10, and 8 (1.1%) participants recalled ≥15. Those who recalled a series of at least 10 animals within a class were older, more often men, and more often retired than those who did not. Moreover, they had a higher total score on animal fluency, letter fluency (i.e., executive functioning), and episodic memory tasks compared to those who did not.DiscussionOur results suggest that the benefit of abundant animal class knowledge gained by personal background does not disproportionally influence animal fluency performance as individuals with such knowledge also performed better on other cognitive tasks unrelated to abundant knowledge of animal classes

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Primary Progressive Aphasias in Bilinguals and Multilinguals

Primary progressive aphasia (PPA) is the result of neurodegeneration affecting language abilities that continue to decline as the disease progresses. There are three main variants of PPA: non‐fluent, semantic, and logopenic. Deficits may occur in different areas of language, such as lexical retrieval, auditory comprehension, syntactic structure, processing morphological components, and repetition abilities. However, the impact on language is not comparable across all individuals with PPA; rather it differs for each of the different variants based on the underlying pattern of neural change. In bilinguals or multilinguals with PPA, the language decline has an added layer of complexity. Decline may occur across the different languages in parallel, or differentially, and a number of factors may affect the pattern of decline. Recognizing the factors that most affect language decline in bilinguals and multilinguals with PPA, along with identifying the neural changes occurring in the brain, can increase our understanding of language organization in the bilingual or multilingual brain. It should be noted that language decline is not the only decline associated with PPA, as changes in cognition and behaviour have also been observed, particularly in the later stages (e.g. Rosen et al. 2006). However, language is the most salient decline in PPA so we focus on language in this chapter

Cross-sectional associations of amyloid burden with semantic cognition in older adults without dementia: A systematic review and meta-analysis

Previous research suggests the presence of subtle semantic decline in early stages of Alzheimer's disease. This study investigated associations between amyloid burden, a biomarker for Alzheimer's disease, and tasks of semantic impairment in older individuals without dementia. A systematic search in MEDLINE, PsycINFO, and Embase yielded 3691 peer-reviewed articles excluding duplicates. After screening, 41 studies with overall 7495 participants were included in the meta-analysis and quality assessment. The overall weighted effect size of the association between larger amyloid burden and larger semantic impairment was 0.10 (95% CI [-0.03; 0.22], p = 0.128) for picture naming, 0.19 (95% CI [0.11; 0.27], p < 0.001) for semantic fluency, 0.15 (95% CI [-0.15; 0.45], p = 0.326) for vocabulary, and 0.10 (95% CI [-0.14; 0.35], p = 0.405; 2 studies) for WAIS Information. Risk of bias was highest regarding comparability, as effect sizes were often not calculated on covariate-adjusted statistics. The relevance of the indicated amyloid-related decline in semantic fluency for research and clinical applications is likely negligible due to the effect's small magnitude. Future research should develop more sensitive metrics of semantic fluency to optimize its use for early detection of Alzheimer's disease-related cognitive impairment