Plasma p-tau217 predicts cognitive impairments up to ten years before onset in normal older adults.

Importance: Positron emission tomography (PET) biomarkers are the gold standard for detection of Alzheimer amyloid and tau in vivo . Such imaging can identify cognitively unimpaired (CU) individuals who will subsequently develop cognitive impartment (CI). Plasma biomarkers would be more practical than PET or even cerebrospinal fluid (CSF) assays in clinical settings. Objective: Assess the prognostic accuracy of plasma p-tau217 in comparison to CSF and PET biomarkers for predicting the clinical progression from CU to CI. Design: In a cohort of elderly at high risk of developing Alzheimer's dementia (AD), we measured the proportion of CU individuals who developed CI, as predicted by Aß (A+) and/or tau (T+) biomarker assessment from plasma, CSF, and PET. Results from each method were compared with (A-T-) reference individuals. Data were analyzed from June 2023 to April 2024. Setting: Longitudinal observational cohort. Participants: Some 228 participants from the PREVENT-AD cohort were CU at the time of biomarker assessment and had 1 - 10 years of follow-up. Plasma was available from 215 participants, CSF from 159, and amyloid- and tau-PET from 155. Ninety-three participants had assessment using all three methods (main group of interest). Progression to CI was determined by clinical consensus among physicians and neuropsychologists who were blind to plasma, CSF, PET, and MRI findings, as well as APOE genotype. Exposures: Plasma Aß 42/40 was measured using IP-MS; CSF Aß 42/40 using Lumipulse; plasma and CSF p-tau217 using UGOT assay. Aß-PET employed the 18 F-NAV4694 ligand, and tau-PET used 18 F-flortaucipir. Main Outcome: Prognostic accuracy of plasma, CSF, and PET biomarkers for predicting the development of CI in CU individuals. Results: Cox proportional hazard models indicated a greater progression rate in all A+T+ groups compared to A-T-groups (HR = 6.61 [95% CI = 2.06 - 21.17] for plasma, 3.62 [1.49 - 8.81] for CSF and 9.24 [2.34 - 36.43] for PET). The A-T+ groups were small, but also characterized with individuals who developed CI. Plasma biomarkers identified about five times more T+ than PET. Conclusion and relevance: Plasma p-tau217 assessment is a practical method for identification of persons who will develop cognitive impairment up to 10 years later. Key Points: Question: Can plasma p-tau217 serve as a prognostic indicator for identifying cognitively unimpaired (CU) individuals at risk of developing cognitive impairments (CI)?Findings: In a longitudinal cohort of CU individuals with a family history of sporadic AD, almost all individuals with abnormal plasma p-tau217 concentrations developed CI within 10 years, regardless of plasma amyloid levels. Similar findings were obtained with CSF p-tau217 and tau-PET. Fluid p-tau217 biomarkers had the main advantage over PET of identifying five times more participants with elevated tau.Meaning: Elevated plasma p-tau217 levels in CU individuals strongly indicate future clinical progression.

Irregular word reading as a marker of semantic decline in Alzheimer's disease: implications for premorbid intellectual ability measurement.

BACKGROUND: Irregular word reading has been used to estimate premorbid intelligence in Alzheimer's disease (AD) dementia. However, reading models highlight the core influence of semantic abilities on irregular word reading, which shows early decline in AD. The primary objective of this study is to ascertain whether irregular word reading serves as an indicator of cognitive and semantic decline in AD, potentially discouraging its use as a marker for premorbid intellectual abilities. METHOD: Six hundred eighty-one healthy controls (HC), 104 subjective cognitive decline, 290 early and 589 late mild cognitive impairment (EMCI, LMCI) and 348 AD participants from the Alzheimer's Disease Neuroimaging Initiative were included. Irregular word reading was assessed with the American National Adult Reading Test (AmNART). Multiple linear regressions were conducted predicting AmNART score using diagnostic category, general cognitive impairment and semantic tests. A generalized logistic mixed-effects model predicted correct reading using extracted psycholinguistic characteristics of each AmNART words. Deformation-based morphometry was used to assess the relationship between AmNART scores and voxel-wise brain volumes, as well as with the volume of a region of interest placed in the left anterior temporal lobe (ATL), a region implicated in semantic memory. RESULTS: EMCI, LMCI and AD patients made significantly more errors in reading irregular words compared to HC, and AD patients made more errors than all other groups. Across the AD continuum, as well as within each diagnostic group, irregular word reading was significantly correlated to measures of general cognitive impairment / dementia severity. Neuropsychological tests of lexicosemantics were moderately correlated to irregular word reading whilst executive functioning and episodic memory were respectively weakly and not correlated. Age of acquisition, a primarily semantic variable, had a strong effect on irregular word reading accuracy whilst none of the phonological variables significantly contributed. Neuroimaging analyses pointed to bilateral hippocampal and left ATL volume loss as the main contributors to decreased irregular word reading performances. CONCLUSIONS: While the AmNART may be appropriate to measure premorbid intellectual abilities in cognitively unimpaired individuals, our results suggest that it captures current semantic decline in MCI and AD patients and may therefore underestimate premorbid intelligence. On the other hand, irregular word reading tests might be clinically useful to detect semantic impairments in individuals on the AD continuum.

Demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy: an international cohort study and individual participant data meta-analysis.

BACKGROUND: Posterior cortical atrophy is a rare syndrome characterised by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing. The disorder has been associated with underlying neuropathological features of Alzheimer's disease, but large-scale biomarker and neuropathological studies are scarce. We aimed to describe demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy in a large international cohort. METHODS: We searched PubMed between database inception and Aug 1, 2021, for all published research studies on posterior cortical atrophy and related terms. We identified research centres from these studies and requested deidentified, individual participant data (published and unpublished) that had been obtained at the first diagnostic visit from the corresponding authors of the studies or heads of the research centres. Inclusion criteria were a clinical diagnosis of posterior cortical atrophy as defined by the local centre and availability of Alzheimer's disease biomarkers (PET or CSF), or a diagnosis made at autopsy. Not all individuals with posterior cortical atrophy fulfilled consensus criteria, being diagnosed using centre-specific procedures or before development of consensus criteria. We obtained demographic, clinical, biofluid, neuroimaging, and neuropathological data. Mean values for continuous variables were combined using the inverse variance meta-analysis method; only research centres with more than one participant for a variable were included. Pooled proportions were calculated for binary variables using a restricted maximum likelihood model. Heterogeneity was quantified using I2. FINDINGS: We identified 55 research centres from 1353 papers, with 29 centres responding to our request. An additional seven centres were recruited by advertising via the Alzheimer's Association. We obtained data for 1092 individuals who were evaluated at 36 research centres in 16 countries, the other sites having not responded to our initial invitation to participate to the study. Mean age at symptom onset was 59·4 years (95% CI 58·9-59·8; I2=77%), 60% (56-64; I2=35%) were women, and 80% (72-89; I2=98%) presented with posterior cortical atrophy pure syndrome. Amyloid ß in CSF (536 participants from 28 centres) was positive in 81% (95% CI 75-87; I2=78%), whereas phosphorylated tau in CSF (503 participants from 29 centres) was positive in 65% (56-75; I2=87%). Amyloid-PET (299 participants from 24 centres) was positive in 94% (95% CI 90-97; I2=15%), whereas tau-PET (170 participants from 13 centres) was positive in 97% (93-100; I2=12%). At autopsy (145 participants from 13 centres), the most frequent neuropathological diagnosis was Alzheimer's disease (94%, 95% CI 90-97; I2=0%), with common co-pathologies of cerebral amyloid angiopathy (71%, 54-88; I2=89%), Lewy body disease (44%, 25-62; I2=77%), and cerebrovascular injury (42%, 24-60; I2=88%). INTERPRETATION: These data indicate that posterior cortical atrophy typically presents as a pure, young-onset dementia syndrome that is highly specific for underlying Alzheimer's disease pathology. Further work is needed to understand what drives cognitive vulnerability and progression rates by investigating the contribution of sex, genetics, premorbid cognitive strengths and weaknesses, and brain network integrity. FUNDING: None.

Assessing processing speed and its neural correlates in the three variants of primary progressive aphasia with a non-verbal tablet-based task.

Prior research has revealed distinctive patterns of impaired language abilities across the three variants of Primary Progressive Aphasia (PPA): nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). However, little is known about whether, and to what extent, non-verbal cognitive abilities, such as processing speed, are impacted in PPA patients. This is because neuropsychological tests typically contain linguistic stimuli and require spoken output, being therefore sensitive to verbal deficits in aphasic patients. The aim of this study is to investigate potential differences in processing speed between PPA patients and healthy controls, and among the three PPA variants, using a brief non-verbal tablet-based task (Match) modeled after the WAIS-III digit symbol coding test, and to determine its neural correlates. Here, we compared performance on the Match task between PPA patients (n = 61) and healthy controls (n = 59) and across the three PPA variants. We correlated performance on Match with voxelwise gray and white matter volumes. We found that lvPPA and nfvPPA patients performed significantly worse on Match than healthy controls and svPPA patients. Worse performance on Match across PPA patients was associated with reduced gray matter volume in specific parts of the left middle frontal gyrus, superior parietal lobule, and precuneus, and reduced white matter volume in the left parietal lobe. To conclude, our behavioral findings reveal that processing speed is differentially impacted across the three PPA variants and provide support for the potential clinical utility of a tabled-based task (Match) to assess non-verbal cognition. In addition, our neuroimaging findings confirm the importance of a set of fronto-parietal regions that previous research has associated with processing speed and executive control. Finally, our behavioral and neuroimaging findings combined indicate that differences in processing speed are largely explained by the unequal distribution of atrophy in these fronto-parietal regions across the three PPA variants.

Social cognition and behavioral changes in patients with posterior cortical atrophy.

Posterior cortical atrophy (PCA) is a rare neurodegenerative condition characterized by progressive visual and visuospatial dysfunction. The consensus criteria state that patients should present "relatively spared behavior and personality" in early stages. However, limited research has focused on these symptoms in PCA. This study compared 157 patients with PCA in early stages of the disease with 352 healthy controls (HC), 202 typical AD (tAD), and 177 logopenic variant primary progressive aphasia (lvPPA) patients from the National Alzheimer's Coordinating Center (NACC) dataset. They were compared using clinician ratings of behavioral symptoms, informant- and clinician-filled questionnaires and patient-facing tests of behavior and social cognition. Results showed that PCA individuals exhibited many behavioral symptoms, the more frequently reported being anxiety, depression, apathy, and irritability. During cognitive testing, clinicians observed disorganized and reactive behaviors, but no insensitive behaviors. Informant reports indicated that PCA patients exhibited higher levels of inhibition and anxiety in response to stimuli associated with non-reward, novelty, and punishment. Social norms knowledge and empathy were overall preserved, although slight decreases in perspective-taking and socioemotional sensitivity were observed on informant-rated questionnaires. Except for more elevated neuropsychiatric symptoms in tAD, the three AD variants had similar profiles. Our findings provide insights into the social cognition and behavioral profiles of PCA, highlighting patterns of preservations and mild impairments, even in the early stages of the disease. These results contribute to a more complete understanding of non-visual symptoms in PCA and have implications for diagnostic and intervention strategies.

Diminished baseline autonomic outflow in semantic dementia relates to left-lateralized insula atrophy.

In semantic dementia (SD), asymmetric degeneration of the anterior temporal lobes is associated with loss of semantic knowledge and alterations in socioemotional behavior. There are two clinical variants of SD: semantic variant primary progressive aphasia (svPPA), which is characterized by predominant atrophy in the anterior temporal lobe and insula in the left hemisphere, and semantic behavioral variant frontotemporal dementia (sbvFTD), which is characterized by predominant atrophy in those structures in the right hemisphere. Previous studies of behavioral variant frontotemporal dementia, an associated clinical syndrome that targets the frontal lobes and anterior insula, have found impairments in baseline autonomic nervous system activity that correlate with left-lateralized frontotemporal atrophy patterns and disruptions in socioemotional functioning. Here, we evaluated whether there are similar impairments in resting autonomic nervous system activity in SD that also reflect left-lateralized atrophy and relate to diminished affiliative behavior. A total of 82 participants including 33 people with SD (20 svPPA and 13 sbvFTD) and 49 healthy older controls completed a laboratory-based assessment of respiratory sinus arrhythmia (RSA; a parasympathetic measure) and skin conductance level (SCL; a sympathetic measure) during a two-minute resting baseline period. Participants also underwent structural magnetic resonance imaging, and informants rated their current affiliative behavior on the Interpersonal Adjective Scale. Results indicated that baseline RSA and SCL were lower in SD than in healthy controls, with significant impairments present in both svPPA and sbvFTD. Voxel-based morphometry analyses revealed left-greater-than-right atrophy related to diminished parasympathetic and sympathetic outflow in SD. While left-lateralized atrophy in the mid-to-posterior insula correlated with lower RSA, left-lateralized atrophy in the ventral anterior insula correlated with lower SCL. In SD, lower baseline RSA, but not lower SCL, was associated with lower gregariousness/extraversion. Neither autonomic measure related to warmth/agreeableness, however. Through the assessment of baseline autonomic nervous system physiology, the present study contributes to expanding conceptualizations of the biological basis of socioemotional alterations in svPPA and sbvFTD.

Irregular word reading as a marker of cognitive and semantic decline in Alzheimer's disease rather than an estimate of premorbid intellectual abilities.

Background: Irregular word reading has been used to estimate premorbid intelligence in Alzheimer's disease (AD) dementia. However, reading models highlight the core influence of semantic abilities on irregular word reading, which shows early decline in AD. The general aim of this study is to determine whether irregular word reading is a valid estimate of premorbid intelligence, or a marker of cognitive and semantic decline in AD. Method: 681 healthy controls (HC), 104 subjective cognitive decline, 290 early and 589 late mild cognitive impairment (EMCI, LMCI) and 348 AD participants from the Alzheimer's Disease Neuroimaging Initiative were included. Irregular word reading was assessed with the American National Adult Reading Test (AmNART). Multiple linear regressions were conducted predicting AmNART score using diagnostic category, general cognitive impairment and semantic tests. A generalized logistic mixed-effects model predicted correct reading using extracted psycholinguistic characteristics of each AmNART words. Deformation-based morphometry was used to assess the relationship between AmNART scores and voxel-wise brain volumes, as well as with the volume of a region of interest placed in the left anterior temporal lobe (ATL). Results: EMCI, LMCI and AD patients made significantly more errors in reading irregular words compared to HC, and AD patients made more errors than all other groups. Across the AD continuum, as well as within each diagnostic group, irregular word reading was significantly correlated to measures of general cognitive impairment / dementia severity. Neuropsychological tests of lexicosemantics were moderately correlated to irregular word reading whilst executive functioning and episodic memory were respectively weakly and not correlated. Age of acquisition, a primarily semantic variable, had a strong effect on irregular word reading accuracy whilst none of the phonological variables significantly contributed. Neuroimaging analyses pointed to bilateral hippocampal and left ATL volume loss as the main contributors to decreased irregular word reading performances. Conclusions: Irregular word reading performances decline throughout the AD continuum, and therefore, premorbid intelligence estimates based on the AmNART should not be considered accurate in MCI or AD. Results are consistent with the theory of irregular word reading impairments as an indicator of disease severity and semantic decline.

Expressive Prosody in Patients With Focal Anterior Temporal Neurodegeneration.

BACKGROUND AND OBJECTIVES: Progressive focal anterior temporal lobe (ATL) neurodegeneration has been historically called semantic dementia. More recently, semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) have been linked with predominant left and right ATL neurodegeneration, respectively. Nonetheless, clinical tools for an accurate diagnosis of sbvFTD are still lacking. Expressive prosody refers to the modulation of pitch, loudness, tempo, and quality of voice used to convey emotional and linguistic information and has been linked to bilateral but right-predominant frontotemporal functioning. Changes in expressive prosody can be detected with semiautomated methods and could represent a useful diagnostic marker of socioemotional functioning in sbvFTD. METHODS: Participants underwent a comprehensive neuropsychological and language evaluation and a 3T MRI at the University of California San Francisco. Each participant provided a verbal description of the picnic scene from the Western Aphasia Battery. The fundamental frequency (f0) range, an acoustic measure of pitch variability, was extracted for each participant. We compared the f0 range between groups and investigated associations with an informant-rated measure of empathy, a facial emotion labeling task, and gray matter (GM) volumes using voxel-based morphometry. RESULTS: Twenty-eight patients with svPPA, 18 with sbvFTD, and 18 healthy controls (HCs) were included. f0 range was significantly different across groups: patients with sbvFTD showed reduced f0 range in comparison with both patients with svPPA (mean difference of -1.4 ± 2.4 semitones; 95% CI -2.4 to -0.4]; p < 0.005) and HCs (mean difference of -1.9 ± 3.0 semitones; 95% CI -3.0 to -0.7]; p < 0.001). A higher f0 range was correlated with a greater informant-rated empathy (r = 0.355; p ≤ 0.05), but not facial emotion labeling. Finally, the lower f0 range was correlated with lower GM volume in the right superior temporal gyrus, encompassing anterior and posterior portions (p < 0.05 FWE cluster corrected). DISCUSSION: Expressive prosody may be a useful clinical marker of sbvFTD. Reduced empathy is a core symptom in sbvFTD; the present results extend this to prosody, a core component of social interaction, at the intersection of speech and emotion. They also inform the long-standing debate on the lateralization of expressive prosody in the brain, highlighting the critical role of the right superior temporal lobe.

Network anatomy in logopenic variant of primary progressive aphasia.

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis.

Atypical forms of Alzheimer's disease: patients not to forget.

PURPOSE OF REVIEW: The aim of this paper is to summarize the latest work on neuroimaging in atypical Alzheimer's disease (AD) patients and to emphasize innovative aspects in the clinic and research. The paper will mostly cover language (logopenic variant of primary progressive aphasia; lvPPA), visual (posterior cortical atrophy; PCA), behavioral (bvAD) and dysexecutive (dAD) variants of AD. RECENT FINDINGS: MRI and PET can detect and differentiate typical and atypical AD variants, and novel imaging markers like brain iron deposition, white matter hyperintensities (WMH), cortical mean diffusivity, and brain total creatine can also contribute. Together, these approaches have helped to characterize variant-specific distinct imaging profiles. Even within each variant, various subtypes that capture the heterogeneity of cases have been revealed. Finally, in-vivo pathology markers have led to significant advances in the atypical AD neuroimaging field. SUMMARY: Overall, the recent neuroimaging literature on atypical AD variants contribute to increase knowledge of these lesser-known AD variants and are key to generate atypical variant-specific clinical trial endpoints, which are required for inclusion of these patients in clinical trials assessing treatments. In return, studying these patients can inform the neurobiology of various cognitive functions, such as language, executive, memory, and visuospatial abilities.

Network anatomy in logopenic variant of primary progressive aphasia.

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills, resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through pre-determined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically-fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporo-parietal junction regions, predominantly follows at least two partially non-overlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis.

Spared speech fluency is associated with increased functional connectivity in the speech production network in semantic variant primary progressive aphasia.

Semantic variant primary progressive aphasia is a clinical syndrome characterized by marked semantic deficits, anterior temporal lobe atrophy and reduced connectivity within a distributed set of regions belonging to the functional network associated with semantic processing. However, to fully depict the clinical signature of semantic variant primary progressive aphasia, it is necessary to also characterize preserved neural networks and linguistic abilities, such as those subserving speech production. In this case-control observational study, we employed whole-brain seed-based connectivity on task-free MRI data of 32 semantic variant primary progressive aphasia patients and 46 healthy controls to investigate the functional connectivity of the speech production network and its relationship with the underlying grey matter. We investigated brain-behaviour correlations with speech fluency measures collected through clinical tests (verbal agility) and connected speech (speech rate and articulation rate). As a control network, we also investigated functional connectivity within the affected semantic network. Patients presented with increased connectivity in the speech production network between left inferior frontal and supramarginal regions, independent of underlying grey matter volume. In semantic variant primary progressive aphasia patients, preserved (verbal agility) and increased (articulation rate) speech fluency measures correlated with increased connectivity between inferior frontal and supramarginal regions. As expected, patients demonstrated decreased functional connectivity in the semantic network (dependent on the underlying grey matter atrophy) associated with average nouns' age of acquisition during connected speech. Collectively, these results provide a compelling model for studying compensation mechanisms in response to disease that might inform the design of future rehabilitation strategies in semantic variant primary progressive aphasia.

Semantic knowledge of social interactions is mediated by the hedonic evaluation system in the brain.

Attaching semantic meaning to sensory information received from both inside and outside our bodies is a fundamental function of the human brain. The theory of Controlled Semantic Cognition (CSC) proposes that the formation of semantic knowledge relies on connections between spatially distributed modality-specific spoke-nodes, and a modality-general hub in the anterior temporal lobes (ATLs). This theory can also be applied to social semantic knowledge, though certain domain-specific spoke-nodes may make a disproportionate contribution to the understanding of social concepts. The ATLs have strong connections with spoke-node structures such as the subgenual ACC (sgACC) and the orbitofrontal cortex (OFC) that play an important role in predicting the hedonic value of stimuli. We hypothesized that in addition to the ATL semantic hub, a social semantic task would also require input from hedonic evaluation structures. We used voxel based morphometry (VBM) to examine structural brain-behavior relationships in 152 patients with neurodegeneration (Alzheimer's disease [N = 12], corticobasal syndrome (N = 18], progressive supranuclear palsy [N = 13], behavioral variant frontotemporal dementia [N = 56], and primary progressive aphasia (PPA) [N = 53]) using the Social Interaction Vocabulary Task (SIVT). This task measures the ability to correctly match a social term (e.g. "gossiping") with a visual depiction of that social interaction. As predicted, VBM showed that worse SIVT scores corresponded with volume loss in bilateral ATL semantic hub regions, but also in the sgACC, OFC, caudate and putamen (pFWE <0.05). These results support the CSC model of a hub-and-spoke organization of social semantic knowledge with the ATL as a domain-general semantic hub, and ventromedial and striatal structures as domain specific spoke-nodes. Importantly, these results suggest that correct comprehension of social semantic concepts requires emotional 'tagging' of a concept by the evaluation system, and that the social deficits observed in some neurodegenerative disease syndromes may be caused by the break-down of this mechanism.

Access, referral, service provision and management of individuals with primary progressive aphasia: A survey of speech-language therapists in Italy.

BACKGROUND AND OBJECTIVES: In Italy, approximately 650 individuals receive a diagnosis of primary progressive aphasia (PPA) every year. Unfortunately, the frequency with which patients are referred to speech-language services is suboptimal, likely due to skepticism regarding the value of speech-language therapy in the context of neurodegeneration. MATERIALS AND METHODS: We conducted a virtual survey of speech and language therapists (SLTs) across Italy, to collect information about the assessment, intervention and management of patients with PPA. To ensure that as many SLTs as possible received the survey, the Italian Federation of SLTs (Federazione Logopedisti Italiani, FLI) aided in disseminating the survey. RESULTS: In total, 336 respondents participated in the online survey, 140 of whom had previous experience with PPA patients. Respondents indicated having seen a total of 428 PPA patients in the previous 24 months (three patients on average, range: 0-40). SLTs who reported never working with PPA identified underdiagnoses, low referral rates and the rarity of the clinical syndrome as major reasons for their lack of experience with PPA. SLTs with experience working with PPA indicated that patients may not have accessed services because of service dysfunction and geographical barriers. Respondents reported using informal interviews during assessments and tests developed for post-stroke aphasia, while impairment-based/restitutive interventions were utilised most often. CONCLUSION: Findings may serve to inform health policy organisations regarding the current shortcomings and needed recommendations for improving the care of individuals with PPA in Italy. Improving awareness of the utility of rehabilitation among SLTs and other clinical service providers may serve to facilitate access to intervention, which in turn will serve to better support individuals living with PPA. WHAT THIS PAPER ADDS: What is already known on the subject Speech and language therapists (SLTs) play a crucial role in the assessment, diagnosis and treatment of people with primary progressive aphasia (PPA). However, the frequency with which individuals with PPA are referred for speech and language services is suboptimal due to skepticism regarding the value of speech and language therapy in the context of neurodegeneration, the scarcity of SLTs with expertise in the treatment of PPA and the lack of awareness of the SLT role amongst referrers. What this paper adds to existing knowledge In recognition of the lack of published information on the provision of speech and language therapy services and clinicians' approaches to the assessment and treatment of individuals with PPA in Italy, we conducted an online survey to evaluate the current referral patterns for speech and language therapy services and to examine the current barriers to access these services for individuals with PPA in Italy. What are the potential or actual clinical implications of this work? The data presented here support that SLTs view treatment as useful for individuals with PPA and other professional figures and may serve to improve access to intervention, which in turn will serve to better support individuals living with PPA. The results highlight the need to inform health policy organisations about current gaps and aid in developing recommendations for improving the care of individuals with PPA, in order to understand how SLTs can best support individuals with PPA and their families.

Altered delay discounting in neurodegeneration: insight into the underlying mechanisms and perspectives for clinical applications.

Steeper delay discounting (i.e., the extent to which future rewards are perceived as less valuable than immediate ones) has been proposed as a transdiagnostic process across different health conditions, in particular psychiatric disorders. Impulsive decision-making is a hallmark of different neurodegenerative conditions but little is known about delay discounting in the domain of neurodegenerative conditions. We reviewed studies on delay discounting in patients with Parkinson's disease (PD) and in patients with dementia (Alzheimer's disease / AD or frontotemporal dementia / FTD). We proposed that delay discounting could be an early marker of the neurodegenerative process. We developed the idea that altered delay discounting is associated with overlapping but distinct neurocognitive mechanisms across neurodegenerative diseases: dopaminergic-related disorders of reward processing in PD, memory/projection deficits due to medial temporal atrophy in AD, modified reward processing due to orbitofrontal atrophy in FTD. Neurodegeneration could provide a framework to decipher the neuropsychological mechanisms of value-based decision-making. Further, delay discounting could become a marker of interest in clinical practice, in particular for differential diagnosis.

[Revue systématique des tests cognitifs validés et/ou ayant des normes de référence pour la population canadienne francophone âgée].

Il est essentiel d'utiliser des tests cognitifs ayant été validés et détenant des normes de référence auprès de la population cible, puisque les réalités culturelles et linguistiques différentes entre l'échantillon de validation ou auprès duquel les normes ont été créées et la population cible peuvent affecter les résultats. Cette revue systématique vise à recenser et décrire les tests cognitifs (incluant tests, questionnaires et grilles d'observation) validés et/ou présentant des normes sur la population âgée canadienne francophone. Au total, 46 articles ont été sélectionnés. Cette revue recense 9 tests validés, 20 tests avec normes de référence et 18 tests validés et avec normes, couvrant la majorité des domaines cognitifs (fonctions mnésiques, attentionnelles, exécutives, perceptivo-motrices et langagières), excepté la cognition sociale. La quasi-totalité des échantillons ont été recrutés au Québec. Les tests relevés présentent majoritairement des indices psychométriques satisfaisants et généralement des normes considérant l'âge, le sexe et l'éducation. Cette revue systématique permettra aux cliniciens et chercheurs canadiens en vieillissement d'orienter optimalement leurs choix de tests cognitifs.

Differential Patterns of Domain-Specific Cognitive Complaints and Awareness Across the Alzheimer's Disease Spectrum.

Background: Characterizing self- and informant-reported cognitive complaints, as well as awareness of cognitive decline (ACD), is useful for an early diagnosis of Alzheimer's disease (AD). However, complaints and ACD related to cognitive functions other than memory are poorly studied. Furthermore, it remains unclear which source of information is the most useful to distinguish various groups on the AD spectrum. Methods: Self- and informant-reported complaints were measured with the Everyday Cognition questionnaire (ECog-Subject and ECog-StudyPartner) in four domains (memory, language, visuospatial, and executive). ACD was measured as the subject-informant discrepancy in the four ECog scores. We compared the ECog and ACD scores across cognitive domains between four groups: 71 amyloid-positive individuals with amnestic AD, 191 amnestic mild cognitive impairment (MCI), or 118 cognitively normal (CN), and 211 amyloid-negative CN controls, selected from the ADNI database. Receiver operating characteristic curves analysis was performed to evaluate the accuracy of the ECog and ACD scores in discriminating clinical groups. Results: Self- and informant-reported complaints were generally distributed as follows: memory, language, executive, and visuospatial (from the most severe to the least severe). Both groups of CN participants presented on average more memory and language complaints than their informant. MCI participants showed good agreement with their informants. AD participants presented anosognosia in all domains, but especially for the executive domain. The four ECog-StudyPartner sub-scores allowed excellent discrimination between groups in almost all classifications and performed significantly better than the other two classifiers considered. The ACD was excellent in distinguishing the participants with AD from the two groups of CN participants. The ECog-Subject was the least accurate in discriminating groups in four of the six classifications performed. Conclusion: In research, the study of complaint and anosognosia should not be reduced solely to the memory domain. In clinical practice, non-amnestic complaints could also be linked to Alzheimer's disease. The presence of an informant also seems necessary given its accuracy as a source of information.

Right temporal degeneration and socioemotional semantics: semantic behavioural variant frontotemporal dementia.

Focal anterior temporal lobe degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant anterior temporal lobe atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia and semantic dementia, patients with early right anterior temporal lobe atrophy are more difficult to diagnose as their symptoms are less well understood. Focal right anterior temporal lobe atrophy is associated with prominent emotional and behavioural changes, and patients often meet, or go on to meet, criteria for behavioural variant frontotemporal dementia. Uncertainty around early symptoms and absence of an overarching clinico-anatomical framework continue to hinder proper diagnosis and care of patients with right anterior temporal lobe disease. Here, we examine a large, well-characterized, longitudinal cohort of patients with right anterior temporal lobe-predominant degeneration and propose new criteria and nosology. We identified individuals from our database with a clinical diagnosis of behavioural variant frontotemporal dementia or semantic variant primary progressive aphasia and a structural MRI (n = 478). On the basis of neuroimaging criteria, we defined three patient groups: right anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 46), frontal-predominant atrophy with relative sparing of the right anterior temporal lobe (n = 79) and left-predominant anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 75). We compared the clinical, neuropsychological, genetic and pathological profiles of these groups. In the right anterior temporal lobe-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%) and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in Emotional Theory of Mind, recognition of famous people (from names and faces) and facial affect naming (despite preserved face perception) than the frontal- and left-predominant anterior temporal lobe-predominant groups. The clinical symptoms in the first 3 years of the disease alone were highly sensitive (81%) and specific (84%) differentiating right anterior temporal lobe-predominant from frontal-predominant groups. Frontotemporal lobar degeneration-transactive response DNA binding protein (84%) was the most common pathology of the right anterior temporal lobe-predominant group. Right anterior temporal lobe-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive decline in semantic memory for concepts of socioemotional relevance. Guided by our results, we outline new diagnostic criteria and propose the name, 'semantic behavioural variant frontotemporal dementia', which highlights the underlying cognitive mechanism and the predominant symptomatology. These diagnostic criteria will facilitate early identification and care of patients with early, focal right anterior temporal lobe degeneration as well as in vivo prediction of frontotemporal lobar degeneration-transactive response DNA binding protein pathology.

Self-reported word-finding complaints are associated with cerebrospinal fluid amyloid beta and atrophy in cognitively normal older adults.

INTRODUCTION: Self-reported word-finding difficulties are among the most frequent complaints in cognitively normal (CN) older adults. However, the clinical significance is still debated. METHODS: We selected 239 CN from the Alzheimer's Disease Neuroimaging Initiative database who had completed the Everyday Cognition (ECog) questionnaire, as well as a lumbar puncture for amyloid beta (Aß) and magnetic resonance imaging. RESULTS: Word-finding complaints, with a few other memory items, were significantly more severe compared to all other cognitive complaints. Ecog-Lang1 (Forgetting names of objects) severity significantly predicted Aß levels in CN, even when controlling for general cognitive complaint, demographic, and psychological variables. Individuals with high Ecog-Lang1 complaints showed atrophy in the left fusiform gyrus and the left rolandic operculum compared to CN with low complaints. DISCUSSION: Overall, our results support the fact that word-finding complaints should be taken seriously. They have the potential to identify CN at risk of AD and support the need to include other cognitive domains in the investigation of subjective cognitive decline.