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Current state-of-the-art diagnostic measures of Alzheimer's disease (AD) are invasive (cerebrospinal fluid analysis), expensive (neuroimaging) and time-consuming (neuropsychological assessment) and thus have limited accessibility as frontline screening and diagnostic tools for AD. Thus, there is an increasing need for additional noninvasive and/or cost-effective tools, allowing identification of subjects in the preclinical or early clinical stages of AD who could be suitable for further cognitive evaluation and dementia diagnostics. Implementation of such tests may facilitate early and potentially more effective therapeutic and preventative strategies for AD. Before applying them in clinical practice, these tools should be examined in ongoing large clinical trials. This review will summarize and highlight the most promising screening tools including neuropsychometric, clinical, blood, and neurophysiological tests.

Although an insidious history of episodic memory difficulty is a typical presenting symptom of Alzheimer's disease, detailed neuropsychological profiling frequently demonstrates deficits in other cognitive domains, including language. Previous studies from our group have shown that language changes may be reflected in connected speech production in the earliest stages of typical Alzheimer's disease. The aim of the present study was to identify features of connected speech that could be used to examine longitudinal profiles of impairment in Alzheimer's disease. Samples of connected speech were obtained from 15 former participants in a longitudinal cohort study of ageing and dementia, in whom Alzheimer's disease was diagnosed during life and confirmed at post-mortem. All patients met clinical and neuropsychological criteria for mild cognitive impairment between 6 and 18 months before converting to a status of probable Alzheimer's disease. In a subset of these patients neuropsychological data were available, both at the point of conversion to Alzheimer's disease, and after disease severity had progressed from the mild to moderate stage. Connected speech samples from these patients were examined at later disease stages. Spoken language samples were obtained using the Cookie Theft picture description task. Samples were analysed using measures of syntactic complexity, lexical content, speech production, fluency and semantic content. Individual case analysis revealed that subtle changes in language were evident during the prodromal stages of Alzheimer's disease, with two-thirds of patients with mild cognitive impairment showing significant but heterogeneous changes in connected speech. However, impairments at the mild cognitive impairment stage did not necessarily entail deficits at mild or moderate stages of disease, suggesting non-language influences on some aspects of performance. Subsequent examination of these measures revealed significant linear trends over the three stages of disease in syntactic complexity, semantic and lexical content. The findings suggest, first, that there is a progressive disruption in language integrity, detectable from the prodromal stage in a subset of patients with Alzheimer's disease, and secondly that measures of semantic and lexical content and syntactic complexity best capture the global progression of linguistic impairment through the successive clinical stages of disease. The identification of disease-specific language impairment in prodromal Alzheimer's disease could enhance clinicians' ability to distinguish probable Alzheimer's disease from changes attributable to ageing, while longitudinal assessment could provide a simple approach to disease monitoring in therapeutic trials.

In its typical form, Alzheimer’s disease (AD) manifests with early impairment in episodic memory. Evidence suggests that language deficits also occur early on in the disease process, and can be detected at the preclinical stage, suggesting that language could constitute an important diagnostic marker for disease. Additionally, a number of variant clinical presentations of AD are recognised, due to an atypical distribution of pathology at onset, including a minority of patients presenting with a slowly progressive language impairment. We review language performance in typical and atypical presentations of AD, and describe a series of recent, novel findings examining the language phenotype of typical AD.

Spoken discourse is a uniquely valuable source of data in cognitive research. A natural way of representing spoken discourse is in the form of a transcript in standard orthography. However, since transcribing is, for neuroscientists at any rate, no more than a means to an end, many researchers give only cursory descriptions of the transcription process, including the assessment of agreement between transcribers. This article introduces a novel approach to the systematic assessment of agreement between transcripts. The method first involves the automated alignment of two texts, followed by the automatic identification and quantification of discrepancies. A similarity score is then computed, providing researchers with a tool to evaluate the accuracy of the pair of transcripts in question. Most importantly, the automated production of a set of comparison tables reveals and summarizes the actual mismatches found, making it possible to identify common causes of discrepancy. Through applying this approach to medical data collected for an investigation of dementia, the present study demonstrates its value in the amendment of transcripts and the improvement of transcription practices, which pave the way towards more reliable transcriptions for research purposes. © The Author 2011. Published by Oxford University Press on behalf of ALLC. All rights reserved.

In this chapter I examine the application of large-scale language analysis to the task of measuring the extent and time-course of language changes associated with the acquisition of power. The study of language corpora (the term is explained in the following section) dates back to mediaeval times, when members of the Dominican order created the first concordances of the Latin Vulgate Bible. The friars’ motivations were far removed from those of contemporary scholars and, lacking electronic computers, they needed several years of coordinated labour to complete their work. In more recent times, concordances of the complete works of Shakespeare were painstakingly constructed as aids to literary scholarship. Today, comprehensive concordances (lists of all the word tokens and their contexts and locations, in alphabetical order) of similar size can be created in a matter of seconds.

It has been claimed that King James VI/I, an antecedent of King George III, suffered from acute porphyria, and that the disease was passed on to George III through his grand-daughter Sophie, mother of George I. The life of James is reviewed and previously-proposed diagnoses are considered. James’s medical history is discussed in detail and, where possible, examined with validated symptom scales. Using an online database of neurological diseases, the authors show that James’s symptomatology is compatible with a diagnosis of Attenuated (mild) Lesch-Nyhan disease; no evidence was found to support a diagnosis of acute porphyria. In addition, there is evidence of associated Asperger traits which may explain some of the King’s unusual behavioural and psycho-social features.

In this paper we report the application of an extensive database of symptoms, signs, laboratory findings and illnesses, to the diagnosis of an historical figure. The medical diagnosis of Augustus d'Este (1794–1848) – widely held to be the first documented case of multiple sclerosis – is reviewed, using the detailed symptom diary, which he kept over many years, as clinical data. Some of the reported features prompted the competing claim that d'Este suffered from acute porphyria, which in turn was used in support of the hypothesis that his grandfather, King George III, also suffered from the disease. We find that multiple sclerosis is statistically the most likely diagnosis, with neuromyelitis optica a strong alternative possibility. The database did not support a diagnosis of any of the acute porphyrias.

Structural and content-related deficits occur in connected discourse of patients with semantic dementia (SD). We used principal components analysis (PCA) to characterise the sources of variation in word usage during picture description by controls and SD patients. This data-driven approach allowed: comparison of the distance between individuals in the two-dimensional space; correlational analyses between principal component (PC) values and performance on other tests; identification of words whose variance contributed most to the definition of the PCs.Transcripts of Cookie Theft picture descriptions from 21 patients with SD and 21 controls were used to generate frequencies of all word types (n = 557) across participants. Frequency values of words with ≥10 occurrences (n= 81) were entered into a PCA. Values of emergent dimensions were correlated with performance on tests of single word meaning. The first PC accounted for 59% of the variance, the second for a further 10%. Patients and controls showed good separation within the resulting space. Factor loading scores indicated that control performance was characterised by function (factor 1) and content (factor 2) word usage, while patients showed a greater tendency to use pronouns, deictic and generic words. Knowledge of single word meaning correlated with factor 1 but not with factor 2. Differences in word usage can differentiate connected speech of SD patients from controls using a rapid, automated, data-driven algorithm. The distinction between groups, loadings on the two components, and their differential correlations with semantic tasks raise the possibility of independent differences in syntax and lexical content.

J. Neurochem. (2010) 115, 814–828. Abstract Vascular cognitive impairment (VCI) encompasses vascular dementia and is the second most common cause of dementing illness after Alzheimer’s disease. The main causes of VCI are: cerebral small vessel disease; multi-infarct dementia; strategic infarct (i.e. located in a functionally-critical brain area); haemorrhage/microbleed; angiopathy (including cerebral amyloid angiopathy); severe hypoperfusion (e.g. cardiac arrhythmia); and hereditary vasculopathy (e.g. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL). In this systematic analysis, we aimed to relate cognitive and neuropathological features of experimental models to clinical VCI. We extracted data from 107 studies covering 16 models. These included: brief global ischaemic insults (in rats, mice or gerbils); chronic global hypoperfusion (rats, mice, gerbils); chronic hypertension (in primates or stroke-prone, spontaneously-hypertensive rats); multiple ischaemic lesions because of intra-vascular emboli (in rodents, rabbits or primates); strategic ischaemic lesions (in rats or mini-pigs); generalised vasculopathies, because of mutant Notch3, hyperhomocysteinaemia, experimental diabetes mellitus or lack of cerebral vasodilator M5 receptors (rats or mice). Most cognitive testing showed deficits in working and reference memory. The lesions observed were microinfarcts, diffuse white matter lesions, hippocampal neuronal death, focal ischaemic lesions and micro-haemorrhages. The most-used model was bilateral carotid artery occlusion in rats, leading to chronic hypoperfusion and white matter injury.

Background: Patients with semantic dementia are impaired in both object naming and, to a lesser extent, in object use (Bozeat, Lambon Ralph, Patterson, & Hodges, 2002a; Hodges, Graham, & Patterson, 1995). To date there have been relatively few studies examining the relearning of object names, and only one examining the relearning of object use. No study has examined relearning object naming, definition, and use simultaneously. Aims: To explore the relatedness of object naming, definition, and object use in semantic dementia; to explore whether or not therapy is effective; and to explore the effectiveness of errorless learning. Methods & Procedures: Two patients with mild to moderate semantic dementia and two matched control participants were tested in naming, defining, and demonstrating the use of 33 household objects. The quality of the definitions was rated as poor, adequate, or good by three independent raters. Three components of object use were examined: hold, orientation, and movement. The assessmen...

The earliest stages of cognitive decline in cases of slowly progressive dementia are difficult to pinpoint, yet detection of the preclinical period of the illness is likely to be of significant importance to understanding Alzheimer's disease and other slowly progressive dementias at both clinical and biological levels. A number of authors have used retrospective analysis to describe preclinical linguistic decline in written texts and spoken language samples. This paper reviews the methods available for classifying and comparing such samples, and presents some exploratory analyses of historical texts derived from verbatim records of preclinical spoken activity. Change in the nature of the language used by Harold Wilson (Prime Minister of the United Kingdom 1964–1970 and 1974–1976) is quantified in the light of a later diagnosis of probable Alzheimer's disease and historical uncertainties about his final months in office.

Among the early symptoms of Alzheimer's disease is a gradual decline of language skills. Longitudinal studies are a useful way to study the development of linguistic abilities in the course of a person's lifetime; subjects producing sufficient language output to allow a study spanning decades are rare but can provide valuable information. In this study, we analysed lexical diversity in three books by Gerard Reve (1923–2006), an acclaimed Dutch literary author who wrote his last novel not long before diagnosed with Alzheimer's disease. The data show a clear-cut decline in lexical diversity, coinciding with a reported 'forgetfulness' starting halfway during the creative process of writing this last novel. The findings match those of Garrard et al. (2005) in their study of Iris Murdoch.

Proton magnetic resonance spectroscopy was used to compare metabolite levels from a posterior cingulate voxel in a group of patients with 2 syndromic subtypes of frontotemporal dementia (n=10) and an age and education-matched group with Alzheimer disease (n=10). Overall, frontotemporal dementia was indistinguishable from Alzheimer disease, though differences in N-acetylaspartate emerged between patients with the SD and progressive nonfluent aphasia subtypes, attributable to 2 atypical results among the latter. Such values may index cases with atrophy in posterior cortical regions presenting with progressive nonfluent aphasia.

The study of semantic memory in patients with Alzheimer's disease (AD) has raised important questions about the representation of conceptual knowledge in the human brain. It is still unknown whether semantic memory impairments are caused by localized damage to specialized regions or by diffuse damage to distributed representations within nonspecialized brain areas. To our knowledge, there have been no direct correlations of neuroimaging of in vivo brain function in AD with performance on tasks differentially addressing visual and functional knowledge of living and nonliving concepts. We used a semantic verification task and resting 18-fluorodeoxyglucose positron emission tomography in a group of mild to moderate AD patients to investigate this issue. The four task conditions required semantic knowledge of (1) visual, (2) functional properties of living objects, and (3) visual or (4) functional properties of nonliving objects. Visual property verification of living objects was significantly correlated with left posterior fusiform gyrus metabolism (Brodmann's area [BA] 37/19). Effects of visual and functional property verification for non-living objects largely overlapped in the left anterior temporal (BA 38/20) and bilateral premotor areas (BA 6), with the visual condition extending more into left lateral precentral areas. There were no associations with functional property verification for living concepts. Our results provide strong support for anatomically separable representations of living and nonliving concepts, as well as visual feature knowledge of living objects, and against distributed accounts of semantic memory that view visual and functional features of living and nonliving objects as distributed across a common set of brain areas.

This article reports the findings from 3 patients with semantic dementia (SD) who were given a novel battery of 33 items from sensory quality categories (SQCs) as previously described by Borgo and Shallice (2001; 2003) and Laiacona, Capitani and Caramazza (2003). Their performance on three tasks (two naming, one word-to-picture matching) was compared with performance on similar tasks using a conventional semantic battery. At the group level, patients performed worse than age-matched controls overall, but neither group showed any differences in performance between domains (i.e., living, nonliving and SQCs). Individual patient analyses, however, showed contrasting profiles in the three patients. The results are discussed in terms of the SFT (Warrington & Shallice, 1984) and individual differences (Lambon-Ralph et al., 2003) accounts of category-specificity in SD.

We describe a patient who came to neurological attention because of his at-risk status for the +16 exon 10 splice mutation in the tau gene (microtubule associated protein tau, MAPT), which had given rise to progressive behavioural disturbances in two of his siblings. The patient began to exhibit early signs of behavioural disturbance at around the age of symptom onset in both of his siblings. Although he did not spontaneously complain of difficulties in the domain of language, he met clinical, radiological and neuropsychological criteria for semantic dementia. On the assumption that his illness is mediated by the same pathological process as those of his siblings, we propose that this clinical picture represents the earliest changes of a semantic impairment - a phase of the illness that is often retrospectively described by patients and their relations, but has never previously been documented at first hand. Although typical of semantic dementia in many respects, the illness had several interesting and atypical features that emerged on detailed testing: first, he exhibited no insight into his difficulties; secondly, progression over a twelve-month interval was unusually slow; thirdly, he evinced a striking and consistent advantage for nonliving over living concepts; fourthly, a differential impairment of distinctive over shared knowledge did not emerge except when items that he could still name were compared with those for which he was anomic. Finally, the availability of post mortem pathological analysis from the brains of both of his affected siblings allowed us to attribute his illness to a specific pathological process which is considered unusual for patients with this clinical phenotype.

This study addresses continuing controversies concerning the nature of semantic impairment in early dementia of the Alzheimer type (DAT), and the relationship between conceptual knowledge and picture naming. A series of analyses of fine-grained feature knowledge data show that: (1) distinctive features of concepts were more vulnerable than shared; (2) the amount of attribute knowledge about a concept was associated reliably, and in a graded fashion, with the ability to name a picture of that item; (3) sensory features were differentially important in naming; and (4) the degree of disruption to different types of attribute knowledge did not vary between items from living and nonliving domains. These findings are discussed in the context of contemporary cognitive and computational models of semantic memory organisation. © 2004 Elsevier Inc. All rights reserved.

The failure to name an object in Alzheimer’s disease (AD) and in the semantic variant of the primary progressive aphasia (sv-PPA) has been generally attributed to semantic memory loss, with a progressive degradation of semantic features. Not all features, however, may have the same relevance in picture naming. We analyzed the relationship between picture naming performance and the loss of semantic features in patients with AD with or without naming impairment, with sv-PPA and in matched controls, assessing the role of distinctiveness, semantic relevance and feature type (sensorial versus non-sensorial) with a sentence verification task. The results showed that distinctive features with high values of semantic relevance were lost only in all patients with naming impairment. The performance on the sensorial distinctive features with high relevance was the best predictor of naming performance only in sv-PPA, while no difference between sensorial and non-sensorial features was found in AD patients.

Advances in automatic text classification have been necessitated by the rapid increase in the availability of digital documents. Machine learning (ML) algorithms can 'learn' from data: for instance a ML system can be trained on a set of features derived from written texts belonging to known categories, and learn to distinguish between them. Such a trained system can then be used to classify unseen texts. In this paper, we explore the potential of the technique to classify transcribed speech samples along clinical dimensions, using vocabulary data alone. We report the accuracy with which two related ML algorithms [naive Bayes Gaussian (NBG) and naive Bayes multinomial (NBM)] categorized picture descriptions produced by: 32 semantic dementia (SD) patients versus 10 healthy, age-matched controls; and SD patients with left- (n=21) versus right-predominant (n=11) patterns of temporal lobe atrophy. We used information gain (IG) to identify the vocabulary features that were most informative to each of these two distinctions. In the SD versus control classification task, both algorithms achieved accuracies of greater than 90%. In the right- versus left-temporal lobe predominant classification, NBM achieved a high level of accuracy (88%), but this was achieved by both NBM and NBG when the features used in the training set were restricted to those with high values of IG. The most informative features for the patient versus control task were low frequency content words, generic terms and components of metanarrative statements. For the right versus left task the number of informative lexical features was too small to support any specific inferences. An enriched feature set, including values derived from Quantitative Production Analysis (QPA) may shed further light on this little understood distinction.

Mixed vascular and Alzheimer-type dementia and pure Alzheimer's disease are both associated with changes in spoken language. These changes have, however, seldom been subjected to systematic comparison. In the present study, we analyzed language samples obtained during the course of a longitudinal clinical study from patients in whom one or other pathology was verified at post mortem. The aims of the study were twofold: first, to confirm the presence of differences in language produced by members of the two groups using quantitative methods of evaluation; and secondly to ascertain the most informative sources of variation between the groups. We adopted a computational approach to evaluate digitized transcripts of connected speech along a range of language-related dimensions. We then used machine learning text classification to assign the samples to one of the two pathological groups on the basis of these features. The classifiers' accuracies were tested using simple lexical features, syntactic features, and more complex statistical and information theory characteristics. Maximum accuracy was achieved when word occurrences and frequencies alone were used. Features based on syntactic and lexical complexity yielded lower discrimination scores, but all combinations of features showed significantly better performance than a baseline condition in which every transcript was assigned randomly to one of the two classes. The classification results illustrate the word content specific differences in the spoken language of the two groups. In addition, those with mixed pathology were found to exhibit a marked reduction in lexical variation and complexity compared to their pure AD counterparts.

The clinical presentation of patients with semantic dementia is dominated by anomia and poor verbal comprehension. Although a number of researchers have argued that these patients have impaired comprehension of non-verbal as well as verbal stimuli, the evidence for semantic deterioration is mainly derived from tasks that include some form of verbal input or output. Few studies have investigated semantic impairment using entirely non-verbal assessments and the few exceptions have been based on results from single cases ([3]: Breedin SD, Saffran EM, Coslett HB. Reversal of the concreteness effect in a patient with semantic dementia. Cognitive Neuropsychology 1994;11:617-660, [12]: Graham KS, Becker JT, Patterson K, Hodges JR. Lost for words: a case of primary progressive aphasia? In: Parkin A, editor. Case studies in the neuropsychology of memory, East Sussex: Lawrence Erlbaum, 1997. pp. 83-110, [21]: Lambon Ralph MA, Howard D. Gogi aphasia or semantic dementia? Simulating and assessing poor verbal comprehension in a case of progressive fluent aphasia. Cognitive Neuropsychology, (in-press).This study employed sound recognition and semantic association tasks to investigate the nature of the verbal and non-verbal comprehension deficit in 10 patients with semantic dementia. The patients were impaired on both verbal and non-verbal conditions of the assessments, and their accuracy on these tasks was directly related to their scores on a range of other tests requiring access to semantic memory. Further analyses revealed that performance was graded by concept and sound familiarity and, in addition, identified significant item consistency across the different conditions of the tasks. These results support the notion that the patients' deficits across all modalities were due to degradation within a single, central network of conceptual knowledge. There were also reliable differences between conditions. The sound-picture matching task proved to be more sensitive to semantic impairment than the word-picture matching equivalent, and the patients performed significantly better on the picture than word version of a semantic association test. We propose that these differences arise directly from the nature of the mapping between input modality and semantic memory. Words and sounds have an arbitrary relationship with meaning while pictures benefit from a degree of systematicity with conceptual knowledge about the object. Copyright (C) 2000 Elsevier Science Ltd.

The clinical differentiation of progressive disorders of language is described in the context of the evolution of current terminology. The syndromes of semantic dementia and progressive non-fluent aphasia can be distinguished on clinical and neuropsychological grounds; the former is characterized by a progressive and selective disintegration of the semantic component of longterm memory. Semantic dementia is also associated with characteristic structural and functional neuroimaging findings, and may represent a form of Pick's disease (focal lobar atrophy without Alzheimer histology). Selective impairment of this fundamental component of human cognition has allowed the empirical investigation of a range of theoretical questions. We discuss ideas about the organization and representation of knowledge, the interaction of semantic and episodic memory, and the contribution of semantic memory to reading ability. Many of these ideas can be informatively modelled in the framework of connectionist theory.

In the context of focal brain injury, selective loss of semantic knowledge in the domain of either natural kinds or artefacts is usually considered to reflect the differential importance of temporal and frontoparietal regions to the representations of perceptual and functional attributes, respectively. It is harder to account far as a feature of a more diffuse process, and previous cross-sectional analyses of patients with dementia of Alzheimer's type (DAT) have differed over whether category effects occur. In our series of 58 patients with probable DAT, we demonstrated a significant group advantage for artefacts, and explored possible reasons for the inconsistency of this finding in other studies. A multiple single-case strategy revealed not only individuals with consistent advantages for artefacts but also individuals with consistent advantages for natural kinds. By ranking the individuals according to measures of naming performance and global intellectual ability, we showed that the strength of the group advantage for artefacts was dependent on the former but not the latter variable. The findings are discussed in the context of two competing theories of semantic breakdown in DAT. One differentiates between domains of knowledge in terms of the structure of semantic representations within a single distributed network; the other emphasizes the importance of different brain regions in the category distinction. We conclude that our findings are in keeping with the predictions of the latter hypothesis.

Owen and Davidson coined the term ‘Hubris Syndrome’ (HS) for a characteristic pattern of exuberant self-confidence, recklessness, and contempt for others, shown by some individuals holding substantial power. Meaning, emotion and attitude are communicated intentionally through language, but psychological and cognitive changes can be reflected in more subtle ways, of which a speaker remains unaware. Of the fourteen symptoms of HS, four imply lexical choices: use of the third person/‘royal we’; excessive confidence; exaggerated self-belief; and supposed accountability to God or History. One other feature (recklessness) could influence language complexity if impulsivity leads to unpredictability. These hypotheses were tested by examining transcribed spoken discourse samples produced by two British Prime Ministers (Margaret Thatcher and Tony Blair) who were said to meet criteria for HS, and one (John Major) who did not. We used Shannon entropy to reflect informational complexity, and temporal correlations (words or phrases whose relative frequency correlated negatively with time in office) and keyness values to identify lexical choices corresponding to periods during which HS was evident. Entropy fluctuated in all three subjects, but consistent (upward) trends in HS-positive subjects corresponded to periods of hubristic behaviour. The first person pronouns ‘I’ and ‘me’ and the word ‘sure’ were among the strongest positive temporal correlates in Blair’s speeches. Words and phrases that correlated in the speeches of Thatcher and Blair but not in those of Major included the phrase ‘we shall’ and ‘duties’ (both negative). The keyness ratio of ‘we’ to ‘I’ was clearly higher throughout the terms of office of Thatcher and Blair that at any point in the premiership of Major, and this difference was particularly marked in the case of Blair. The findings are discussed in the context of historical evidence and ideas for enhancing the signal to noise ratio put forward.

OBJECTIVE: The aim of the present study was to quantify the semantic content of connected speech produced by patients at a uniformly early stage of pathologically proven Alzheimer's disease (AD). A secondary aim was to establish whether semantic units were reduced globally, or whether there was a disproportionate reduction of specific classes of information. METHOD: Discourse samples were obtained from 18 AD patients and 18 matched controls, all pathologically confirmed. Semantic unit identification was scored overall and for four subclasses: subjects, locations, objects, and actions. Idea density and efficiency were calculated. RESULTS: AD transcripts showed significantly reduced units overall, particularly actions and subjects, as well as reduced efficiency. Total semantic units and a combination of subject-, location-, and object-related units ("noun" units) correlated with the Expression subscore on the Cambridge Cognitive Examination (CAMCOG). Subject related units correlated with the CAMCOG Abstract Thinking scale. Logistic regression analyses confirmed that all measures that were lower in AD than controls were predictive of group membership. An exploratory comparison between units expressed mainly using nouns and those mainly using verbs showed that the latter was the stronger of these two predictors. CONCLUSIONS: The present study adds a lexico-semantic dimension to the linguistic profile based on discourse analysis in typical AD, recently described by the same authors. 2012, 83(11): 1056-1062). The suggestion of differential importance of verb and noun use in the present study may be related to the reduction in syntactic complexity that was reported, using the same set of discourse samples, in the earlier study.

Diffusion Tensor Imaging (DTI) Segmentation (D-SEG) relies on variation in tissue microstructure characteristics of the diffusion tensor to segment regions of the brain with similar diffusion properties. Previously shown to be a reliable tool for parcelating and classifying volumes of interest (VOIs) within brain tumours, generating objective tissue type boundaries (Jones et al., 2014), it also relates to differences in age, executive function and working memory (Williams et al., unpublished data). We applied D-SEG to a novel data set comprising 18 DTI scans; 9 controls and 9 patients with clinically and/or radiologically confirmed focal dementia syndromes: 4 Progressive non-fluent Aphasia (PnFA), 2 Semantic Dementia (SD) and 3 Logopenic Aphasia (LPA). The D-SEG clustering technique takes isotropic (p) and anisotropic (q) diffusion values plotted in a 2D space and uses iterative k-means clustering analysis to segment the images into areas representing tissue with similar diffusion properties. We found a statistical difference between patients and control groups in 2 of the segments, specifically grey matter and well organised white matter. Greater grey matter was positively correlated with scores on the Mini Linguistic State Examination (MLSE). These findings add to the growing body of work supporting D-SEG as a valid tool for image analysis in clinical populations.

Background Primary progressive aphasia (PPA) is a clinical syndrome characterised by progressive decline in components of the language system. Recent evidence suggests that the logopenic/phonological (LPA) variant is a reliable in vivo marker of Alzheimer related pathology. The aim of this study was to determine if patients with clinically typical early stage Alzheimer9s disease (AD) display a characteristic language disorder that resembles LPA, or if LPA is a clinical manifestation of an atypical form of AD. Methods Spoken language samples were obtained using the Cookie Theft picture description task from 18 post mortem confirmed cases of AD, where speech samples were taken at the first point of clinical diagnosis, and 18 post mortem confirmed healthy controls. Spoken samples were transcribed from tape recordings and analysed using the scoring system described by Wilson et al . Results Group comparisons between normal controls and AD patients showed no significant overall differences. Individual review of the linguistic variables compared with the PPA variants showed that a third of patients had normal language (n=6). The remainder showed varied patterns of linguistic impairment. In the majority of the affected group, the most salient feature was a reduction in one or more measures of syntactic complexity. One patient9s deficit was comparable to that found in LPA. Conclusions The impairment found in clinically typical early stage AD did not correspond consistently to the linguistic profiles described in any of the sub-syndromes of PPA. The only reliably distinguishing feature was a reduction across a range of syntactic complexity measures. The findings suggest that LPA represents an atypical clinical presentation of AD rather than a common clinical feature of typical AD.

Background Primary progressive aphasia (PPA) is a clinical syndrome characterised by progressive decline in components of the language system. Recent evidence suggests that the logopenic/phonological (LPA) variant is a reliable in vivo marker of Alzheimer related pathology. The aim of this study was to determine if patients with clinically typical early stage Alzheimer9s disease (AD) display a characteristic language disorder that resembles LPA, or if LPA is a clinical manifestation of an atypical form of AD. Methods Spoken language samples were obtained using the Cookie Theft picture description task from 18 post mortem confirmed cases of AD, where speech samples were taken at the first point of clinical diagnosis, and 18 post mortem confirmed healthy controls. Spoken samples were transcribed from tape recordings and analysed using the scoring system described by Wilson et al . Results Group comparisons between normal controls and AD patients showed no significant overall differences. Individual review of the linguistic variables compared with the PPA variants showed that a third of patients had normal language (n=6). The remainder showed varied patterns of linguistic impairment. In the majority of the affected group, the most salient feature was a reduction in one or more measures of syntactic complexity. One patient9s deficit was comparable to that found in LPA. Conclusions The impairment found in clinically typical early stage AD did not correspond consistently to the linguistic profiles described in any of the sub-syndromes of PPA. The only reliably distinguishing feature was a reduction across a range of syntactic complexity measures. The findings suggest that LPA represents an atypical clinical presentation of AD rather than a common clinical feature of typical AD.

The study of patients affected by disorders of the central nervous system is one of the crucial research methods for investigating the organization of cognitive functions in the brain. However, many clinicians remain unaware of the significant advances that have taken place in the field of cognitive neuroscience in the last decades. This book provides an introduction to the cognitive and behavioural aspects of the clinical practice of neurology. Most of the contributors to this book combine an active clinical practice with a leading role in their respective research area, and have provided concise summaries of the theoretical advances which they consider as potentially relevant for the clinical evaluation and treatment of patients. This general approach has led to a format which is different from the many textbooks of neuropsychology that have appeared in the last few years. The organization of the material follows the main issues of diagnostic evaluation, clinical presentation and management. As a consequence, the book deals not only with the classical neuropsychological syndromes associated with stroke and degenerative dementias, but also with other common clinical conditions, such as multiple sclerosis, head injury, epilepsy and psychiatric disorders, which are often neglected in neuropsychology textbooks. Part I - Assessment Methods 1: Jean-Francois Demonet: Clinical examination 2: Jeremie Pariente: Neuropsychological testing 3: Guillaume Thierry: Neuroimaging and other ancillary techniques Part II - Neuropsychological Syndromes Associated with Focal Brain Damage Julien Bogousslavsky: Introduction 4: Jubin Abutalebi & Stefano F Cappa: Language disorders 5: Ferdinand Binkofski & Kathrin Reetz: Apraxia 6: Angelo Maravita: Spatial disorders 7: Sandra Lehmann & Armin Schnider: Memory disorders 8: Jean-Marie Annoni: Neurobehavioural disorders after stroke 9: Stefano F Cappa & Lisa Cipolotti: Cognitive and behavioural disorders associated with space-occupying lesions Part III - Dementias 10: Peter Garrard: Differential diagnosis in dementia 11: Andrew J Larner: Alzheimer's Disease 12: Jared Narvid & Maria Luisa Gorno-Tempini: Frontotemporal lobar dementia 13: John Bowler: Vascular dementia 14: John E Duda & Ian G McKeith: Cortical Lewy body disease: dementia with Lewy bodies and Parkinson's disease with dementia 15: William S Brooks, Clement T Loy, John B J Kwok & Peter R Schofield: Genetics of dementia Part IV - Cognitive Disorders in other Neurological and Psychiatric Diseases 16: Anna Mazzucchi: Cognitive and behavioural disorders following traumatic brain injury 17: Daniela Wyss & Jurg Kesselring: Neuropsychological problems: cognitive and affective disturbances in MS 18: Christoph Helmstaedter: Neuropsychology of epilepsy 19: J H Barnett & Paul C Fletcher: Cognition in schizophrenia 20: Belinda Lennox & Paul C Fletcher: Neurocognition of depression 21: Sean A Spence: 'Others' and others: hysteria and the divided self Part V - Treatment Issues 22: Ulrich Mueller: Pharmacological treatment 23: Stefano F Cappa: Rehabilitation of cognitive disorders

Many cognitive psychological, computational, and neuropsychological approaches to the organisation of semantic memory have incorporated the idea that concepts are, at least partly, represented in terms of their fine-grained features. We asked 20 normal volunteers to provide properties of 64 concrete items, drawn from living and nonliving categories, by completing simple sentence stems (e.g., an owl is __, has __, can__). At a later date, the same participants rated the same concepts for prototypicality and familiarity. The features generated were classified as to type of knowledge (sensory, functional, or encyclopaedic), and also quantified with regard to both dominance (the number of participants specifying that property for that concept) and distinctiveness (the proportion of exemplars within a conceptual category of which that feature was considered characteristic). The results demonstrate that rated prototypicality is related to both the familiarity of the concept and its distance from the average of the exemplars within the same category (the category centroid). The feature database was also used to replicate, resolve, and extend a variety of previous observations on the structure of semantic representations. Specifically, the results of our analyses (1) resolve two conflicting claims regarding the relative ratio of sensory to other kinds of attributes in living vs. nonliving concepts; (2) offer new information regarding the types of features - across different domains - that distinguish concepts from their category coordinates; and (3) corroborate some previous claims of higher intercorrelations between features of living things than those of artefacts.

Vascular cognitive impairment (VCI) encompasses vascular dementia and is the second most common cause of dementing illness after Alzheimer's disease. The main causes of VCI are: cerebral small vessel disease; multi-infarct dementia; strategic infarct (i.e. located in a functionally-critical brain area); haemorrhage/microbleed; angiopathy (including cerebral amyloid angiopathy); severe hypoperfusion (e.g. cardiac arrhythmia); and hereditary vasculopathy (e.g. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL). In this systematic analysis, we aimed to relate cognitive and neuropathological features of experimental models to clinical VCI. We extracted data from 107 studies covering 16 models. These included: brief global ischaemic insults (in rats, mice or gerbils); chronic global hypoperfusion (rats, mice, gerbils); chronic hypertension (in primates or stroke-prone, spontaneously-hypertensive rats); multiple ischaemic lesions because of intra-vascular emboli (in rodents, rabbits or primates); strategic ischaemic lesions (in rats or mini-pigs); generalised vasculopathies, because of mutant Notch3, hyperhomocysteinaemia, experimental diabetes mellitus or lack of cerebral vasodilator M(5) receptors (rats or mice). Most cognitive testing showed deficits in working and reference memory. The lesions observed were microinfarcts, diffuse white matter lesions, hippocampal neuronal death, focal ischaemic lesions and micro-haemorrhages. The most-used model was bilateral carotid artery occlusion in rats, leading to chronic hypoperfusion and white matter injury.

INTRODUCTION : The spinocerebellar ataxias (SCAs), are rare neurodegenerative disorders caused by distinct genetic mutations. Clinically, the SCAs are characterised by progressive ataxia and a variety of other features, including cognitive dysfunction. The latter is consistent with a growing body of evidence supporting a cognitive as well as motor role for the cerebellum. Recent suggestions of cerebellar involvement in social cognition have not been extensively explored in these conditions. The availability of definitive molecular diagnosis allows genetically defined subgroups of SCA patients, with distinct patterns of cerebellar and extracerebellar involvement, to be tested comparatively using a common battery of tests of general, social and emotional cognition. METHODS: : Nine patients with SCA6, and 6 with SCA3 were assessed using a comprehensive battery of neuropsychological instruments, encompassing domains of memory, language, visuo-spatial skills, calculation, attention and executive function, emotional processing and theory of mind (ToM). RESULTS : There were no deficits in visuo-spatial processing or calculation in either group, while individuals with naming and attentional difficulties were seen in both. Deficits in memory and executive function were present in both conditions, albeit more pronounced in SCA3. By contrast, both groups demonstrated consistently poor performance on ToM tests, and normal attribution of social and emotional responses. CONCLUSION : The data support the hypothesis that the cerebellum is important for cognitive as well as motor activity. The pattern of overlap of domain impairments provides tentative preliminary evidence that there is a cerebellar contribution to aspects of memory and executive function and ToM, and that other domains depend more on neural system outside the cerebellum. The findings relating to ToM are relevant to the possibility of cerebellar involvement in autism.

A novel, non-verbal test of semantic feature knowledge is introduced, enabling subordinate knowledge of four important concept attributes--colour, sound, environmental context and motion--to be individually probed. This methodology provides more specific information than existing non-verbal semantic tests about the status of attribute knowledge relating to individual concept representations. Performance on this test of a group of 12 patients with semantic dementia (10 male, mean age: 64.4 years) correlated strongly with their scores on more conventional tests of semantic memory, such as naming and word-to-picture matching. The test's overlapping structure, in which individual concepts were probed in two, three or all four modalities, provided evidence of performance consistency on individual items between feature conditions. Group and individual analyses revealed little evidence for differential performance across the four feature conditions, though sound and colour correlated most strongly, and motion least strongly, with other semantic tasks, and patients were less accurate on the motion features of living than non-living concepts (with no such conceptual domain differences in the other conditions). The results are discussed in the context of their implications for the place of semantic dementia within the classification of progressive aphasic syndromes, and for contemporary models of semantic representation and organization.

The question of whether information relevant to meaning (semantics) and structure (syntax) relies on a common language processor or on separate subsystems has proved difficult to address definitively because of the confounds involved in comparing the two types of information. At the sentence level syntactic and semantic judgments make different cognitive demands, while at the single word level, the most commonly used syntactic distinction (between nouns and verbs) is confounded with a fundamental semantic difference (between objects and actions). The present study employs a different syntactic contrast (between count nouns and mass nouns), which is crossed with a semantic difference (between naturally occurring and man-made substances) applying to words within a circumscribed semantic field (foodstuffs). We show, first, that grammaticality judgments of a patient with semantic dementia are indistinguishable from those of a group of age-matched controls, and are similar regardless of the status of his semantic knowledge about the item. In a second experiment we use the triadic task in a group of age-matched controls to show that similarity judgments are influenced not only by meaning (natural vs. manmade), but also implicitly by syntactic information (count vs. mass). Using the same task in a patient with semantic dementia we show that the semantic influences on the syntactic dimension are unlikely to account for this pattern in normals. These data are discussed in relation to modular vs. nonmodular models of language processing, and in particular to the semantic-syntactic distinction.

Iris Murdoch (I.M.) was among the most celebrated British writers of the post-war era. Her final novel, however, received a less than enthusiastic critical response on its publication in 1995. Not long afterwards, I.M. began to show signs of insidious cognitive decline, and received a diagnosis of Alzheimer's disease, which was confirmed histologically after her death in 1999. Anecdotal evidence, as well as the natural history of the condition, would suggest that the changes of Alzheimer's disease were already established in I.M. while she was writing her final work. The end product was unlikely, however, to have been influenced by the compensatory use of dictionaries or thesauri, let alone by later editorial interference. These facts present a unique opportunity to examine the effects of the early stages of Alzheimer's disease on spontaneous written output from an individual with exceptional expertise in this area. Techniques of automated textual analysis were used to obtain detailed comparisons among three of her novels: her first published work, a work written during the prime of her creative life and the final novel. Whilst there were few disparities at the levels of overall structure and syntax, measures of lexical diversity and the lexical characteristics of these three texts varied markedly and in a consistent fashion. This unique set of findings is discussed in the context of the debate as to whether syntax and semantics decline separately or in parallel in patients with Alzheimer's disease.

Presenilin (PSEN)1 mutations are responsible for many cases of autosomal dominant Alzheimer disease (AD), although the clinical spectrum has not been fully defined. The authors describe two members of a kindred with a novel PSEN1 mutation (R278I) presenting with language impairment and relative preservation of memory. Screening for PSEN1 mutations may be appropriate in cases of familial dementia even where the clinical phenotype is not typical of AD.