R. Rhys Davies

Clinicopathological correlates in frontotemporal dementia

The term frontotemporal dementia (FTD) encompasses a range of clinical syndromes that are believed not to map reliably onto the spectrum of recognized pathologies. This study reexamines the relationships between clinical and pathological subtypes of FTD in a large series from two centers (n = 61). Clinical subtypes defined were behavioral variant FTD (n = 26), language variants (semantic dementia, n = 9; and progressive nonfluent aphasia, n = 8), and motor variants (corticobasal degeneration, n = 9; and motor neuron disease, n = 9), although most cases presented with a combination of behavioral and language problems. Unexpectedly, some behavioral cases (n = 5) had marked amnesia at presentation. The pathological subtypes were those with tau‐immunopositive inclusions (with Pick bodies, n = 20; or without, n = 11), those with ubiquitin immunopositive inclusions (n = 16), and those lacking distinctive histology (n = 14). Behavioral symptoms and semantic dementia were associated with a range of pathologies. In contrast, other clinical phenotypes had relatively uniform underlying pathologies: motor neuron disease predicted ubiquitinated inclusions, parkinsonism and apraxia predicted corticobasal pathology, and nonfluent aphasia predicted Pick bodies. Therefore, the pathological substrate can be predicted in a significant proportion of FTD patients, which has important implications for studies targeting mechanistic treatments. Ann Neurol 2004

Survival in frontotemporal dementia

Objectives: To establish survival in patients with pathologically confirmed frontotemporal dementia (FTD) and to determine whether clinical or pathologic subtype affects prognosis. Methods: The authors reviewed the presenting clinical features of 61 patients with dementia and pathologically confirmed FTD studied in Sydney (n = 31) and Cambridge (n = 30) over a 10-year period. Data were available on time of symptom onset, diagnosis, institutionalization, and death. Cases were classified pathologically as tau-positive and tau-negative. Results: Of the 61 patients with FTD, 26 presented with frontal variant (fvFTD), 9 with semantic dementia, 8 with progressive nonfluent aphasia (PNFA), 9 with associated motor neuron disease (FTD-MND), and 9 with corticobasal degeneration features. There was no difference between the groups in age at symptom onset (overall mean 58.5 ± 7.8 years), but at diagnosis the PNFA (68.3 ± 2.7) group was significantly older than the fvFTD (59.9 ± 7.4) and FTD-MND (57.7 ± 7.9) groups. The median survival from symptom onset and from diagnosis was 6 ± 1.1 years (95% CI) for fvFTD and 3 ± 0.4 years for FTD-MND. Survival across subgroups was equivalent except for the FTD-MND group, which had significantly shorter survival. Cases with tau-positive pathology had an older age at onset and a significantly better prognosis: median survival 9.0 ± 0.9 years vs 5.0 ± 1.1 years. Conclusions: FTD is a malignant disorder with limited life expectancy. FTD-MND has the shortest duration both before and after diagnosis. Tau-positivity is associated with a more slowly progressive form of FTD.

Functional specialization in the human medial temporal lobe

Investigations of memory in rats and nonhuman primates have demonstrated functional specialization within the medial temporal lobe (MTL), a set of heavily interconnected structures including the hippocampal formation and underlying entorhinal, perirhinal, and parahippocampal cortices. Most studies in humans, however, especially in patients with brain damage, suggest that the human MTL is a unitary memory system supporting all types of declarative memory, our conscious memory for facts and events. To resolve this discrepancy, amnesic patients with either selective hippocampal damage or more extensive MTL damage were tested on variations of an object discrimination task adapted from the nonhuman primate literature. Although both groups were equally impaired on standard recall-based memory tasks, they exhibited different profiles of performance on the object discrimination test, arguing against a unitary view of MTL function. Cases with selective hippocampal damage performed normally, whereas individuals with broader MTL lesions were impaired. Furthermore, deficits in this latter group were related not to the number of discriminations to be learned and remembered, but to the degree of “feature ambiguity,” a property of visual discriminations that can emerge when features are part of both rewarded and unrewarded stimuli. These findings resolve contradictions between published studies in humans and animals and introduce a new way of characterizing the impairments that arise after damage to the MTL.

The human perirhinal cortex and semantic memory

Studies in macaque monkeys indicate that the perirhinal cortex in the temporal lobe participates in object memory. This function may be analogous to aspects of human semantic memory (knowledge of objects, concepts, faces and words). To date, the status of perirhinal cortex has not specifically been investigated in patients with semantic deficits as seen in semantic dementia, the temporal lobe variant of frontotemporal dementia. High‐resolution three‐dimensional magnetic resonance imaging was performed in subjects with semantic dementia and Alzheimers disease (characterized in its early stages by selective episodic memory impairment) and in healthy age‐matched controls. Hippocampal, perirhinal, temporopolar and entorhinal cortex volumes were measured by outlining areas on successive scan slices according to recognized landmarks. The entorhinal and hippocampal regions were further subdivided into anterior and posterior parts. In keeping with the hypothesized contribution of the perirhinal cortex to semantic memory function, we found greater involvement of this region, together with the temporopolar and anterior entorhinal cortices, in semantic dementia than in either Alzheimers disease patients or control subjects. Performance on a range of semantic tests also correlated with perirhinal volume. Bilateral reduction in hippocampal volume compared with controls was seen in Alzheimers disease. In conclusion, atrophy of the human perirhinal cortex, and of directly connected areas, was associated with semantic memory impairment but not episodic memory impairment, as predicted from the primate work.

Clinical significance of lobar atrophy in frontotemporal dementia: application of an MRI visual rating scale.

Background/Aims: The status of imaging findings in the clinical diagnosis of frontotemporal dementia (FTD) remains uncertain; while they may be supportive of a diagnosis of frontotemporal dementia, they are not mandatory. Our aim was to assess patterns of lobar atrophy in a large sample of clinically defined, prospectively studied, patients using a magnetic resonance image (MRI) rating scale, to (1) determine whether imaging findings warrant a more prominent position in FTD diagnosis and (2) correlate the extent of lobar atrophy with clinical data. Methods: We adapted a recently devised post mortem rating scale for FTD to rate lobar atrophy on MRI scans. The areas rated included the frontal cortex and both anterior and posterior temporal regions bilaterally. All available brain scans from all patients seen in the Cambridge Dementia Clinic (n = 258) diagnosed as having FTD, together with controls (n = 20), were used to assess the reliability of the method. A subset of these (n = 121) were used for clinico-anatomic analysis. Results: The scale proved quick and reliable (intra-, inter-rater k = 0.80, 0.67). MRI scans were abnormal in the majority of patients (75%), with focal atrophy present in 100% of semantic dementia (SD) patients. By contrast, nearly half (47%) of the patients with clinical behavioural variant FTD had scans within the normal range. Behavioural cases with normal scans generally had fewer cognitive deficits and milder functional impairment than those with abnormal scans, yet displayed a clinically indistinguishable behavioural syndrome. They were not, however, simply at an earlier stage of the disease. Conclusions: MRI findings should form part of the diagnostic criteria for SD; the absence of atrophy on MRI in many behavioural cases raises the prospect that the behavioural syndrome of FTD is not specific for patients with a neurodegenerative disease.

Development of an MRI rating scale for multiple brain regions: comparison with volumetrics and with voxel-based morphometry

IntroductionWe aimed to devise a rating method for key frontal and temporal brain regions validated against quantitative volumetric methods and applicable to a range of dementia syndromes.MethodsFour standardised coronal MR images from 36 subjects encompassing controls and cases with Alzheimer’s disease (AD) and frontotemporal dementia (FTD) were used. After initial pilot studies, 15 regions produced good intra- and inter-rater reliability. We then validated the ratings against manual volumetry and voxel-based morphometry (VBM) and compared ratings across the subject groups.ResultsValidation against both manual volumetry (for both frontal and temporal lobes), and against whole brain VBM, showed good correlation with visual ratings for the majority of the brain regions. Comparison of rating scores across disease groups showed involvement of the anterior fusiform gyrus, anterior hippocampus and temporal pole in semantic dementia, while anterior cingulate and orbitofrontal regions were involved in behavioural variant FTD.ConclusionThis simple visual rating can be used as an alternative to highly technical methods of quantification, and may be superior when dealing with single cases or small groups.

Differing profiles of face and scene discrimination deficits in semantic dementia and Alzheimer's disease

Recent work in Alzheimers disease (AD) and semantic dementia (SD) has reported a double dissociation in AD and SD on tests of visual discrimination, with poor performance on spatial tests in AD and impaired face discrimination in SD. This pattern has been attributed to the different patterns of atrophy seen in the medial temporal lobe (MTL) in these two neurodegenerative conditions. To investigate whether this functional distinction would extend to another task that employed different types of spatial and object stimuli, two groups of AD and SD patients were assessed on a simple test involving discriminations between blended stimuli. While neither group showed impairment when asked to discriminate objects and colour patches, the SD patients showed a selective deficit in the discrimination of faces whereas the AD patients had significant difficulties discriminating landscapes. These findings extend existing theoretical accounts of MTL function, and challenge current concepts of cognitive impairment in dementia.

The neural basis of semantic memory: Evidence from semantic dementia

Semantic dementia (SD) is a syndrome of progressive impairment in semantic memory. Fifty-eight brain regions were measured in seven post mortem SD cases, ten normal controls and two disease controls (diagnosis frontotemporal dementia and motor neuron disease, FTD-MND). Manual segmentation of the whole brain has not previously been undertaken in a series of SD cases, either post mortem or during life. Widespread volume loss relative to controls was found in SD, with anterior temporal lobe regions bearing the brunt (>60% atrophy of temporopolar and perirhinal cortices bilaterally). Comparison of regional volumes in SD and FTD-MND found greater atrophy in SD only in temporopolar and perirhinal volumes. The sole region showing atrophy relative to controls in FTD-MND but not SD was motor cortex. Posterior temporal and frontal regions were not consistently affected and no significant asymmetry of atrophy was found. In summary, whole-brain regional evaluation in SD, in comparison with normal controls and FTD-MND, found anterior temporal atrophy encompassing the perirhinal cortex with relative sparing of adjacent posterior temporal regions.

Lobar atrophy in frontotemporal dementia: diagnostic and prognostic implications.

We review the practical importance of lobar atrophy in frontotemporal dementia (FTD), for diagnosis and prognosis. We discuss specific patterns of frontotemporal atrophy that denote clinical and pathological subtypes of FTD (e.g. semantic dementia). We also discuss the unsatisfactory clinical experience of interpreting MRI scans in individual FTD cases, especially the behavioural presentations (without aphasic or motor impairments). This issue is explored by examining the FTD phenocopy concept. Lobar atrophy emerges as a key observation in defining behavioural FTD patients whose symptoms are likely to progress. In a situation where objective clinical data are few, we highlight the importance of applying caution before diagnosing FTD is the absence of visible brain atrophy.