Semantic and phonemic verbal fluency tests: Normative data for the Turkish population.

Semantic and phonemic verbal fluency tests are widely used neuropsychological assessments of executive functions and language skills and are easy to administer. The aim of this study was to determine the impact of age, education, and gender on semantic and phonemic verbal fluency tests and to establish normative data for Turkish adults aged between 18 and 86 years. The results revealed significant main effects of age and education on all subscores of verbal fluency tests. Furthermore, an interaction effect between age and education was observed on semantic fluency and letter K fluency scores. While no significant differences were found among the 18-29, 30-39, and 40-49 age groups in any of the subscores, performance on the tests decreased with increasing age. Significant differences were observed among all education groups in all subscores. No main or interaction effects of gender were found on any subscore. These normative data could prove useful in clinical and research settings for the assessment of cognitive impairment.

Designing an effective semantic fluency test for early MCI diagnosis with machine learning.

Semantic fluency tests are one of the key tests used in batteries for the early detection of Mild Cognitive Impairment (MCI) as the impairment in speech and semantic memory are among the first symptoms, attracting the attention of a large number of studies. Several new semantic categories and variables capable of providing complementary information of clinical interest have been proposed to increase their effectiveness. However, this also extends the time required to complete all tests and get the overall diagnosis. Therefore, there is a need to reduce the number of tests in the batteries and thus the time spent on them while maintaining or increasing their effectiveness. This study used machine learning methods to determine the smallest and most efficient combination of semantic categories and variables to achieve this goal. We utilized a database containing 423 assessments from 141 subjects, with each subject having undergone three assessments spaced approximately one year apart. Subjects were categorized into three diagnostic groups: Healthy (if diagnosed as healthy in all three assessments), stable MCI (consistently diagnosed as MCI), and heterogeneous MCI (when exhibiting alternations between healthy and MCI diagnoses across assessments). We obtained that the most efficient combination to distinguish between these categories of semantic fluency tests included the animals and clothes semantic categories with the variables corrects, switching, clustering, and total clusters. This combination is ideal for scenarios that require a balance between time efficiency and diagnosis capability, such as population-based screenings.

A mediation approach in resting-state connectivity between the medial prefrontal cortex and anterior cingulate in mild cognitive impairment.

Mild cognitive impairment (MCI) is recognized as the prodromal phase of dementia, a condition that can be either maintained or reversed through timely medical interventions to prevent cognitive decline. Considerable studies using functional magnetic resonance imaging (fMRI) have indicated that altered activity in the medial prefrontal cortex (mPFC) serves as an indicator of various cognitive stages of aging. However, the impacts of intrinsic functional connectivity in the mPFC as a mediator on cognitive performance in individuals with and without MCI have not been fully understood. In this study, we recruited 42 MCI patients and 57 healthy controls, assessing their cognitive abilities and functional brain connectivity patterns through neuropsychological evaluations and resting-state fMRI, respectively. The MCI patients exhibited poorer performance on multiple neuropsychological tests compared to the healthy controls. At the neural level, functional connectivity between the mPFC and the anterior cingulate cortex (ACC) was significantly weaker in the MCI group and correlated with multiple neuropsychological test scores. The result of the mediation analysis further demonstrated that functional connectivity between the mPFC and ACC notably mediated the relationship between the MCI and semantic fluency performance. These findings suggest that altered mPFC-ACC connectivity may have a plausible causal influence on cognitive decline and provide implications for early identifications of neurodegenerative diseases and precise monitoring of disease progression.

Levodopa modulates semantic fluency and uniqueness in non-demented patients with progressive supranuclear palsy.

INTRODUCTION: Semantic fluency is the ability to name items from a given category within a limited time, which relies on semantic knowledge, working memory, and executive function. Similar to patients with Parkinson's disease (PD), patients with progressive supranuclear palsy (PSP) scored lower than healthy adults in the well-established semantic fluency test. However, it is unclear how unique are the produced words. This study examined the relationship between semantic fluency and words' uniqueness in patients with PSP. METHODS: Twenty-seven patients with PSP Richardson's syndrome (PSP-RS), 37 patients with PD, and 41 healthy controls (HC) performed a standard semantic fluency test (animals), and their verbal responses were audio-recorded. We used the uniqueness to reflect the ability to produce both original and effective work, that is, creativity. RESULTS: The PSP-RS group produced fewer correct words and fewer unique words than the PD and HC groups. Moreover, the correlation between fluency and uniqueness was positive in the HC and PD groups but negative in the PSP-RS group. Importantly, the actual levodopa dose was positively correlated with the fluency but negatively correlated with the uniqueness in PSP-RS. The PSP-RS patients who took a greater dose of levodopa tended to produce more correct words but fewer unique words. CONCLUSIONS: These results suggested that levodopa may modulate semantic fluency and uniqueness in the early stages of PSP-RS.

Genome-Wide Epistatic Network Analyses of Semantic Fluency in Older Adults.

Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683, p = 2.52 × 10-8; rs880179, p = 4.83 × 10-8) mapped to the CMYAS gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10-5 < p < 7.35 × 10-3), of which two were replicated (p < 3.10 × 10-3). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.

Baseline functional connectivity predicts who will benefit from neuromodulation: evidence from primary progressive aphasia.

Background: Identifying the characteristics of individuals who demonstrate response to an intervention allows us to predict who is most likely to benefit from certain interventions. Prediction is challenging in rare and heterogeneous diseases, such as primary progressive aphasia (PPA), that have varying clinical manifestations. We aimed to determine the characteristics of those who will benefit most from transcranial direct current stimulation (tDCS) of the left inferior frontal gyrus (IFG) using a novel heterogeneity and group identification analysis. Methods: We compared the predictive ability of demographic and clinical patient characteristics (e.g., PPA variant and disease progression, baseline language performance) vs. functional connectivity alone (from resting-state fMRI) in the same cohort. Results: Functional connectivity alone had the highest predictive value for outcomes, explaining 62% and 75% of tDCS effect of variance in generalization (semantic fluency) and in the trained outcome of the clinical trial (written naming), contrasted with <15% predicted by clinical characteristics, including baseline language performance. Patients with higher baseline functional connectivity between the left IFG (opercularis and triangularis), and between the middle temporal pole and posterior superior temporal gyrus, were most likely to benefit from tDCS. Conclusions: We show the importance of a baseline 7-minute functional connectivity scan in predicting tDCS outcomes, and point towards a precision medicine approach in neuromodulation studies. The study has important implications for clinical trials and practice, providing a statistical method that addresses heterogeneity in patient populations and allowing accurate prediction and enrollment of those who will most likely benefit from specific interventions.

Evaluating Cognitive-Motor Interference in Multiple Sclerosis: A Technology-Based Approach.

BACKGROUND: People with multiple sclerosis (PwMS) frequently present both cognitive and motor impairments, so it is reasonable to assume they may have difficulties in executing dual-tasks (DT). The aim of the present study is to identify novel technology-based parameters to assess cognitive-motor interference (CMI) in PwMS. In particular, we focused on the definition of dual-task cost (DTC) measures using wearable and portable tools such as insoles and mobile apps. METHODS: All participants underwent a verbal fluency task (cognitive single-task, ST), a motor ST of walking, and a combination of these tasks (DT). Number of words uttered in the cognitive ST and steps recorded by insoles were used to calculate the motor and cognitive DTC. RESULTS: The number of steps strongly correlated with the walked meters for both single- (r = 0.88, p < 0.05) and dual- (r = 0.91, p < 0.05) tasks. Motor but not cognitive performances significantly worsened during DT. Over the cognitive ST and DT, the number of pronounced words progressively decreased, probably due to the activation of different cognitive processes. Cognitive efforts could be the cause of cognitive task prioritization. CONCLUSIONS: Our findings promote the use of low-cost devices to assess CMI easily in the clinical context and to detect ecologically valid DT impairments.

Predicting clinical progression and cognitive decline in patients with relapsing-remitting multiple sclerosis: a 6-year follow-up study.

INTRODUCTION: Cognitive impairment occurs from the earliest stages of multiple sclerosis (MS) and progresses over time. The introduction of disease modifying therapies (DMTs) has changed the prognosis for MS patients, offering a potential opportunity for improvement in the cognitive arena as well. MATERIAL AND METHODS: 41 patients with relapsing-remitting multiple sclerosis (MS) were recruited to the study. Thirty patients were available for final follow-up and were included in the analysis. Baseline (BL) brain MRI including volumetry and neuropsychological tests were performed. Blood samples were collected at BL and follow-up (FU) and were tested for: vascular endothelial growth factor (VEGF), soluble vascular cell adhesion molecule-1 (sVCAM1), soluble platelet-endothelial CAM-1 (sPECAM1), and soluble intercellular CAM-1 (sICAM-1). Patients were invited for a final neuropsychological follow-up after a median of 6 years. Disease activity (relapses, EDSS increase, new/active brain lesions on MRI) was analysed between BL and FU. RESULTS: The study group deteriorated in the Rey-Osterrieth Complex Figure (ROCF) test (p = 0.001), but improved significantly in three other tests, i.e. semantic fluency test (p = 0.013), California Verbal Learning Test (CVLT, p = 0.016), and Word Comprehension Test (WCT, p < 0.001). EDSS increase correlated negatively with semantic fluency and WCT scores (r = -0.579, p = 0.001 and r = -0.391, p = 0.033, respectively). Improvements in semantic fluency test and WCT correlated positively with baseline deep grey matter, grey matter, and cortical volumes (p < 0.05, r > 0). Higher EDSS on FU correlated significantly negatively with baseline left and right pallidum, right caudate, right putamen, right accumbens, and cortical volume (p < 0.05, r < 0). No significant relationship was found between the number of relapses and EDSS on FU or neuropsychological deteriorations. Improvements in WCT and CVLT correlated positively with baseline sPECAM1 and sVCAM1 results, respectively (r > 0, p < 0.05). Deterioration in ROCF test correlated significantly with higher levels of baseline VEGF and sVCAM1 (p < 0.05). CONCLUSIONS: Brain volume is an important predictor of future EDSS and cognitive functions outcome. MS patients have a potential for improving in neuropsychological tests over time. It remains to be established whether this is related to successful disease modification with immunotherapy. Baseline volumetric measures are stronger predictors of cognitive performance than relapse activity, which yet again highlights the importance of atrophy in MS prognosis.

The Role of Verbal Fluency as a Variable in Reading and Comprehension Skills in Bengali.

The study explored the role of verbal fluency in determining reading and comprehension skills in Bengali among 10-year old typically developing Bengali children. Robust correlations were found between semantic fluency and word reading (0.63) as well as semantic fluency and comprehension (0.70). Good correlation was found between letter fluency and comprehension (0.49), and, word reading and comprehension (0.62). The findings suggest that good word storing capacity and executive functions led to enhanced automaticity of retrieval and verbal fluency, which together with improved orthographic and phonological processing led to good word reading scores, contributing to lesser cognitive load thereby easing out the complex text comprehension task. Transcending narrow empirical base of reading theories derived from Western writing typologies delimited to orthographic depth and psycholinguistic grain size, the study contends that verbal fluency is another interesting variable determining the reading and comprehension skills in Bengali along with visuo-spatial complexity and complex phonology-orthography inconsistencies.

A right convergence area of the prefrontal lobe is involved in the improvement of semantic fluency in patients with post-stroke aphasia.

OBJECTIVES: This study aimed to longitudinally observe the improvement mechanism of semantic fluency in subacute post-stroke aphasia (PSA) patients using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Twelve PSA patients, about one month after onset, were enrolled in this study and received speech-language therapy (SLT) for one month. Auditory comprehension and semantic fluency were evaluated using the Western Aphasia Battery (WAB) and the Animal Fluency Test. Before and after treatment, rs-fMRI data were collected, and the dice similarity coefficient was used to measure the spatial similarity between each patient's lesion and a reference lesion. The left posterior inferior temporal gyrus (pITG) was used as a seed to calculate the normalized functional connectivity in whole-brain voxel analysis using DPABI software for statistical analysis. RESULTS: The dice similarity coefficient between each patient's lesion and the reference lesion showed moderate to high intensity (0.57 ± 0.14) in the Montreal Neurological Institute space. After treatment, we found a significant increase in functional connectivity between the left pITG and the right prefrontal lobe convergence area (peak t = 8.219, Gaussian random field multiple comparison correction, voxel p < 0.001, cluster p < 0.05). The increase in functional connectivity was negatively correlated with the improvement in auditory comprehension (r =-0.707, p = 0.033) and positively correlated with the improvement in semantic fluency (r = 0.79, p = 0.02). CONCLUSION: The improvement of semantic fluency in subacute PSA patients may require the participation of the right convergence area of the prefrontal lobe.

Semantic fluency in primary school-age children with vision impairment.

PURPOSE: Semantic fluency is potentially a useful tool for vocabulary assessment in children with vision impairment because it contains no visual test stimuli. It is not known whether in the primary school years children with vision impairment perform more poorly on semantic fluency tasks compared to their sighted peers. METHOD: We compared semantic fluency performance of two groups of 5- to 11-year-old British English speaking children-one group with vision impairment and one without. We also investigated within-group differences in performance, based on severity of vision impairment. We administered one category (animals) to children with vision impairment (n = 45) and sighted children (n = 30). Participants had one minute to respond. Responses were coded for accuracy, error type, clusters, and switches. RESULT: Correct responses increased with age within each group. Groups did not differ significantly on any outcome measure. Severity of vision impairment did not impact task performance. CONCLUSION: Results suggested that semantic fluency performance-at least for the category animals-is not different in children with vision impairment compared to sighted children. Findings also suggest that semantic fluency could be a suitable addition to the tools that speech-language pathologists use to assess language abilities in children with vision impairment.

Functional and structural connectivity correlates of semantic verbal fluency deficits in first-episode psychosis.

INTRODUCTION: Semantic verbal fluency (SVF) impairments are debilitating and present early in the course of psychotic illness. Deficits within frontal, parietal, and temporal brain regions contribute to this deficit, as long-range communication across this functionally integrated network is critical to SVF. This study sought to isolate disruptions in functional and structural connectivity contributing to SVF deficits during first-episode psychosis in the schizophrenia spectrum (FESz). METHODS: Thirty-three FESz and 34 matched healthy controls (HC) completed the Animal Naming Task to assess SVF. Magnetoencephalography was recorded during an analogous covert SVF task, and phase-locking value (PLV) used to measure functional connectivity between inferior frontal and temporoparietal structures bilaterally. Diffusion imaging was collected to measure fractional anisotropy (FA) of the arcuate fasciculus, the major tract connecting frontal and temporoparietal language areas. RESULTS: SVF scores were lower among FESz compared to HC. While PLV and FA did not differ between groups overall, FESz exhibited an absence of the left-lateralized nature of both measures observed in HC. Among FESz, larger right-hemisphere PLV was associated with worse SVF performance (ρ = -0.51) and longer DUP (ρ = -0.50). DISCUSSION: In addition to worse SVF, FESz exhibited diminished leftward asymmetry of structural and functional connectivity in fronto-temporoparietal SVF network. The relationship between theta-band hyperconnectivity and poorer performance suggests a disorganized executive network and may reflect dysfunction of frontal cognitive control centers. These findings illustrate an aberrant pattern across the distributed SVF network at disease onset and merit further investigation into development of asymmetrical hemispheric connectivity and its failure among high-risk populations.

Comparison of verbal fluency performance in Kannada-speaking adults with and without euthymic bipolar disorder type 1.

Individuals with euthymic bipolar disorder (BD) type I exhibit deficits in executive functions. Although less explored in the BD population, the tasks of verbal fluency (VF) have shown great potential in understanding semantic organization. This study provides an extensive exploration across the letter and semantic VF tasks in 27 demographically matched euthymic BD-I and healthy controls (HC). The groups were compared on measures of the total number of correct words (TNCW), temporal pattern analysis, number of clusters (NC), mean cluster size (MCS), number of switches (NS), and error pattern. An overall reduction in letter fluency scores (the TNCW, number of switches, and NC) as compared to semantic fluency scores was noted for both groups, with a significantly greater decrease in the BD-1 group. The MCS and temporal pattern were relatively similar across the two groups. The influence of education with no gender difference was observed between groups with error types prevalent in both groups. The study findings call attention toward assessing the VF performance in persons with BD in terms of error production and the strategies employed (clustering-switching).

Optimising verbal fluency analysis in neurological patients with dysarthria: examples from Parkinson's disease and hereditary ataxia.

BACKGROUND: Verbal fluency tests (VFTs) are widely used to assess cognitive-linguistic performance in neurological diseases. However, the influence of dysarthria on performance in tests requiring oral responses is unclear in ataxia and Parkinson's disease. OBJECTIVES: To determine the impact of dysarthria on VFT performance and evaluate the validity and reliability of alternative methods for analyzing VFT data. METHOD: Trained raters evaluated dysarthria using VFT recordings in people with ataxia (N = 61) or Parkinson's disease (PD; N = 69). Total Correct Items scores and qualitative parameters (intrusions, ambiguous verbalizations, perseverations, and interjections) were compared across semantic, phonemic, and alternating fluency tasks. Disease severity was considered as a covariate in the regression model. RESULTS: VFT dysarthria ratings correlated with the benchmark (ground truth) dysarthria scores derived from a monologue. Ambiguous responses resulting from unclear speech impeded the rater's ability to determine if a response was correct. Regression analysis indicated that more severe dysarthria ratings predicted diminished scores in all three tasks (semantic fluency, phonemic fluency and alternating fluency) in the ataxia group. The contribution of disease severity to semantic, phonemic and alternating fluency was reduced substantially in the ataxia group after accounting for dysarthria severity in the model in both groups. CONCLUSIONS: Dysarthria severity can be estimated based on speech samples derived from VFT. Dysarthria can lead to lower total correct items and is associated with more ambiguous verbalizations in VFT. Dysarthria severity should be considered when interpreting VFT performance in common movement disorders.

Application of the Semantic Fluency Test in the Screening of Mandarin-Chinese-Speaking Older Adults with Mild Dementia of the Alzheimer Type.

Semantic fluency tests have been widely used as a screening test for dementia of Alzheimer type. However, few studies have explored the application of semantic fluency tests in Mandarin Chinese speakers. This study aimed to explore the feasibility of using different semantic fluency test categories to distinguish between older adults without cognitive impairments and those with dementia of Alzheimer type in Taiwan. A total of 58 healthy older adults and 54 individuals with dementia of Alzheimer type were recruited. Semantic categories of "animals", "fruits", "vegetables", "birds", "means of transportations" and "musical instruments" were administered to participants. The scores from two groups of participants for each category were analyzed. Significant differences in the test scores of each category between two groups of participants were found. The results also revealed that the variables related to whether the participant had dementia, gender, age, and years of schooling significantly influenced the semantic fluency scores for each category. Among all the demographic characteristic of participants, the diagnosis of dementia was the most determining factor. Furthermore, this study proposed optimal cutoff points and calculated the AUC for various test durations (i.e., 30 s, 45 s and 60 s) and semantic categories in the semantic fluency test, which may serve as a reference that would help clinical personnel distinguish between older adults without cognitive impairments and those with dementia of Alzheimer type in Taiwan.

Methodologies for task-fMRI based prognostic biomarkers in response to aphasia treatment.

With the diversity in aphasia coupled with diminished gains at the chronic phase, it is imperative to deliver effective rehabilitation plans. Treatment outcomes have therefore been predicted using lesion-to-symptom mapping, but this method lacks holistic functional information about the language-network. This study, therefore, aims to develop whole-brain task-fMRI multivariate analysis to neurobiologically inspect lesion impacts on the language-network and predict behavioral outcomes in persons with aphasia (PWA) undergoing language therapy. In 14 chronic PWA, semantic fluency task-fMRI and behavioral measures were collected to develop prediction methodologies for post-treatment outcomes. Then, a recently developed imaging-based multivariate method to predict behavior (i.e., LESYMAP) was optimized to intake whole-brain task-fMRI data, and systematically tested for reliability with mass univariate methods. We also accounted for lesion size in both methods. Results showed that both mass univariate and multivariate methods identified unique biomarkers for semantic fluency improvements from baseline to 2-weeks post-treatment. Additionally, both methods demonstrated reliable spatial overlap in task-specific areas including the right middle frontal gyrus when identifying biomarkers of language discourse. Thus whole-brain task-fMRI multivariate analysis has the potential to identify functionally meaningful prognostic biomarkers even for relatively small sample sizes. In sum, our task-fMRI based multivariate approach holistically estimates post-treatment response for both word and sentence production and may serve as a complementary tool to mass univariate analysis in developing brain-behavior relationships for improved personalization of aphasia rehabilitation regimens.

Semantic fluency in 3-6 years old preschoolers: which executive functions?

Semantic Fluency (SF) increases with age, along with the lexicon and the strategies to access it. Among the cognitive processes involved in controlling lexical access, Executive Functions (EF) play an essential role. Nevertheless, which EF, namely inhibition, working memory, and cognitive flexibility, are specifically tapped by SF during preschool years, when these basic EF components are developing and differentiating, is still unknown. The study had a two-fold aim: 1. to analyze in preschoolers the role of EF basic components on SF; 2. to investigate if EF mediated the effect of age on SF. A total of 296 typically developing preschoolers (M age = 57.86; SD = 9.91; month range = 33-74) were assessed with an SF task and EF tasks measuring the main EF basic components. Results showed that during preschool, response inhibition, working memory, and cognitive flexibility were significant predictors of SF, explaining 27% of its variance. Moreover, the effect of age on the SF task performance correlated with the improvement of these EF components. This study supports the importance of considering cognitive control processes in 3-6 year-old preschoolers as they underline important competencies for the child's development, such as the ability to quickly access vocabulary.

Phonological and Semantic Fluency in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Semantic and Phonological fluency (SF and PF) are routinely evaluated in patients with Alzheimer's disease (AD). There are disagreements in the literature regarding which fluency task is more affected while developing AD. Most studies focus on SF assessment, given its connection with the temporoparietal amnesic system. PF is less reported, it is related to working memory, which is also impaired in probable and diagnosed AD. Differentiating between performance on these tasks might be informative in early AD diagnosis, providing an accurate linguistic profile. OBJECTIVE: Compare SF and PF performance in healthy volunteers, volunteers with probable AD, and patients with AD diagnosis, considering the heterogeneity of age, gender, and educational level variables. METHODS: A total of 8 studies were included for meta-analysis, reaching a sample size of 1,270 individuals (568 patients diagnosed with AD, 340 with probable AD diagnosis, and 362 healthy volunteers). RESULTS: The three groups consistently performed better on SF than PF. When progressing to a diagnosis of AD, we observed a significant difference in SF and PF performance across our 3 groups of interest (p = 0.04). The age variable explained a proportion of this difference in task performance across the groups, and as age increases, both tasks equally worsen. CONCLUSION: The performance of SF and PF might play a differential role in early AD diagnosis. These tasks rely on partially different neural bases of language processing. They are thus worth exploring independently in diagnosing normal aging and its transition to pathological stages, including probable and diagnosed AD.

Longitudinal changes in qualitative aspects of semantic fluency in presymptomatic and prodromal genetic frontotemporal dementia.

BACKGROUND: The semantic fluency test is one of the most widely used neuropsychological tests in dementia diagnosis. Research utilizing the qualitative, psycholinguistic information embedded in its output is currently underexplored in presymptomatic and prodromal genetic FTD. METHODS: Presymptomatic MAPT (n = 20) and GRN (n = 43) mutation carriers, and controls (n = 55) underwent up to 6 years of neuropsychological assessment, including the semantic fluency test. Ten mutation carriers became symptomatic (phenoconverters). Total score and five qualitative fluency measures (lexical frequency, age of acquisition, number of clusters, cluster size, number of switches) were calculated. We used multilevel linear regression modeling to investigate longitudinal decline. We assessed the co-correlation of the qualitative measures at each time point with principal component analysis. We explored associations with cognitive decline and grey matter atrophy using partial correlations, and investigated classification abilities using binary logistic regression. RESULTS: The interrater reliability of the qualitative measures was good (ICC = 0.75-0.90). There was strong co-correlation between lexical frequency and age of acquisition, and between clustering and switching. At least 4 years pre-phenoconversion, GRN phenoconverters had fewer but larger clusters (p < 0.001), and fewer switches (p = 0.004), correlating with lower executive function (r = 0.87-0.98). Fewer switches was predictive of phenoconversion, correctly classifying 90.3%. Starting at least 4 years pre-phenoconversion, MAPT phenoconverters demonstrated an increase in lexical frequency (p = 0.009) and a decline in age of acquisition (p = 0.034), correlating with lower semantic processing (r = 0.90). Smaller cluster size was predictive of phenoconversion, correctly classifying 89.3%. Increase in lexical frequency and decline in age of acquisition were associated with grey matter volume loss of predominantly temporal areas, while decline in the number of clusters, cluster size, and switches correlated with grey matter volume loss of predominantly frontal areas. CONCLUSIONS: Qualitative aspects of semantic fluency could give insight into the underlying mechanisms as to why the "traditional" total score declines in the different FTD mutations. However, the qualitative measures currently demonstrate more fluctuation than the total score, the measure that seems to most reliably deteriorate with time. Replication in a larger sample of FTD phenoconverters is warranted to identify if qualitative measures could be sensitive cognitive biomarkers to identify and track mutation carriers converting to the symptomatic stage of FTD.

Language dysfunction correlates with cognitive impairments in older adults without dementia mediated by amyloid pathology.

Background: Previous studies have explored the application of non-invasive biomarkers of language dysfunction for the early detection of Alzheimer's disease (AD). However, language dysfunction over time may be quite heterogeneous within different diagnostic groups. Method: Patient demographics and clinical data were retrieved from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database for the participants without dementia who had measures of cerebrospinal fluid (CSF) biomarkers and language dysfunction. We analyzed the effect of longitudinal neuropathological and clinical correlates in the pathological process of semantic fluency and confrontation naming. The mediation effects of AD biomarkers were also explored by the mediation analysis. Result: There were 272 subjects without dementia included in this analysis. Higher rates of decline in semantic fluency and confrontation naming were associated with a higher risk of progression to MCI or AD, and a greater decline in cognitive abilities. Moreover, the rate of change in semantic fluency was significantly associated with Aß deposition, while confrontation naming was significantly associated with both amyloidosis and tau burden. Mediation analyses revealed that both confrontation naming and semantic fluency were partially mediated by the Aß aggregation. Conclusion: In conclusion, the changes in language dysfunction may partly stem from the Aß deposition, while confrontation naming can also partly originate from the increase in tau burden. Therefore, this study sheds light on how language dysfunction is partly constitutive of mild cognitive impairment and dementia and therefore is an important clinical predictor.