We report a quantitative investigation of the visual identification and auditory comprehension deficits of 4 patients who had made a partial recovery from herpes simplex encephalitis. Clinical observations had suggested the selective impairment and selective preservation of certain categories of visual stimuli. In all 4 patients a significant discrepancy between their ability to identify inanimate objects and inability to identify living things and foods was demonstrated. In 2 patients it was possible to compare visual and verbal modalities and the same pattern of dissociation was observed in both. For 1 patient, comprehension of abstract words was significantly superior to comprehension of concrete words. Consistency of responses was recorded within a modality in contrast to a much lesser degree of consistency between modalities. We interpret our findings in terms of category specificity in the organization of meaning systems that are also modality specific semantic systems.

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The selective impairment of semantic memory is described in three patients with diffuse cerebrallesions. These patients, selected on the basis of a failure to recognize or identify common objects (agnosia for objects), were investigated in detail. In particular, their perceptual, language and memory functions were assessed, and the limits and properties of their recognition difficulties explored. It was found that knowledge of pictorial representations of objects, and of words, was impaired or impoverished, and in both instances knowledge of subordinate categories was more vulnerable than superordinate categories. Evidence is presented that this impairment of semantic memory cannot be accounted for by intellectual impairment, sensory or perceptual deficits, or expressive language disorder. The implications of damage to the semantic memory system for the operation of other cognitive systems, in particular short and long-term memory functions, are considered. Some tentative evidence for the structural basis for a hierarchically organized modality-specific semantic memory system is discussed.

We report a quantitative investigation of the visual identification and auditory comprehension deficits of 4 patients who had made a partial recovery from herpes simplex encephalitis. Clinical observations had suggested the selective impairment and selective preservation of certain categories of visual stimuli. In all 4 patients a significant discrepancy between their ability to identify inanimate objects and inability to identify living things and foods was demonstrated. In 2 patients it was possible to compare visual and verbal modalities and the same pattern of dissociation was observed in both. For 1 patient, comprehension of abstract words was significantly superior to comprehension of concrete words. Consistency of responses was recorded within a modality in contrast to a much lesser degree of consistency between modalities. We interpret our findings in terms of category specificity in the organization of meaning systems that are also modality specific semantic systems.

An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43–68 years) and duration (1.7–22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features consistent with either type A or B TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus and cerebellum were a consistent feature of these cases, in contrast to the similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control cases with frontotemporal lobar degeneration–TAR DNA-binding protein. These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.

In this study we report our investigations of the residual auditory-verbal comprehension skills of a global dysphasic who had sustained a major left hemisphere infarction. Clinically V.E.R.'s capacity for propositional speech and her comprehension of the simplest verbal instructions appeared to be absent. Nevertheless using matching-to-sample techniques it was possible to demonstrate the selective preservation (foods, animals and flowers) and the selective impairment (objects) of specific semantic categories. Furthermore there was evidence from analyses of response consistency and presentation rate effects that her deficit was primarily one of access to the full semantic representation of words. We suggest that this access impairment arose because the system had become refractory, such refractoriness being category specific.

The hippocampal formation (HF) is known from pathological and MRI studies to be severely atrophied in established Alzheimer's disease. However, it is unclear when the earliest changes in the HF occur. We performed a longitudinal study of asymptomatic individuals at risk of autosomal dominant familial Alzheimer's disease in order to assess presymptomatic changes in the HF. Seven at risk members of a familial Alzheimer's disease pedigree associated with the amyloid precursor protein 717 valine to glycine mutation underwent serial MR scanning and neuropsychological assessments over 3 years. These assessments were compared with results from 38 normal controls. During the study three at risk subjects became clinically affected. Volumetric measurement of the HF showed that asymmetrical atrophy developed in these subjects before the appearance of symptoms. Verbal and visual memory measures declined in parallel with hippocampal loss. A loss of up to 8% per annum of the volume of the HF occurred in the 2 years over which symptoms first appeared. These findings may have implications for early diagnosis of Alzheimer's disease.

Relating clinical symptoms to neuroanatomical profiles of brain damage and ultimately to tissue pathology is a key challenge in the field of neurodegenerative disease and particularly relevant to the heterogeneous disorders that comprise the frontotemporal lobar degeneration spectrum. Here we present a retrospective analysis of clinical, neuropsychological and neuroimaging (volumetric and voxel-based morphometric) features in a pathologically ascertained cohort of 95 cases of frontotemporal lobar degeneration classified according to contemporary neuropathological criteria. Forty-eight cases (51%) had TDP-43 pathology, 42 (44%) had tau pathology and five (5%) had fused-in-sarcoma pathology. Certain relatively specific clinicopathological associations were identified. Semantic dementia was predominantly associated with TDP-43 type C pathology; frontotemporal dementia and motoneuron disease with TDP-43 type B pathology; young-onset behavioural variant frontotemporal dementia with FUS pathology; and the progressive supranuclear palsy syndrome with progressive supranuclear palsy pathology. Progressive non-fluent aphasia was most commonly associated with tau pathology. However, the most common clinical syndrome (behavioural variant frontotemporal dementia) was pathologically heterogeneous; while pathologically proven Pick's disease and corticobasal degeneration were clinically heterogeneous, and TDP-43 type A pathology was associated with similar clinical features in cases with and without progranulin mutations. Volumetric magnetic resonance imaging, voxel-based morphometry and cluster analyses of the pathological groups here suggested a neuroanatomical framework underpinning this clinical and pathological diversity. Frontotemporal lobar degeneration-associated pathologies segregated based on their cerebral atrophy profiles, according to the following scheme: asymmetric, relatively localized (predominantly temporal lobe) atrophy (TDP-43 type C); relatively symmetric, relatively localized (predominantly temporal lobe) atrophy (microtubule-associated protein tau mutations); strongly asymmetric, distributed atrophy (Pick's disease); relatively symmetric, predominantly extratemporal atrophy (corticobasal degeneration, fused-in-sarcoma pathology). TDP-43 type A pathology was associated with substantial individual variation; however, within this group progranulin mutations were associated with strongly asymmetric, distributed hemispheric atrophy. We interpret the findings in terms of emerging network models of neurodegenerative disease: the neuroanatomical specificity of particular frontotemporal lobar degeneration pathologies may depend on an interaction of disease-specific and network-specific factors.