John R. Hodges

Classification of primary progressive aphasia and its variants

This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for the 3 variants of PPA—nonfluent/agrammatic, semantic, and logopenic—were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as “imaging-supported” if the expected pattern of atrophy is found and “with definite pathology” if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations.

The prevalence of frontotemporal dementia

Objective To estimate the prevalence of frontotemporal dementia (FTD) and other degenerative early-onset dementias in a geographically defined population. Background Early-onset dementia (at age <65 years) results in high psychiatric morbidity and caregiver burden. Prevalence figures are available for early-onset AD but not for FTD, a dementia that is almost invariably of early onset. Methods Case ascertainment was by review of case records of three specialist clinic databases and inpatient admissions at a university hospital in Cambridge, United Kingdom, for patients with dementia who were <65 years of age, living in Cambridge City or East or South Cambridgeshire (population 326,019) on May 30, 2000. All the relevant health services in the area were also contacted for potential cases. Diagnosis of various dementias was based on published criteria. All patients with potential FTD were examined by the study investigators and underwent structural neuroimaging. The 1998 population estimates for the area were used to calculate age and sex prevalence with confidence intervals for AD, FTD, and other causes of dementia. Results A total of 108 patients (66 men and 42 women) with dementia with onset before they were 65 years of age were identified, of whom 60 were <65 years on the census date, giving an overall prevalence of 81 (95% CI, 62.8 to 104.5) per 100,000 in the 45- to 64-year age group. The prevalences of early-onset FTD and AD were the same: 15 per 100,000 (8.4 to 27.0) in the 45- to 64-year-old population. The mean age at onset of FTD was 52.8 years and there was a striking male preponderance (14:3). It is possible case ascertainment methods resulted in a relative underrepresentation of some forms of dementia. Conclusions Frontotemporal dementia is a more common cause of early-onset dementia than previously recognized and appears to be more common in men.

A voxel-based morphometry study of semantic dementia : Relationship between temporal lobe atrophy and semantic memory

The cortical anatomy of 6 patients with semantic dementia (the temporal lobe variant of frontotemporal dementia) was contrasted with that of a group of age‐matched normal subjects by using voxel‐based morphometry, a technique that identifies changes in gray matter volume on a voxel‐by‐voxel basis. Among the circumscribed regions of neuronal loss, the left temporal pole (Brodmann area 38) was the most significantly and consistently affected region. Cortical atrophy in the left hemisphere also involved the inferolateral temporal lobe (Brodmann area 20/21) and fusiform gyrus. In addition, the right temporal pole (Brodmann area 38), the ventromedial frontal cortex (Brodmann area 11/32) bilaterally, and the amygdaloid complex were affected, but no significant atrophy was measured in the hippocampus, entorhinal, or caudal perirhinal cortex. The degree of semantic memory impairment across the 6 cases correlated significantly with the extent of atrophy of the left anterior temporal lobe but not with atrophy in the adjacent ventromedial frontal cortex. These results confirm that the anterior temporal lobe is critically involved in semantic processing, and dissociate its function from that of the adjacent frontal region. Ann Neurol 2000; 47:36–45

Structure and Deterioration of Semantic Memory: A Neuropsychological and Computational Investigation.

Wernicke (1900, as cited in G. H. Eggert, 1977) suggested that semantic knowledge arises from the interaction of perceptual representations of objects and words. The authors present a parallel distributed processing implementation of this theory, in which semantic representations emerge from mechanisms that acquire the mappings between visual representations of objects and their verbal descriptions. To test the theory, they trained the model to associate names, verbal descriptions, and visual representations of objects. When its inputs and outputs are constructed to capture aspects of structure apparent in attribute-norming experiments, the model provides an intuitive account of semantic task performance. The authors then used the model to understand the structure of impaired performance in patients with selective and progressive impairments of conceptual knowledge. Data from 4 well-known semantic tasks revealed consistent patterns that find a ready explanation in the model. The relationship between the model and related theories of semantic representation is discussed.

Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia.

We have previously reported a large Danish pedigree with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 3 (FTD3). Here we identify a mutation in CHMP2B, encoding a component of the endosomal ESCRTIII complex, and show that it results in aberrant mRNA splicing in tissue samples from affected members of this family. We also describe an additional missense mutation in an unrelated individual with FTD. Aberration in the endosomal ESCRTIII complex may result in FTD and neurodegenerative disease.

A brief cognitive test battery to differentiate Alzheimer's disease and frontotemporal dementia

Objectives: To validate a simple bedside test battery designed to detect mild dementia and differentiate AD from frontotemporal dementia (FTD). Methods: Addenbrookes Cognitive Examination (ACE) is a 100-point test battery that assesses six cognitive domains. Of 210 new patients attending a memory clinic, 139 fulfilled inclusion criteria and comprised dementia (n = 115) and nondementia (n = 24) groups. The composite and the component scores on the ACE for the two groups were compared with those of 127 age- and education-matched controls. Norms and the probability of diagnosing dementia at different prevalence rates were calculated. To evaluate the ACEs ability to differentiate early AD from FTD, scores of the cases diagnosed with dementia with a Clinical Dementia Rating < 1 (AD = 56, FTD = 24, others = 20) were compared. Results: Two cut-off values for the ACE composite score (88 and 83) were of optimal utility depending on the target population. The ACE had high reliability, construct validity, and sensitivity (93%, using 88 as cut-off). Using the lower cut-off of 83, the ACE had a higher sensitivity (82%) and predictive value than the Mini-Mental State Examination for a wide range of dementia prevalence. The ACE differentiated AD from FTD, and the VLOM ratio (derived using component scores: [verbal fluency + language]/[orientation + memory]) of <2.2 for FTD and >3.2 for AD was highly discriminating. Conclusion: The ACE is a brief and reliable bedside instrument for early detection of dementia, and offers a simple objective index to differentiate AD and FTD in mildly demented patients.

Semantic memory impairment in Alzheimer's disease: Failure of access or degraded knowledge?

A battery of neuropsychological tests designed to assess semantic knowledge about the same items both within and across different modalities was administered to a group of 22 patients with dementia of the Alzheimer type (DAT) and 26 matched controls. The DAT patients were impaired on tests of category fluency, picture naming, spoken word-picture matching, picture sorting and generation of verbal definitions. A relative preservation of superordinate knowledge on the sorting and definition tests, as well as a disproportionate reduction in the generation of exemplars from lower order categories was noted. Analysis of the errors made by each patient across the different tests, revealed a significant correspondence between the individual items. These findings offer compelling evidence that the semantic breakdown in DAT is caused by storage degradation.

IS SEMANTIC MEMORY CONSISTENTLY IMPAIRED EARLY IN THE COURSE OF ALZHEIMER'S DISEASE? NEUROANATOMICAL AND DIAGNOSTIC IMPLICATIONS

To establish whether semantic memory is consistently impaired in patients with very mild dementia of Alzheimers type (DAT), we assessed episodic and semantic memory in 52 patients with DAT who were divided into three sub-groups according to dementia severity on the Mini-Mental State Examination (minimal > 23, mild 17-23 and moderate < 17) and 24 matched controls. The minimal group showed impairment on the following semantic memory measures: category fluency, naming of line drawings, naming to verbal description, answering semantic feature questions and a non-verbal picture-picture matching task (the Pyramids and Palm Trees Test). The mild and moderate groups showed additional deficits on picture sorting and word-picture matching tests. Within the minimal and mild groups there was, however, considerable heterogeneity. While some patients showed a consistent impairment across all of the semantic memory tests, others were impaired on only on a subset of these tests and a few even performed flawlessly. In contrast, all patients showed a profound deficit in episodic memory: delayed recall of new verbal and non-verbal material appears to be a particularly sensitive marker of early DAT. These data are in keeping with recent neuropathological studies demonstrating that the transentorhinal region is consistently involved at a very early stage. Lesions in this site cause a functional disconnection of the hippocampus, and hence a profound episodic memory disorder. The fact that many, but not all, patients with early disease also show impairment of semantic memory suggests that damage to the transentorhinal region is not sufficient to produce significant disruption of semantic memory. Such disruption reliably occurs, we hypothesize, only when the pathology extends to the temporal neocortex proper.

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

Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer's disease?

OBJECTIVES To investigate the prevalence of changes in mood, personality, and behaviour in frontotemporal dementia (FTD) and Alzheimers disease (AD) and hence, which features reliably distinguish between them. To establish whether the frontal and temporal variants of FTD are characterised by different behavioural changes. METHODS A questionnaire was designed to assess a wide range of neuropsychiatric changes; it incorporated features reported in previous studies of FTD and components of the neuropsychiatric inventory.1 This was completed by 37 carers of patients with Alzheimers disease (AD) and 33 patients with frontotemporal dementia (FTD), comprising 20 with temporal variant FTD (tv FTD) or semantic dementia and 13 with frontal variant FTD (fv FTD). An exploratory principal components factor analysis and discriminant function analysis was applied. RESULTS Factor analysis showed four robust and meaningful symptom clusters: factor 1—stereotypic and eating behaviour; factor 2—executive dysfunction and self care; factor 3—mood changes; factor 4—loss of social awareness. Only stereotypic and altered eating behaviour and loss of social awareness reliably differentiated AD from FTD with no effect of disease severity. By contrast, executive dysfunction, poor self care, and restlessness showed a significant effect of disease severity only, with the more impaired patients scoring more highly. Changes in mood were found to be equally prevalent in the three patient groups. Analysis of individual symptoms showed increased rates of mental rigidity and depression in the patients with semantic dementia compared with those with fv FTD. Conversely, the latter group showed greater disinhibition. Discriminant function analysis correctly classified 71.4% overall and 86.5% of the patients with AD. CONCLUSIONS This questionnaire disclosed striking differences between patients with FTD and AD, but only stereotypic behaviour, changes in eating preference, disinhibition, and features of poor social awareness reliably separated the groups. The patients with fv FTD and semantic dementia were behaviourally very similar, reflecting the involvement of a common network, the ventral frontal lobe, temporal pole, and amygdala. Dysexecutive symptoms and poor self care were found to be affected by the severity of the disease, reflecting perhaps spread to dorsolateral prefrontal areas relatively late in the course of both FTD and AD. This questionnaire may be of value in the diagnosis and the monitoring of therapies.