Andrew Graham

Measuring Executive Functions in Childhood: Problems and Solutions?

In this review we outline some of the current issues surrounding the measurement of executive function (EF) in children. Beginning with the theoretical background to the concept of EF we then review the difficulties in measuring EF in adult populations, and argue that these difficulties may, at least in part, be overcome when working with children, so that developmental studies of EF may provide special insights into the organisation of EF. Next, we review three research areas that have attracted considerable interest in childhood EF: (i) developmental disorders; (ii) new methodologies for investigating the normative development of EF (including three task batteries - CANTAB, TEA-Ch and MARS); and (iii) the relationship between Theory of Mind (ToM) and EF. Finally, we consider what progress has been made so far in the fractionation of EF into component processes, and what remains to be done to achieve this important goal.

Activities of daily living in frontotemporal dementia and Alzheimer disease.

Objective: To evaluate activities of daily living (ADLs) in three clinical variants of frontotemporal dementia and the relationship to cognitive dysfunction. Methods: Fifty-nine patients and caregivers participated in this cross-sectional study: behavioral variant frontotemporal dementia (bv-FTD, n = 15), progressive nonfluent aphasia (PNFA, n = 10), semantic dementia (n = 15), and Alzheimer disease (AD, n = 19). Caregivers were interviewed with the Disability Assessment for Dementia (DAD) to provide two outcome measures about ADLs: basic and instrumental ADLs (BADLs, IADL). In addition, patients were rated on the Clinical Dementia Rating Scale (CDR), and performance on cognitive measures (Addenbrookes Cognitive Examination Revised [ACE-R]) was assessed. Results: On the DAD, the bv-FTD group was most affected (56% of normal), whereas PNFA and semantic dementia patients were least impaired (83% and 85%); AD was intermediate (76%). The opposite pattern was seen on the ACE-R, where PNFA and semantic dementia groups were most affected, and bv-FTD showed least impairment; AD was again intermediate. Scores on the DAD did not correlate with cognitive measures, CDR, or disease duration. We further analyzed which aspect of ADLs was most affected, and a unique pattern of deficits emerged for the bv-FTD group (initiation affected > planning > execution for BADLs). Conclusion: Frontotemporal dementia has a devastating effect on activities of daily living, which is of considerable importance to caregivers and not captured by bedside cognitive tests.

How preserved is episodic memory in behavioral variant frontotemporal dementia

Objective: Studies have shown variable memory performance in patients with behavioral variant frontotemporal dementia (bvFTD). Our study investigated whether this variability is due to the admixture of patients with true bvFTD and phenocopy patients. We also sought to compare performance of patients with bvFTD and patients with Alzheimer disease (AD). Methods: We analyzed neuropsychological memory performance in patients with a clinical diagnosis of bvFTD divided into those who progressed (n = 50) and those who remained stable (n = 39), patients with AD (n = 64), and healthy controls (n = 64). Results: Patients with progressive bvFTD were impaired on most memory tests to a similar level to that of patients with early AD. Findings from a subset of patients with progressive bvFTD with confirmed FTLD pathology (n = 10) corroborated these findings. By contrast, patients with phenocopy bvFTD performed significantly better than progressors and patients with AD. Logistic regression revealed that patients with bvFTD can be distinguished to a high degree (85%) on the immediate recall score of a word list learning test (Rey Auditory Verbal Learning Test). Conclusions: Our results provide evidence for an underlying memory deficit in “real” or progressive behavioral variant frontotemporal dementia (bvFTD) similar to Alzheimer disease, though the groups differ in orientation scores, with patients with bvFTD being intact. Exclusion solely based on impaired neuropsychological memory performance can potentially lead to an underdiagnosis of FTD.

Patterns of Frontal Lobe Atrophy in Frontotemporal Dementia: A Volumetric MRI Study

Objectives: Frontotemporal dementia (FTD), the second commonest degenerative cause of dementia under the age of 65, often presents with striking changes in behaviour and personality in association with frontal lobe atrophy. Based on the behavioural changes observed in FTD, it is commonly assumed that the orbitofrontal cortex is the earliest and most severely affected frontal sub-region. However, evidence to support this assumption has to date been largely lacking. Methods: Using a novel volumetric MRI method, we performed a detailed volumetric analysis of six frontal regions in 12 subjects with the frontal or behavioural variant of FTD (fvFTD) and 12 age-, education- and sex-matched normal controls. The regions studied were: the orbitofrontal and insula regions (representing the orbitobasal cortex); the inferior and middle frontal regions (representing the dorsolateral prefrontal areas); and the superior frontal and anterior cingulate regions (representing the medial prefrontal areas). Results: As a group, the fvFTD patients showed atrophy involving all six regions. We then segregated the 12 patients into three sub-groups according to their overall degree of atrophy. In the mildest group (n = 3) all regions fell within 2 standard deviations of normal. In the intermediate group (n = 6) only the orbitofrontal region (bilaterally) fell clearly outside the control range (>2 z scores below the control mean); the next most atrophic region in this group was the right insular region. The severe group (n = 3) had generalized atrophy throughout the frontal regions measured. Conclusions: In conclusion, patients with the earliest stages of fvFTD show no significant loss of volume in any frontal lobe area as measured by a novel MRI volumetric technique. When volume loss does occur, changes are initially seen in the orbitofrontal cortex before atrophy becomes more widespread. These results provide some partial support for the often-quoted assumption that the orbitofrontal cortex is the locus of earliest pathology in fvFTD, although these findings must be regarded as preliminary in view of the small numbers of patients involved.

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.

Differential Impairment of Source Memory in Progressive Versus Non-progressive Behavioral Variant Frontotemporal Dementia

Episodic memory has recently been shown to be impaired in the behavioral variant of frontotemporal dementia (bvFTD) when so-called non-progressive cases are excluded. Such non-progressive cases present with the behavioral features of bvFTD, but show no evidence of cognitive decline over time. To date, evidence regarding episodic memory performance in bvFTD subgroups on more stringent tasks is lacking. We investigated temporal and spatial source memory in progressive (n = 7) versus non-progressive (n = 12) bvFTD. BvFTD cases were retrospectively classified based on general cognitive decline on the Addenbrookes Cognitive Examination Revised, and the presence of atrophy on structural neuroimaging, over 3 years following diagnosis. Progressors showed impaired temporal and spatial source retrieval. Non-progressors displayed temporal source deficits only. These differential source memory profiles point to the variability of episodic memory performance in bvFTD, and underscore the importance of differential diagnosis of bvFTD subgroups using longitudinal and neuroimaging data.

CADASIL presenting with a behavioural variant frontotemporal dementia phenotype

The behavioural variant of frontotemporal dementia (bvFTD) is characterised by personality change with a decline in cognition. We describe two patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) who presented with behavioural phenotypes similar to bvFTD. The first patient presented with progressive personality and behavioural change, had florid white matter hyperintensity, and had a novel missense mutation C366W in exon 7 of the Notch3 gene. The second patient presented with progressive memory impairment and marked personality changes after a transient ischaemic attack. In this second patient, the radiological features were subtle and only the family history of stroke prompted testing for CADASIL using Notch3 genotyping. We present these patients to demonstrate that CADASIL may mimic bvFTD, with little clinical or radiological evidence to distinguish the two. CADASIL may be an under-recognised diagnosis in apparent bvFTD. Screening Notch3 in a substantial and unselected cohort of frontotemporal dementia patients might be appropriate to investigate this possibility.