Development of novel clinical examination scales for the measurement of disease severity in Creutzfeldt-Jakob disease.

OBJECTIVE: To use a robust statistical methodology to develop and validate clinical rating scales quantifying longitudinal motor and cognitive dysfunction in sporadic Creutzfeldt-Jakob disease (sCJD) at the bedside. METHODS: Rasch analysis was used to iteratively construct interval scales measuring composite cognitive and motor dysfunction from pooled bedside neurocognitive examinations collected as part of the prospective National Prion Monitoring Cohort study, October 2008-December 2016.A longitudinal clinical examination dataset constructed from 528 patients with sCJD, comprising 1030 Motor Scale and 757 Cognitive Scale scores over 130 patient-years of study, was used to demonstrate scale utility. RESULTS: The Rasch-derived Motor Scale consists of 8 items, including assessments reliant on pyramidal, extrapyramidal and cerebellar systems. The Cognitive Scale comprises 6 items, and includes measures of executive function, language, visual perception and memory. Both scales are unidimensional, perform independently of age or gender and have excellent inter-rater reliability. They can be completed in minutes at the bedside, as part of a normal neurocognitive examination. A composite Examination Scale can be derived by averaging both scores. Several scale uses, in measuring longitudinal change, prognosis and phenotypic heterogeneity are illustrated. CONCLUSIONS: These two novel sCJD Motor and Cognitive Scales and the composite Examination Scale should prove useful to objectively measure phenotypic and clinical change in future clinical trials and for patient stratification. This statistical approach can help to overcome obstacles to assessing clinical change in rapidly progressive, multisystem conditions with limited longitudinal follow-up.

Cognitive decline heralds onset of symptomatic inherited prion disease.

The clinical effectiveness of any disease-modifying treatment for prion disease, as for other neurodegenerative disorders, will depend on early treatment before damage to neural tissue is irrevocable. Thus, there is a need to identify markers that predict disease onset in healthy at-risk individuals. Whilst imaging and neurophysiological biomarkers have shown limited use in this regard, we recently reported progressive neurophysiological changes in individuals with the inherited prion disease mutation P102L. We have also previously demonstrated a signature pattern of fronto-parietal dysfunction in mild prion disease. Here we address whether these cognitive features anticipate the onset of symptoms in a unique sample of patients with inherited prion disease. In the cross-sectional analysis, we analysed the performance of patients at three time points in the course of disease onset: prior to symptoms (n = 27), onset of subjective symptoms without positive clinical findings (n = 8) and symptomatic with positive clinical findings (n = 24). In the longitudinal analysis, we analysed data from 24 patients who were presymptomatic at the time of recruitment and were followed up over a period of up to 17 years, of whom 16 remained healthy and eight converted to become symptomatic. In the cross-sectional analysis, the key finding was that, relative to a group of 25 healthy non-gene carrier controls, patients with subjective symptoms but without positive clinical findings were impaired on a smaller but similar set of tests (Trail Making Test part A, Stroop test, Performance IQ, gesture repetition, figure recall) to those previously found to be impaired in mild prion disease. In the longitudinal analysis, Trail Making Test parts A and B, Stroop test and Performance IQ scores significantly discriminated between patients who remained presymptomatic and those who converted, even before the converters reached criteria for formal diagnosis. Notably, performance on the Stroop test significantly discriminated between presymptomatic patients and converters before the onset of clinical symptoms [area under the curve = 0.83 (95% confidence interval, 0.62-1.00), P = 0.009]. Thus, we report here, for the first time, neuropsychological abnormalities in healthy patients prior to either symptom onset or clinical diagnosis of inherited prion disease. This constitutes an important component of an evolving profile of clinical and biomarker abnormalities in this crucial group for preventive medicine.

A case study investigating the role of the anterior temporal lobes in general semantics and semantics specific to persons, emotions and social conceptual knowledge.

The role of the anterior temporal lobes (ATLs) in semantic representation remains still much debated. Long thought to support domain-general semantic processing, recent accounts have alternatively suggested that they may be preferentially involved in the processing of person-related semantic knowledge. Several studies have supported such a distinction, but few have either examined both types of semantic processing together, or considered the role of potentially important confounding variables. Here, we address these issues by investigating both domain-general and person-specific semantic processing in a patient with focal ATL damage. The patient presents with dense anterograde and retrograde amnesia. Performance was impaired on tests of general semantic knowledge, but most striking deficits were for person-related semantics, including recognition and identification, knowledge of emotions and social conceptual knowledge. This unique case provides compelling evidence that, in addition to the role in general semantic knowledge, the ATLs are critical for person-related semantics.

Putaminal diffusion tensor imaging measures predict disease severity across human prion diseases.

Therapeutic trials of disease-modifying agents in neurodegenerative disease typically require several hundred participants and long durations for clinical endpoints. Trials of this size are not feasible for prion diseases, rare dementia disorders associated with misfolding of prion protein. In this situation, biomarkers are particularly helpful. On diagnostic imaging, prion diseases demonstrate characteristic brain signal abnormalities on diffusion-weighted MRI. The aim of this study was to determine whether cerebral water diffusivity could be a quantitative imaging biomarker of disease severity. We hypothesized that the basal ganglia were most likely to demonstrate functionally relevant changes in diffusivity. Seventy-one subjects (37 patients and 34 controls) of whom 47 underwent serial scanning (23 patients and 24 controls) were recruited as part of the UK National Prion Monitoring Cohort. All patients underwent neurological assessment with the Medical Research Council Scale, a functionally orientated measure of prion disease severity, and diffusion tensor imaging. Voxel-based morphometry, voxel-based analysis of diffusion tensor imaging and regions of interest analyses were performed. A significant voxel-wise correlation of decreased Medical Research Council Scale score and decreased mean, radial and axial diffusivities in the putamen bilaterally was observed (P < 0.01). Significant decrease in putamen mean, radial and axial diffusivities over time was observed for patients compared with controls (P = 0.01), and there was a significant correlation between monthly decrease in putamen mean, radial and axial diffusivities and monthly decrease in Medical Research Council Scale (P < 0.001). Step-wise linear regression analysis, with dependent variable decline in Medical Research Council Scale, and covariates age and disease duration, showed the rate of decrease in putamen radial diffusivity to be the strongest predictor of rate of decrease in Medical Research Council Scale (P < 0.001). Sample size calculations estimated that, for an intervention study, 83 randomized patients would be required to provide 80% power to detect a 75% amelioration of decline in putamen radial diffusivity. Putamen radial diffusivity has potential as a secondary outcome measure biomarker in future therapeutic trials in human prion diseases.

Impaired spatial processing in visual perception, imagery and art-making following parieto-occipital infarcts.

Visual imagery, like vision as such, is widely thought to be supported by two distinct and dissociable processing streams, dedicated to object representation and spatial analysis respectively. However, this simple dichotomy has been contested, with recent studies suggesting that impairments in perception-for-action and visuo-spatial imagery may reflect a more general deficit in space-based attention. Although previous studies have revealed the impact of brain damage on artistic expression, few have examined the impact on artistic expression in terms of the perceptual and spatial components of either visual processing or visual imagery. Here we present the case of an artist whose artistic expression was dramatically affected following devastating posterior brain damage. Of particular interest, we demonstrate how these changes relate to impairments in integrating and aligning different spatial features in both visual processing and visual imagery, suggestive of a general simultanagnosia not previously described.

The language disorder of prion disease is characteristic of a dynamic aphasia and is rarely an isolated clinical feature.

BACKGROUND: Akinetic mutism is a key diagnostic feature of prion diseases, however, their rapidly progressive nature makes detailed investigation of the language disorder in a large cohort extremely challenging. This study aims to position prion diseases in the nosology of language disorders and improve early clinical recognition. METHODS: A systematic, prospective investigation of language disorders in a large cohort of patients diagnosed with prion diseases. 568 patients were included as a sub-study of the National Prion Monitoring Cohort. All patients had at least one assessment with the MRC Scale, a milestone-based functional scale with language and non-language components. Forty patients, with early symptoms and able to travel to the study site, were also administered a comprehensive battery of language tests (spontaneous speech, semantics, syntax, repetition, naming, comprehension and lexical retrieval under different conditions). RESULTS: 5/568 (0.9%) patients presented with leading language symptoms. Those with repeated measurements deteriorated at a slower rate in language compared to non-language milestones. Amongst the subgroup of 40 patients who underwent detailed language testing, only three tasks-semantic and phonemic fluency and sentence comprehension-were particularly vulnerable early in the disease. These tasks were highly correlated with performance on non-verbal executive tests. Patients were also impaired on a test of dynamic aphasia. CONCLUSION: These results provide evidence that the language disorder in prion disease is rarely an isolated clinical or cognitive feature. The language abnormality is indicative of a dynamic aphasia in the context of a prominent dysexecutive syndrome, similar to that seen in patients with the degenerative movement disorder progressive supranuclear palsy (PSP).

Successful short-term re-learning and generalisation of concepts in semantic dementia.

Patients with semantic dementia (SD) can rapidly and successfully re-learn word labels during cognitive intervention. This new learning, however, usually remains rigid and context-dependent. Conceptual enrichment (COEN) training is a therapy approach aimed to produce more flexible and generalisable learning in SD. In this study we compare generalisation and maintenance of learning after COEN with performance achieved using a classical naming therapy (NT). The study recruited a 62-year-old woman with SD. An AB1ACAB2 experimental design was implemented, with naming performance assessed at baseline, post- intervention, 3 and 6 weeks after the end of each treatment phase. Three generalisation tasks were also assessed pre- and post-intervention. Naming post-intervention improved significantly following both therapies, however, words trained using COEN therapy showed a significantly greater degree of generalisation than those trained under NT. In addition, only words trained with COEN continued to show significant improvements compared with baseline performance when assessed 6 weeks after practice ceased. It was concluded that therapies based on conceptual enrichment of the semantic network facilitate relearning of words and enhance generalisation in patients with SD.

Frontotemporal lobar degeneration and social behaviour: Dissociation between the knowledge of its consequences and its conceptual meaning.

Inappropriate social behaviour is an early symptom of frontotemporal lobar degeneration (FTLD) in both behavioural variant frontotemporal dementia (bvFTD) and semantic dementia (SD) subtypes. Knowledge of social behaviour is essential for appropriate social conduct. The superior anterior temporal lobe (ATL) has been identified as one key neural component for the conceptual knowledge of social behaviour, but it is unknown whether this is dissociable from knowledge of the consequences of social behaviour. Here, we used a newly-developed test of knowledge about long-term and short-term consequences of social behaviour to investigate its impairment in patients with FTLD relative to a previously-developed test of social conceptual knowledge. We included 19 healthy elderly control participants and 19 consecutive patients with features of bvFTD or SD and defined dissociations as performance differences between tasks for each patient (Bonferroni-corrected p < .05). Knowledge of long-term consequences was selectively impaired relative to short-term consequences in five patients and the reverse dissociation occurred in one patient. Six patients showed a selective impairment of social concepts relative to long-term consequences with the reverse dissociation occurring in one patient. These results corroborate the hypothesis that knowledge of long-term consequences of social behaviour is dissociable from knowledge of short-term consequences, as well as of social conceptual knowledge. Confirming our hypothesis, we found that patients with more marked grey matter (GM) volume loss in frontopolar relative to right superior ATL regions of interest exhibited poorer knowledge of the long-term consequences of social behaviour relative to the knowledge of its conceptual meaning and vice versa (n = 15). These findings support the hypothesis that frontopolar and ATL regions represent distinct aspects of social knowledge. This suggests that rather than being unable to suppress urges to behave inappropriately, FTLD patients often lose the knowledge of what appropriate social behaviour is and can therefore not be expected to behave accordingly.

Neuroanatomical correlates of prion disease progression - a 3T longitudinal voxel-based morphometry study.

PURPOSE: MRI has become an essential tool for prion disease diagnosis. However there exist only a few serial MRI studies of prion patients, and these mostly used whole brain summary measures or region of interest based approaches. We present here the first longitudinal voxel-based morphometry (VBM) study in prion disease. The aim of this study was to systematically characterise progressive atrophy in patients with prion disease and identify whether atrophy in specific brain structures correlates with clinical assessment. METHODS: Twenty-four prion disease patients with early stage disease (3 sporadic, 2 iatrogenic, 1 variant and 18 inherited CJD) and 25 controls were examined at 3T with a T1-weighted 3D MPRAGE sequence at multiple time-points (2-6 examinations per subject, interval range 0.1-3.2 years). Longitudinal VBM provided intra-subject and inter-subject image alignment, allowing voxel-wise comparison of progressive structural change. Clinical disease progression was assessed using the MRC Prion Disease Rating Scale. Firstly, in patients, we determined the brain regions where grey and white matter volume change between baseline and final examination correlated with the corresponding change in MRC Scale score. Secondly, in the 21/24 patients with interscan interval longer than 3 months, we identified regions where annualised rates of regional volume change in patients were different from rates in age-matched controls. Given the heterogeneity of the cohort, the regions identified reflect the common features of the different prion sub-types studied. RESULTS: In the patients there were multiple regions where volume loss significantly correlated with decreased MRC scale, partially overlapping with anatomical regions where yearly rates of volume loss were significantly greater than controls. The key anatomical areas involved included: the basal ganglia and thalamus, pons and medulla, the hippocampal formation and the superior parietal lobules. There were no areas demonstrating volume loss significantly higher in controls than patients or negative correlation between volume and MRC Scale score. CONCLUSIONS: Using 3T MRI and longitudinal VBM we have identified key anatomical regions of progressive volume loss which correlate with an established clinical disease severity index and are relevant to clinical deterioration. Localisation of the regions of progressive brain atrophy correlating most strongly with clinical decline may help to provide more targeted imaging endpoints for future clinical trials.

The role of working memory and verbal fluency in autobiographical memory in early Alzheimer's disease and matched controls.

Retrieval of autobiographical memories (AMs) is important for "sense of self". Previous research and theoretical accounts suggest that working memory (WM) and semantic and phonemic fluency abilities facilitate the hierarchical search for, and reliving of past, personal events in the mind's eye. However, there remains a lack of consensus as to the nature of the relationships between these cognitive functions and the truly episodic aspects of AM. The present study therefore aimed to explore the associations between these variables in a sample with a wide range of cognitive abilities. The study incorporated a between-groups component, and a correlational component with multiple regression. Participants with Alzheimer's disease (n=10) and matched healthy controls (n=10) were assessed on measures of semantic and episodic AM search and retrieval, auditory and spatial WM, and semantic and phonemic fluency. The AD group produced less episodic AM content compared to controls. Semantic fluency predicted episodic AM retrieval independent of age effects but there were no significant relationships between measures of phonemic fluency, WM and episodic AM. The results suggest that the ability to maintain hierarchical search of the semantic knowledge-base is important for truly episodic reliving, and interventions for people with AM impairment might therefore benefit from incorporating structured, individualised external memory-aids to facilitate AM search and retrieval.

Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years.

Patients with iatrogenic Creutzfeldt-Jakob disease due to administration of cadaver-sourced growth hormone during childhood are still being seen in the UK 30 years after cessation of this treatment. Of the 77 patients who have developed iatrogenic Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked change in genotype profile at polymorphic codon 129 of the prion protein gene (PRNP) from predominantly valine homozygous to a mixed picture of methionine homozygous and methionine-valine heterozygous over time. The incubation period of iatrogenic Creutzfeldt-Jakob disease is significantly different between all three genotypes. This experience is a striking contrast with that in France and the USA, which may relate to contamination of different growth hormone batches with different strains of human prions. We describe the clinical, imaging, molecular and autopsy features in 22 of 24 patients who have developed iatrogenic Creutzfeldt-Jakob disease in the UK since 2003. Mean age at onset of symptoms was 42.7 years. Gait ataxia and lower limb dysaesthesiae were the most frequent presenting symptoms. All had cerebellar signs, and the majority had myoclonus and lower limb pyramidal signs, with relatively preserved cognitive function, when first seen. There was a progressive decline in neurological and cognitive function leading to death after 5-32 (mean 14) months. Despite incubation periods approaching 40 years, the clinical duration in methionine homozygote patients appeared to be shorter than that seen in heterozygote patients. MRI showed restricted diffusion in the basal ganglia, thalamus, hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The electroencephalogram was abnormal in 15 patients and cerebrospinal fluid 14-3-3 protein was positive in half the patients. Neuropathological examination was conducted in nine patients. All but one showed synaptic prion deposition with numerous kuru type plaques in the basal ganglia, anterior frontal and parietal cortex, thalamus, basal ganglia and cerebellum. The patient with the shortest clinical duration had an atypical synaptic deposition of abnormal prion protein and no kuru plaques. Taken together, these data provide a remarkable example of the interplay between the strain of the pathogen and host prion protein genotype. Based on extensive modelling of human prion transmission barriers in transgenic mice expressing human prion protein on a mouse prion protein null background, the temporal distribution of codon 129 genotypes within the cohort of patients with iatrogenic Creutzfeldt-Jakob disease in the UK suggests that there was a point source of infecting prion contamination of growth hormone derived from a patient with Creutzfeldt-Jakob disease expressing prion protein valine 129.

The cognitive profile of prion disease: a prospective clinical and imaging study.

OBJECTIVES: Prion diseases are dementing illnesses with poorly defined neuropsychological features. This is probably because the most common form, sporadic Creutzfeldt-Jakob disease, is often rapidly progressive with pervasive cognitive decline making detailed neuropsychological investigation difficult. This study, which includes patients with inherited, acquired (iatrogenic and variant) and sporadic forms of the disease, is the only large-scale neuropsychological investigation of this patient group ever undertaken and aimed to define a neuropsychological profile of human prion diseases. METHODS: A tailored short cognitive examination of all of the patients (n = 81), with detailed neuropsychological testing in a subset with mild disease (n = 30) and correlation with demographic, clinical, genetic (PRNP mutation and polymorphic codon 129 genotype), and other variables (MRI brain signal change in cortex, basal ganglia or thalamus; quantitative research imaging, cerebrospinal fluid 14-3-3 protein). RESULTS: Comparison with healthy controls showed patients to be impaired on all tasks. Principal components analysis showed a major axis of fronto-parietal dysfunction that accounted for approximately half of the variance observed. This correlated strongly with volume reduction in frontal and parietal gray matter on MRI. Examination of individual patients' performances confirmed early impairment on this axis, suggesting characteristic cognitive features in mild disease: prominent executive impairment, parietal dysfunction, a largely expressive dysphasia, with reduced motor speed. INTERPRETATION: Taken together with typical neurological features, these results complete a profile that should improve differential diagnosis in a clinical setting. We propose a tailored neuropsychological battery for early recognition of clinical onset of symptoms with potential for use in clinical trials involving at-risk individuals.

Restoration of conceptual knowledge in a case of semantic dementia.

Patients with semantic dementia (SD) may undergo successful relearning of object names, but these gains are usually restricted to the trained exemplars, demonstrating poor generalization. We hypothesized that generalization could be improved by restoring an item's semantic network through specific strategies that recruit the remaining personal semantic memories (conceptual enrichment therapies). We describe the case of a patient with SD who showed greater generalization of learning following a conceptual enrichment therapy than when learning items in a word-retrieval therapy. Our results suggest that enhancing an item's semantic network connections may result in improved generalization of learning in SD. A learning mechanism in the presence of compromised hippocampi is also discussed.

Compulsive versifying after treatment of transient epileptic amnesia.

Compulsive production of verse is an unusual form of hypergraphia that has been reported mainly in patients with right temporal lobe seizures. We present a patient with transient epileptic amnesia and a left temporal seizure focus, who developed isolated compulsive versifying, producing multiple rhyming poems, following seizure cessation induced by lamotrigine. Functional neuroimaging studies in the healthy brain implicate left frontotemporal areas in generating novel verbal output and rhyme, while dysregulation of neocortical and limbic regions occurs in temporal lobe epilepsy. This case complements previous observations of emergence of altered behavior with reduced seizure frequency in patients with temporal lobe epilepsy. Such cases suggest that reduced seizure frequency has the potential not only to stabilize or improve memory function, but also to trigger complex, specific behavioral alterations.

A cognitive chameleon: lessons from a novel MAPT mutation case.

We report a case of frontotemporal dementia caused by a novel MAPT mutation (Q351R) with a remarkably long amnestic presentation mimicking familial Alzheimer's disease. Longitudinal clinical, neuropsychological and imaging data provide convergent evidence for predominantly bilateral anterior medial temporal lobe involvement consistent with previously established neuroanatomical signatures of MAPT mutations. This case supports the notion that the neural network affected in MAPT mutations is determined to a large extent by the underlying molecular pathology. We discuss the diagnostic significance of anomia in the context of atypical amnesia and the impact of impaired episodic and semantic memory systems on autobiographical memory.

A novel prion disease associated with diarrhea and autonomic neuropathy.

BACKGROUND: Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multifocal central nervous system degeneration that is usually dominated by dementia and cerebellar ataxia. Approximately 15% of cases of recognized prion disease are inherited and associated with coding mutations in the gene encoding prion protein (PRNP). The availability of genetic diagnosis has led to a progressive broadening of the recognized spectrum of disease. METHODS: We used longitudinal clinical assessments over a period of 20 years at one hospital combined with genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular genetic, and biochemical studies, as well as studies of animal transmission, to characterize a novel prion disease in a large British kindred. We studied 6 of 11 affected family members in detail, along with autopsy or biopsy samples obtained from 5 family members. RESULTS: We identified a PRNP Y163X truncation mutation and describe a distinct and consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathological examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Transmission studies in laboratory mice were negative. CONCLUSIONS: Abnormal forms of prion protein that were found in multiple peripheral tissues were associated with diarrhea, autonomic failure, and neuropathy. (Funded by the U.K. Medical Research Council and others.).

Binding deficits in memory following medial temporal lobe damage in patients with voltage-gated potassium channel complex antibody-associated limbic encephalitis.

Some prominent studies have claimed that the medial temporal lobe is not involved in retention of information over brief intervals of just a few seconds. However, in the last decade several investigations have reported that patients with medial temporal lobe damage exhibit an abnormally large number of errors when required to remember visual information over brief intervals. But the nature of the deficit and the type of error associated with medial temporal lobe lesions remains to be fully established. Voltage-gated potassium channel complex antibody-associated limbic encephalitis has recently been recognized as a form of treatable autoimmune encephalitis, frequently associated with imaging changes in the medial temporal lobe. Here, we tested a group of these patients using two newly developed visual short-term memory tasks with a sensitive, continuous measure of report. These tests enabled us to study the nature of reporting errors, rather than only their frequency. On both paradigms, voltage-gated potassium channel complex antibody patients exhibited larger errors specifically when several items had to be remembered, but not for a single item. Crucially, their errors were strongly associated with an increased tendency to report the property of the wrong item stored in memory, rather than simple degradation of memory precision. Thus, memory for isolated aspects of items was normal, but patients were impaired at binding together the different properties belonging to an item, e.g. spatial location and object identity, or colour and orientation. This occurred regardless of whether objects were shown simultaneously or sequentially. Binding errors support the view that the medial temporal lobe is involved in linking together different types of information, potentially represented in different parts of the brain, regardless of memory duration. Our novel behavioural measures also have the potential to assist in monitoring response to treatment in patients with memory disorders, such as those with voltage-gated potassium channel complex antibody limbic encephalitis.

Staging of the cognitive decline in Alzheimer's disease: insights from a detailed neuropsychological investigation of mild cognitive impairment and mild Alzheimer's disease.

OBJECTIVE: The decline of episodic memory in Alzheimer's disease (AD) is well established, but the exact appearance and staging of deficits in other cognitive domains is sometimes contentious. The current investigation attempted to elucidate the appearance of additional cognitive deficits in the non-episodic domains and to understand these deficits with respect to the known pathological staging of AD. METHODS: A cross-sectional investigation compared cognitively normal age-matched controls with patients with mild AD and mild cognitive impairment (MCI) using a detailed neuropsychological assessment. RESULTS: The systematic investigation of cognitive performance across the major cognitive domains demonstrates that the appearance of additional cognitive deficits in MCI and AD can be predicted, with impaired semantic cognition performance pre-empting the appearance of attention/executive dysfunction and visuospatial deficits in the majority of patients with MCI. CONCLUSIONS: This progressive pattern of cognitive deficits fits with the known pathological staging of AD, and the data further highlight the relative rarity of pure amnestic MCI. These results indicate that any neuropsychological test battery used to assess patients with MCI should include language and semantic memory tests in addition to typical episodic memory tests, as changes within this domain might be a sensitive indication of incipient AD.

Emergence and progression of 'non-semantic' deficits in semantic dementia.

Although semantic dementia (SD) is defined as a selective disruption of conceptual knowledge, a number of group studies have now demonstrated that SD patients also show impaired performance on tasks not usually considered to have a high semantic load (e.g., reading words aloud and lexical or object decision). The aim of the current study was to document the relative deterioration, over time, of a number of semantic and so-called 'non-semantic' tasks in LF, a single case of SD for whom - by virtue of his work as a published cartoonist - we also have extensive data regarding his pre-morbid linguistic and drawing skills. In five testing rounds over a period of five years we administered semantic tests of object naming and object definition (on both of which LF was progressively impaired, as expected for a diagnosis of SD), plus verbal and non-verbal 'non-semantic' tasks of reading aloud, spelling, object and lexical decision, and delayed copy drawing. Initially, his only striking 'non-semantic' deficit was in the domain of spelling - a pronounced surface dysgraphia in an individual with demonstrably superior pre-morbid spelling skill. Over time, and in line with his declining semantic system, LF's performance gradually deteriorated on all of the 'non-semantic' tasks. The most vulnerable items on most tasks were those with low frequency and an atypical form. This report adds to the growing body of evidence that a number of cognitive processes not usually considered to be 'semantic' in their demands rely on the integrity of semantic knowledge for successful execution. Furthermore, it provides the first indication that these non-semantic deficits might emerge in an order predictable from the typicality structure of the relevant domain.

Aberrant pattern of scanning in prosopagnosia reflects impaired face processing.

Visual scanpath recording was used to investigate the information processing strategies used by a prosopagnosic patient, SC, when viewing faces. Compared to controls, SC showed an aberrant pattern of scanning, directing attention away from the internal configuration of facial features (eyes, nose) towards peripheral regions (hair, forehead) of the face. The results suggest that SC's face recognition deficit can be linked to an inability to assemble an accurate and unified face percept due to an abnormal allocation of attention away from the internal face region. Extraction of stimulus attributes necessary for face identity recognition is compromised by an aberrant face scanning pattern.