Lexical markers of disordered speech in primary progressive aphasia and 'Parkinson-plus' disorders.

Connected speech samples elicited by a picture description task are widely used in the assessment of aphasias, but it is not clear what their interpretation should focus on. Although such samples are easy to collect, analyses of them tend to be time-consuming, inconsistently conducted and impractical for non-specialist settings. Here, we analysed connected speech samples from patients with the three variants of primary progressive aphasia (semantic, svPPA = 9; logopenic, lvPPA = 9; and non-fluent, nfvPPA = 9), progressive supranuclear palsy (PSP Richardson's syndrome = 10), corticobasal syndrome (CBS = 13) and age-matched healthy controls ( = 24).

Does epilepsy differentially affect different types of memory?

Despite the recognition that epilepsy can substantially disrupt memory, there are few published accounts of whether and how this disruption varies across different types of memory and/or different types of epilepsy. This review explores four main questions: (1) Are working, episodic and semantic memory differentially affected by epilepsy? (2) Do various types of epilepsy, and their treatment, have different, specifiable effects on memory? (3) Are the usual forms of neuropsychological assessments of memory - many or most designed for other conditions - appropriate for patients with epilepsy? (4) How can research on epilepsy contribute to our understanding of the neuroscience of memory? We conclude that widespread and multifactorial problems are seen in working memory in all patient groups, while patients with temporal lobe epilepsy seem particularly prone to episodic memory deficit, and those with frontal lobe epilepsy to executive function deficits that may in turn impair semantic control. Currently, it is difficult to make individual patient predictions about likely memory deficits based on seizure aetiology and type, but it is possible to guide and tailor neuropsychological assessments in an individualised way.

The impact of bilateral versus unilateral anterior temporal lobe damage on face recognition, person knowledge and semantic memory.

The functional importance of the anterior temporal lobes (ATLs) has come to prominence in two active, albeit unconnected literatures-(i) face recognition and (ii) semantic memory. To generate a unified account of the ATLs, we tested the predictions from each literature and examined the effects of bilateral versus unilateral ATL damage on face recognition, person knowledge, and semantic memory. Sixteen people with bilateral ATL atrophy from semantic dementia (SD), 17 people with unilateral ATL resection for temporal lobe epilepsy (TLE; left = 10, right = 7), and 14 controls completed tasks assessing perceptual face matching, person knowledge and general semantic memory.

The graded multidimensional geometry of phenotypic variation and progression in neurodegenerative syndromes.

Clinical variants of Alzheimer's disease and frontotemporal lobar degeneration display a spectrum of cognitive-behavioural changes varying between individuals and over time. Understanding the landscape of these graded individual-/group-level longitudinal variations is critical for precise phenotyping; however, this remains challenging to model. Addressing this challenge, we leverage the National Alzheimer's Coordinating Center database to derive a unified geometric framework of graded longitudinal phenotypic variation in Alzheimer's disease and frontotemporal lobar degeneration.

Drawing from name in semantic dementia reveals graded object knowledge representations in anterior temporal lobe.

Semantic dementia (SD) is characterized by progressive impairment in conceptual knowledge due to anterior temporal lobe (ATL) neurodegeneration. Extended neuropsychological assessments can quantitatively demonstrate the semantic impairment, but this graded loss of knowledge can also be readily observed in the qualitative observation of patients' recall of single concepts. Here, we present the results of a simple task of object drawing-from-name, by patients with SD (N = 19), who have isolated atrophy of the ATL bilaterally.

(What) can patients with semantic dementia learn?

Semantic Dementia (SD) is a neurodegenerative disease characterised by progressive deterioration of semantic knowledge, resulting in diminished understanding of concepts, whether encountered in verbal or non-verbal form. Over the past three decades, a number of studies employing a range of treatment techniques and learning methods have examined whether patients with SD can relearn previously known concepts or learn and retain new information. In this article, we review this research, addressing two main questions: a) Can aspects of semantic knowledge that are 'lost' due to degeneration be re-acquired? b) How much do other memory systems (working and episodic memory) interact with and depend on semantic memory? Several studies demonstrate successful relearning of previously known words and concepts in SD, particularly after regular, prolonged practice; but this success tends to diminish once practice ceases, and furthermore often fails to generalise to other instances of the same object/concept.

A neuroanatomical and cognitive model of impaired social behaviour in frontotemporal dementia.

Impaired social cognition is a core deficit in frontotemporal dementia (FTD). It is most commonly associated with the behavioural-variant of FTD, with atrophy of the orbitofrontal and ventromedial prefrontal cortex. Social cognitive changes are also common in semantic dementia, with atrophy centred on the anterior temporal lobes.

The neural substrates of transdiagnostic cognitive-linguistic heterogeneity in primary progressive aphasia.

Background: Clinical variants of primary progressive aphasia (PPA) are diagnosed based on characteristic patterns of language deficits, supported by corresponding neural changes on brain imaging. However, there is (i) considerable phenotypic variability within and between each diagnostic category with partially overlapping profiles of language performance between variants and (ii) accompanying non-linguistic cognitive impairments that may be independent of aphasia magnitude and disease severity. The neurobiological basis of this cognitive-linguistic heterogeneity remains unclear.

Temporal lobe perceptual predictions for speech are instantiated in motor cortex and reconciled by inferior frontal cortex.

Humans use predictions to improve speech perception, especially in noisy environments. Here we use 7-T functional MRI (fMRI) to decode brain representations of written phonological predictions and degraded speech signals in healthy humans and people with selective frontal neurodegeneration (non-fluent variant primary progressive aphasia [nfvPPA]). Multivariate analyses of item-specific patterns of neural activation indicate dissimilar representations of verified and violated predictions in left inferior frontal gyrus, suggestive of processing by distinct neural populations.

Verbal fluency tests assess global cognitive status but have limited diagnostic differentiation: evidence from a large-scale examination of six neurodegenerative diseases.

Verbal fluency is widely used as a clinical test, but its utility in differentiating between neurodegenerative dementias and progressive aphasias, and from healthy controls, remains unclear. We assessed whether various measures of fluency performance could differentiate between Alzheimer's disease, behavioural variant of frontotemporal dementia, non-fluent and semantic variants of primary progressive aphasia, progressive supranuclear palsy, corticobasal syndrome and healthy controls. Category and letter fluency tasks were administered to 33 controls and 139 patients at their baseline clinical visit.

Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia.

Frontotemporal dementia is clinically and neuropathologically heterogeneous, but neuroinflammation, atrophy and cognitive impairment occur in all of its principal syndromes. Across the clinical spectrum of frontotemporal dementia, we assess the predictive value of in vivo neuroimaging measures of microglial activation and grey-matter volume on the rate of future cognitive decline. We hypothesized that inflammation is detrimental to cognitive performance, in addition to the effect of atrophy.

Understanding the multidimensional cognitive deficits of logopenic variant primary progressive aphasia.

The logopenic variant of primary progressive aphasia is characterized by early deficits in language production and phonological short-term memory, attributed to left-lateralized temporoparietal, inferior parietal and posterior temporal neurodegeneration. Despite patients primarily complaining of language difficulties, emerging evidence points to performance deficits in non-linguistic domains. Temporoparietal cortex, and functional brain networks anchored to this region, are implicated as putative neural substrates of non-linguistic cognitive deficits in logopenic variant primary progressive aphasia, suggesting that degeneration of a shared set of brain regions may result in co-occurring linguistic and non-linguistic dysfunction early in the disease course.

A 'Mini Linguistic State Examination' to classify primary progressive aphasia.

There are few available methods for qualitatively evaluating patients with primary progressive aphasia. Commonly adopted approaches are time-consuming, of limited accuracy or designed to assess different patient populations. This paper introduces a new clinical test-the Mini Linguistic State Examination-which was designed uniquely to enable a clinician to assess and subclassify both classical and mixed presentations of primary progressive aphasia.

Language Disorder in Progressive Supranuclear Palsy and Corticobasal Syndrome: Neural Correlates and Detection by the MLSE Screening Tool.

: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) affect speech and language as well as motor functions. Clinical and neuropathological data indicate a close relationship between these two disorders and the non-fluent variant of primary progressive aphasia (nfvPPA). We use the recently developed Mini Linguistic State Examination tool (MLSE) to study speech and language disorders in patients with PSP, CBS, and nfvPPA, in combination with structural magnetic resonance imaging (MRI).

Semantic memory impairment in dementia: A cross-cultural adaptation study.

Background: Semantic memory deficits are frequently encountered in dementia and distinct patterns of semantic impairment characterize the subtypes of dementia. Life course and cultural experiences significantly influence semantic memory. Hence, there is a need to assess semantic memory using culturally appropriate tests, to aid accurate diagnosis of dementia and facilitate cross-cultural collaborative research.

Predicting loss of independence and mortality in frontotemporal lobar degeneration syndromes.

Objective: To test the hypothesis that in syndromes associated with frontotemporal lobar degeneration, behavioural impairment predicts loss of functional independence and motor clinical features predict mortality, irrespective of diagnostic group.

Methods: We used a transdiagnostic approach to survival in an epidemiological cohort in the UK, testing the association between clinical features, independence and survival in patients with clinical diagnoses of behavioural variant frontotemporal dementia (bvFTD n=64), non-fluent variant primary progressive aphasia (nfvPPA n=36), semantic variant primary progressive aphasia (svPPA n=25), progressive supranuclear palsy (PSP n=101) and corticobasal syndrome (CBS n=68). A principal components analysis identified six dimensions of clinical features.

In vivo PET imaging of neuroinflammation in familial frontotemporal dementia.

Introduction: We report patterns of neuroinflammation and abnormal protein aggregation in seven cases of familial frontotemporal dementia (FTD) with mutations in MAPT, GRN and C9orf72 genes.

Methods: Using positron emission tomography (PET), we explored the association of the distribution of activated microglia, as measured by the radioligand [C]PK11195, and the regional distribution of tau or TDP-43 pathology, indexed using the radioligand [F]AV-1451. The familial FTD PET data were compared with healthy controls.

Graded, multidimensional intra- and intergroup variations in primary progressive aphasia and post-stroke aphasia.

Language impairments caused by stroke (post-stroke aphasia, PSA) and neurodegeneration (primary progressive aphasia, PPA) have overlapping symptomatology, nomenclature and are classically divided into categorical subtypes. Surprisingly, PPA and PSA have rarely been directly compared in detail. Rather, previous studies have compared certain subtypes (e.

Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes.

The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome.

Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum.

The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the localization of tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used PET in vivo with (i) 11C-PK-11195, a marker of activated microglia and a proxy index of neuroinflammation; and (ii) 18F-AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and TDP-43-related disease, and which is used as a surrogate marker of non-amyloid-β protein aggregation.

Anterior temporal lobe is necessary for efficient lateralised processing of spoken word identity.

In the healthy human brain, the processing of language is strongly lateralised, usually to the left hemisphere, while the processing of complex non-linguistic sounds recruits brain regions bilaterally. Here we asked whether the anterior temporal lobes, strongly implicated in semantic processing, are critical to this special treatment of spoken words. Nine patients with semantic dementia (SD) and fourteen age-matched controls underwent magnetoencephalography and structural MRI.

Striking loss of second language in bilingual patients with semantic dementia.

Background: Studies of bilingual or multilingual patients with neurodegenerative diseases that disrupt language like the primary progressive aphasias (PPA) may contribute valuable information on language organization in the bilingual brain and on the factors affecting language decline. There is limited literature on bilingual PPA and in particular on semantic dementia, a type of PPA with selective loss of semantic memory. We studied the nature and severity of naming and comprehension deficits across languages in bilingual patients with semantic dementia (SD).

Language impairment in progressive supranuclear palsy and corticobasal syndrome.

Although commonly known as movement disorders, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may present with changes in speech and language alongside or even before motor symptoms. The differential diagnosis of these two disorders can be challenging, especially in the early stages. Here we review their impact on speech and language.

[F]AV-1451 binding is increased in frontotemporal dementia due to C9orf72 expansion.

The PET ligand [F]AV-1451 was developed to bind tau pathology in Alzheimer's disease, but increased binding has been shown in both genetic tauopathies and in semantic dementia, a disease strongly associated with TDP-43 pathology. Here we assessed [F]AV-1451 binding in behavioral variant frontotemporal dementia due to a hexanucleotide repeat expansion in C9orf72, characterized by TDP-43 pathology. We show that the C9orf72 mutation increases binding in frontotemporal cortex, with a distinctive distribution of binding compared with healthy controls.