Tracking progression in frontotemporal lobar degeneration: serial MRI in semantic dementia.

BACKGROUND: Semantic dementia is a sporadic neurodegenerative disorder characterized by the progressive erosion of semantic processing and is one of the canonical subtypes of frontotemporal lobar degeneration. This study aimed to characterize the pattern of global and regional longitudinal brain atrophy in semantic dementia and to identify imaging biomarkers that could underpin therapeutic trials. METHODS: Twenty-one patients with semantic dementia (including eight pathologically confirmed cases) underwent whole-brain and region-of-interest analyses on volumetric brain MRI scans at two time points. Sample size estimates for trials were subsequently calculated using these data. RESULTS: Mean (SD) whole-brain atrophy rate was 39.6 (31.9) mL/y [3.2 (12.0) mL/y in controls], with ventricular enlargement of 8.9 (4.4) mL/y [1.0 (1.0) mL/y in controls]. All patients had a smaller left temporal lobe at baseline [left mean 31.9 (6.9) mL, right mean 49.2 (9.5) mL; p < 0.0001]; however, the mean rate of atrophy was significantly greater in the right temporal lobe [right 3.9 (1.7) mL/y, left 2.8 (1.2) mL/y; p = 0.02]. Similarly, whereas the left hippocampus was smaller at baseline, the mean atrophy rate was significantly greater in the right hippocampus. Using the atrophy rates generated, sample size requirements for clinical trials were found to be smallest for temporal lobe measurement. CONCLUSIONS: These findings show that the rate of tissue loss in the right temporal lobe overtakes the left temporal lobe as semantic dementia evolves, consistent with the later development of symptoms attributable to right temporal lobe dysfunction. Furthermore, our findings demonstrate that MRI measures of temporal lobe volume loss could provide a feasible and sensitive index of disease progression in semantic dementia.

Neuropsychological correlates of whole brain atrophy in Alzheimer's disease.

Alzheimer's disease (AD) is associated with excess whole brain volume loss, and progressive cognitive impairment. We aimed to study the extent to which these two potential biomarkers of AD progression are correlated. Forty-six patients with sporadic AD were tested with a neuropsychometric battery including test of verbal and visual memory, vocabulary, arithmetic, naming, visuoperceptual skills and reasoning at two time-points, approximately 1 year apart; annualised rates of change for each test were calculated. Each subject also attended for up to twelve T1-weighted volumetric MRI scans at fixed intervals over a 2-year period. For each individual all possible scan-pairs were positionally registered, and whole brain atrophy rates were calculated using the brain boundary shift integral. Linear mixed models were used to investigate associations between atrophy rate and coincident change in each neuropsychometric score. Each model estimated the effect of a unit change in score, plus the additional effect of a fall to floor, after adjusting for baseline levels. 467 MRI scans were performed, permitting 2199 individual measures of change to be made. The model-derived mean atrophy rate was 2.23% per year with a between-subject SD of 0.99% per year. Increasing atrophy rate was significantly associated with rate of change in a number of non-memory based neuropsychological scores, with the strongest association seen with longitudinal change in matrix reasoning (p=0.004). These results provide further evidence that cerebral atrophy is a clinically relevant marker of AD progression. This methodology whereby data from patients falling to floor on a given test may be included and accounted for, rather than discarded, may find broader application in clinical studies incorporating neuropsychometric outcomes.

Development of selective verbal memory impairment secondary to a left thalamic infarct: a longitudinal case study.

A 68 year old man suffered an acute dysphasic episode with persistent memory disturbance while taking part as a control in a longitudinal magnetic resonance imaging (MRI) study. A small new left thalamic infarct involving the mamillo-thalamic tract could be demonstrated on volumetric MRI, coinciding with the development of a selective verbal memory impairment. This suggests that lateralisation of cognitive processing of visual and verbal material exists at the thalamic as well as the cortical level. High resolution volumetric MRI may be helpful in demonstrating small subcortical infarcts that may not be seen using computed tomography or conventional MRI.

Clinical features of frontotemporal dementia due to the intronic tau 10(+16) mutation.

OBJECTIVE: To describe the clinical features of nine British families with neuropathologically verified frontotemporal dementia (FTD) due to the intronic tau exon 10(+16) mutation. METHODS: Retrospective chart reviews of family members with FTD belonging to nine tau 10(+16) mutation pedigrees in whom neuropathologic examination had been carried out. APOE genotype was determined for those patients for whom DNA was available. RESULTS: The median age at onset was 50 years (range 37 to 59 years; n = 30). The median age at death was 61 years (range 42 to 72 years; n = 33). The median duration of the disease was 11 years (range 3 to 22 years; n = 25) for those who have died and is 17 years (range 15 to 23 years; n = 3) for those living. The most common presenting symptom was disinhibition (n = 23). A minority presented with frontal dysexecutive symptoms, apathy, impairment of episodic memory, or depression. All of these patients subsequently developed personality and behavioral change. Memory impairment, language deficits, ritualistic behavior, hyperphagia, and hyperorality were frequent symptoms. Parkinsonism, neuroleptic sensitivity, or primitive reflexes were present in half of the patients, where these data were available. The clinical features of ALS were absent. Neuropathologic examination of 12 patients demonstrated the hallmark tau-positive neuronal and glial inclusions. APOE genotype did not account for the considerable variation in age at onset, age at death, duration of disease, or severity of estimated brain atrophy. CONCLUSIONS: All cases fulfilled the clinical criteria for a diagnosis of FTD. Despite similar clinical phenotypes, there was considerable variation in age at onset and duration of disease both between and within families, suggesting the presence of an effect due to other genetic or environmental factors.

A disorder of colour perception associated with abnormal colour after-images: a defect of the primary visual cortex.

A 64 year old woman with posterior cortical atrophy secondary to probable Alzheimer's disease is described. Her presenting symptom was of seeing objects as abnormally coloured after prior exposure to a coloured stimulus. Formal testing disclosed that the patient experienced colour after-images of abnormal latency, duration, and amplitude.The demonstration of prolonged colour after-images in a patient with a cortical disease process provides strong evidence that the generation of colour after-images is mediated at least in part by the visual cortex. A mechanism for the generation of colour after-images is proposed in which abnormal prolongation of the images results from excessive rebound inhibition of previously excited wavelength selective neurons in V1. This may occur as a consequence of the relative sparing of inhibitory interneurons in V1 in the context of the degeneration of excitatory neurons that occurs in Alzheimer's disease.

A particular difficulty in discriminating between mirror images.

We investigated the selective impairment of mirror image discrimination in a patient with bilateral parieto-occipital lesions (FIM). We report a difficulty with the discrimination between mirror images more selective than has been previously reported (Turnbull OH, McCarthy RA. Failure to discriminate between mirror-image objects: a case of viewpoint-independent object recognition? Neurocase 1996;2:63). FIM was asked to judge, in five same/different experiments, whether pairs of simultaneously presented line drawings of objects were identical. FIM demonstrated only a minor impairment in discriminating between orientations in the picture plane but was at chance in making discrimination between mirror images. An experiment with normal observers established that our results were not due to differences in task difficulty. Two further experiments investigated the effects of rotation on the discrimination of letters and geometric shapes. FIM's impairment extended to geometric shapes but not to letters. These results would be consistent with the preservation of an abstract representation for object recognition that did not code the difference between mirror image views.

Refractory dyslexia: evidence of multiple task-specific phonological output stores.

We investigated the case of a patient whose reading was characterized by multiple phonemic paraphasic errors. An error analysis of a large corpus of reading responses (758 words, 86 non-words) highlighted the preponderance of phonological errors which did not occur in his naming, repetition or spontaneous speech. His comprehension of the written word was relatively preserved, even for words he was unable to read aloud. We suggest that his impairment lies at the level of the phonological output store. We also demonstrate that his reading performance was facilitated by increasing the response-stimulus delay. The strong influence of temporal factors is shown to be task-specific. Two main points are drawn from our results. First, we argue that our patient can be characterized as having a refractory access type of deficit; to our knowledge, no previous case of a refractory deficit affecting word reading has been reported. Secondly, the task specificity of both the phonological error pattern and the sensitivity to temporal factors is difficult to reconcile with the idea of a unitary phonological output store. Contrary to orthodox neuropsychological models, we propose that there are independent stores specific for reading and spoken output.

Neuropsychological profiles of familial Alzheimer's disease associated with mutations in the presenilin 1 and amyloid precursor protein genes.

Patients with familial Alzheimer's disease and a subset known to have presenilin mutations were compared with sporadic cases on a comprehensive battery of cognitive tests. These included measures of memory, intelligence, language and perception. The three groups were very comparable, in terms of severity, on global measures of dementia. However, their profiles/patterns of cognitive impairment differed in two respects; the group with sporadic Alzheimer's disease were significantly more impaired on tests of object naming and object perception than either the group with familial Alzheimer's disease or group with familial Alzheimer's disease and presenilin mutations, yet they scored at a significantly higher level on the measure of verbal intelligence. This study provides further evidence of the heterogeneity of the disease process.

Repeating without semantics: surface dysphasia?

We describe our investigations of MNA, who had a progressive, severe and global loss of semantic knowledge (semantic dementia). Her verbal vocabulary was restricted to a few common words and she was also unable to recognize common objects from sight. By contrast, she had a well-preserved digit span (7-8 digits). In this series of experiments, we focused on her ability to repeat lists and sentences in which familiarity, meaningfulness, morphology and syntactic structure were manipulated. In list repetition tasks, we found that MNA showed a reliable effect of phonological similarity, word frequency and stimulus lexicality, but was unaffected by linguistic complexity, word length, semantic coherence or the status of individual stimuli as "known" or "unknown". In sentence repetition, her performance was not influenced by any semantic variables. However, there was a substantial effect of the frequency of the constituent vocabulary, even for words outside the range of her retained vocabulary. The influence of syntax was restricted to minor effects of morphology. The phonemes of syllables and the syllables of words are bound by their co-occurrence rather than their meaning. We conclude that the phonological representation of words is functionally independent of the semantic system.

Acalculia: deficits of operational and quantity number knowledge.

We describe the standardization of three new tests of knowledge of quantity facts, number operations and multiplication facts. We also report a validation study in which a group of 50 patients with cortical degenerative disorders were tested on these three new tests of number processing. Our results show that the quantity facts and number operations tests are sensitive measures of number processing abilities. Performance on the three new tests and the Graded Difficulty Arithmetic (GDA) test were found to be significantly impaired in the Alzheimer's Disease (AD) group. The frontotemporal dementia (FTD) group was subdivided into those with a semantic dementia (SD) and those with prominent frontal features (Non-SD). The semantic dementia subgroup was more impaired than both the AD patient group and the nonsemantic FTD subgroup on the quantity facts test. A more fine grained analysis reveals several interesting patterns of performance, including a dissociation between impaired performance on the quantity facts and number operations tests and preserved performance on the GDA. The findings attest the value of comparing performance on the GDA and our new tests in delineating the nature of an individual's number processing deficits. Implications for the relation between simple arithmetic fact knowledge and higher level number processing are discussed.

Homophone meaning generation: a new test of verbal switching for the detection of frontal lobe dysfunction.

Executive functions in their broadest sense may be impaired in patients with frontal lobe lesions. The Wisconsin Card Sorting Test, perhaps the most robust test sensitive to frontal lobe dysfunction, requires the flexibility to switch a response pattern to meet the change in task demands. However this task has only two category switches and normal respondents tend to score at ceiling. Verbal fluency tasks also incorporate a switching component and it was hypothesized that a word generation task that maximized a switching requirement might provide a more satisfactory verbal measure of frontal lobe dysfunction. A new test of homophone meaning generation that requires multiple switches between verbal concepts (e.g., tick = insect, correct, etc.) was devised. Normative data was obtained from a sample of 170 control participants. Seventy-one patients with unilateral anterior or posterior cerebral lesions were also tested. A normal distribution of scores was obtained in the standardization sample. The anterior lesion groups were more impaired than the posterior groups. There were no significant differences due to laterality. This homophone meaning generation task is a measure of frontal lobe dysfunction that has the advantage of psychometric properties that permit measurement of the degree of impairment.

The failure of language comprehension at sentence and phrasal levels in a patient who can speak normally.

An unexpected dissociation between intact propositional speech and impaired language comprehension was observed in a right handed patient following a right hemisphere stroke. Although CHO's comprehension was intact at the single word level, his ability to comprehend a wide range of sentence structures was profoundly impaired. This deficit was observed in the context of normal sentence production both with regard to semantic and syntactic content. This case provides further evidence for the independence of on-line language input and output systems.

Failure at object identification improves mirror image matching.

In a previous report ([5]: Davidoff J & Warrington EK. The bare bones of object recognition: implications from a case of object recognition impairment. Neuropsychologia 1999;37:279-92) the inability to differentiate between mirror images was recorded in a patient with excellent canonical view recognition. We now extend our investigation to a patient (JBA) with probable Alzheimer's disease in whom canonical view recognition was compromised. The reciprocal inhibition of two aspects of object processing are demonstrated in JBA. The patient's ability to detect mirror image rotations was dependent on her inability to identify the object. Paradoxically, her performance was more impaired for those stimuli that she was able to identify than those she was not.

Semantic dementia with ubiquitin-positive tau-negative inclusion bodies.

Three cases are reported with dementia and ubiquitin-positive but tau-negative inclusion bodies. All patients had a semantic dementia and the clinical details of two of these have been published as the first description of a selective semantic memory impairment. The original diagnosis had been of Pick's disease based on frontotemporal atrophy, but re-examination has revealed ubiquitin-positive but tau-negative inclusions as well as neurites in the frontotemporal cortices and ubiquitin-positive, intracytoplasmic inclusions in the granule cells of the dentate fascia. These inclusions are identical to those reported in association with amyotrophic lateral sclerosis (motor neuron disease), but none were seen in brainstem or spinal cord motor neurons.

The role of the left hemisphere in verbal and spatial reasoning tasks.

Laterality of reasoning processes have long been a source of investigation. Differing formats of verbal and spatial reasoning tasks have meant it has not been possible to extricate true performance level from artefacts of input and output modalities. The Verbal and Spatial Reasoning Test (VESPAR) offers this opportunity, by virtue of matched sets of verbal and spatial inductive reasoning problems. Two series of 40 patients with unilateral left and right hemisphere lesions were tested on two verbal and two spatial subtests of the VESPAR, together with a battery of baseline tests. The performance of the left and right hemisphere lesion cases was compared with a normal standardisation sample. Whereas only the left hemisphere group failed the verbal sections, both left and right hemisphere groups failed the spatial sections. The influence of aphasia on spatial reasoning was considered to be an incomplete explanation for the failure of the left hemisphere group on the spatial sections. It is concluded that this investigation provides firmer evidence of a crucial role for the left hemisphere in both verbal and spatial abstract reasoning processes.

Progressive frontal gait disturbance with atypical Alzheimer's disease and corticobasal degeneration.

OBJECTIVES: The clinical neuropsychological, neuroradiological, and neuropathological description of two patients presenting with a frontal gait disturbance. METHODS: Clinical case note review, neuropsychological assessment, functional imaging with (15)O(2) and (18)F-fluorodopa PET, and neuropathology. RESULTS: Both patients presented with frontal gait impairment and only later developed more widespread cognitive impairment. In both cases (15)O(2) PET disclosed focal hypometabolism in the medial frontal lobes and in one patient (18)F-fluorodopa uptake into the caudate and putamen was normal. The neuropathological examination in one patient showed Alzheimer's histopathology together with large swollen eosinophilic neurons characteristic of corticobasal degeneration, which were particularly prominent in the medial frontal lobes. CONCLUSION: Focal degeneration of the medial frontal lobes may present as an isolated gait disturbance and should be considered in the differential diagnosis of patients who present without an obvious structural abnormality on neuroimaging.

The bare bones of object recognition: implications from a case of object recognition impairment.

Three experiments were designed to investigate the performance of a patient (RK) who could name objects when presented in conventional views but showed catastrophic failures in identification from unconventional views. The aim of all three experiments was to assess the properties of the central representations that allow recognition of objects presented in conventional but not unconventional views. All three experiments showed that RK had problems in object identification not apparent from his naming performance. In the first experiment, RK was found to be extremely impaired at recognising the parts of objects even though he could name the whole object. In the second experiment, alterations in colour, shape and parts of objects were undetected in stimuli that he could name. In the third experiment, RK showed considerable difficulty with mirror-images and inversion tasks. The explanation for RK's impaired object recognition could not be attributed to defects to his early visual processing. We argue that RK's recognition is achieved through abstract (object-centred) representations that are global rather than local, and quite independent of their spatial framework. These abstract representations we take to be the essential bare bones for object recognition.

Presymptomatic cognitive deficits in individuals at risk of familial Alzheimer's disease. A longitudinal prospective study.

A longitudinal study of asymptomatic individuals at risk of autosomal dominant familial Alzheimer's disease was performed to assess the earliest clinical and neuropsychological features of the disease. Over a 6-year period, 63 subjects underwent serial assessments. During the study, 10 subjects developed symptoms of episodic memory loss and subsequently progressed to fulfil criteria for possible or probable Alzheimer's disease. The mean time (+/-SD) from first assessment to the appearance of symptoms was 2.6+/-1.4 years. The subjects who remained well were similar to those who became clinically affected in terms of age, family history and initial Mini-Mental State Examination. Individuals who later became clinically affected already had significantly lower verbal memory (P=0.003) and performance IQ (P=0.030) scores at their first assessment, when they were ostensibly unaffected. Subsequent assessments showed progressive decline in multiple cognitive domains. Blinded assessment of serial imaging revealed the appearance of diffuse cerebral and medial temporal lobe atrophy in subjects only once they were clinically affected. These findings imply that in familial Alzheimer's disease cognitive decline predates symptoms by several years and that verbal memory deficits precede more widespread deterioration. This may have implications for the detection and treatment of Alzheimer's disease at an early stage.

The abstraction of numerical relations: a role for the right hemisphere in arithmetic?

Arithmetical reasoning ability has been investigated in a group study of patients with unilateral cerebral lesions. Two series of 38 and 39 patients, who had suffered unilateral cerebral lesions of the right and left cerebral hemisphere, respectively, were investigated. They completed a neuropsychological battery that included a test of computation (Graded Difficulty Arithmetic, GDA; Jackson & Warrington, 1986), and a new test of numerical series completion (Arithmetical Reasoning Test, ART). Whereas the left-hemisphere lesion group were markedly more impaired on the GDA compared to both the right-hemisphere lesion group and a standardization sample, both lesion groups were equally severely impaired on the ART. It is suggested that the abstraction of numerical relations, which is essential to numerical series completion, relies on the integrity of the right hemisphere. A global model of arithmetic processing that incorporates these findings is proposed.