Measuring progression in frontotemporal dementia - Implications for therapeutic interventions
ABSTRACT There is a need for instruments which can measure progression of disease in frontotemporal dementia (FTD), particularly with respect to the assessment of potential therapeutic agents.
The Cambridge Early Onset Dementia Clinic database was reviewed for all prospectively enrolled cases of FTD with documented scores on the Mini-Mental State Examination (MMSE) or Addenbrooke's Cognitive Examination (ACE) on at least two occasions. We identified 50 cases fulfilling these criteria: pathologic confirmation was present in 11 of 16 patients who had died, 12 of the remainder had imaging abnormalities on their initial scans, and 22 had structural scans no different from controls. We compared these groups to a cohort with early AD (n = 25) and healthy controls (n = 10).
There was clear cognitive decline (measured by the MMSE and ACE) in patients who had died, and those with documented atrophy on initial MRI scan. In contrast, patients with FTD with normal scans showed no change in cognitive scores over a much longer interval, and serial ACE measurements paralleled those of controls. Power calculations showed that the inclusion of these patients with FTD would significantly increase the number of cases needed in any therapeutic trial.
Addenbrooke's Cognitive Examination is a simple monitoring tool which can detect progression of disease in frontotemporal dementia over a 1- to 2-year interval without the need for serial imaging. We estimated that a clinical trial that enrolled subjects with abnormal MR scans would require 135 subjects per group to detect a small effect, and 35 for a medium effect.
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ABSTRACT: Most of our learning activity takes place in a social context. I examined how social interactions influence associative learning in neurodegenerative diseases and atypical neurodevelopmental conditions primarily characterised by social cognitive and memory dysfunctions. Participants were individuals with high-functioning autism (HFA, n = 18), early-stage behavioural variant frontotemporal dementia (bvFTD, n = 16) and Alzheimer's disease (AD, n = 20). The leading symptoms in HFA and bvFTD were social and behavioural dysfunctions, whereas AD was characterised by memory deficits. Participants received three versions of a paired associates learning task. In the game with boxes test, objects were hidden in six candy boxes placed in different locations on the computer screen. In the game with faces, each box was labelled by a photo of a person. In the real-life version of the game, participants played with real persons. Individuals with HFA and bvFTD performed well in the computer games, but failed on the task including real persons. In contrast, in patients with early-stage AD, social interactions boosted paired associates learning up to the level of healthy control volunteers. Worse performance in the real life game was associated with less successful recognition of complex emotions and mental states in the Reading the Mind in the Eyes Test. Spatial span did not affect the results. When social cognition is impaired, but memory systems are less compromised (HFA and bvFTD), real-life interactions disrupt associative learning; when disease process impairs memory systems but social cognition is relatively intact (early-stage AD), social interactions have a beneficial effect on learning and memory.Cortex 03/2014; 54C:200-209. DOI:10.1016/j.cortex.2014.02.018 · 6.04 Impact Factor
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ABSTRACT: Behavioural-variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) patients experience behavioural and emotion recognition alterations, yet understanding of how socioemotional processing is affected with disease progression is minimal. Additionally, evidence suggests that bvFTD patients with limited brain atrophy on neuroimaging at presentation (bvFTD-la) have a more benign course than those with marked atrophy (bvFTD-ma). Longitudinal investigation of these patients, however, is lacking. We investigated general cognition, emotion recognition and sarcasm detection in 20 bvFTD (8 with limited brain atrophy) and 17 AD patients longitudinally and used mixed models analyses to determine the level and rates of decline across groups over time. At baseline, all patient groups performed worse than controls on general cognition and emotion recognition measures. The bvFTD-ma group showed significant impairment on the sarcasm detection task compared with controls. Longitudinally, an overall effect of time was present for general cognition (p<0.001); however, the rate of decline did not differ across groups. Trends for interactions between time and diagnosis were observed for both emotion recognition tasks (p=0.055; p=0.062), with the bvFTD-ma group declining more rapidly than AD or bvFTD-la groups. On the sarcasm detection task, the bvFTD-ma and AD patients declined, whereas bvFTD-la patients remained stable over time (p=0.002). Tasks of sarcasm detection represent a clinically useful tool to differentiate between bvFTD and AD at baseline. Furthermore, tasks of socioemotional functioning can track progression within bvFTD and identify bvFTD patients more likely to show a faster rate of decline.Journal of neurology, neurosurgery, and psychiatry 02/2014; 85(10). DOI:10.1136/jnnp-2013-307098 · 5.58 Impact Factor
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ABSTRACT: Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia (FTD). Targets for intervention have been identified, therapies are being developed, and clinical trials are advancing. A major challenge for FTD research is that multiple underlying pathologies can be associated with heterogeneous phenotypes. The neuropsychological profiles associated with FTD spectrum disorders often include executive dysfunction, language impairments and behavioral disturbance. Behavioral variant FTD is characterized by an initial presentation of changes in personality, behavior and/or emotion, which are often difficult to objectively capture using traditional neuropsychological measures. The two principal language variants of FTD are Progressive Nonfluent Aphasia (PNFA) with predominant agrammatic/non-fluent impairments and Semantic Dementia (SD) with semantic impairments and visual agnosia. Selection of appropriate endpoints for clinical trials is critical to ensure that the measures are adequately sensitive to detect change, yet specific enough to isolate signal from noise, and acceptable to regulatory agencies. Given the anticipated potential for small effect sizes, measures must be able to identify small incremental changes over time. It is also imperative that the measures provide adequate coverage of the constructs or behaviors of interest. Selected outcome measures should be suitable for repeat administration, yet relatively robust to practice effects to ensure that observed changes reflect true signal variance and not residual effects due to repeated measurement or poor reliability. To facilitate widespread adoption as an endpoint, measures should be readily accessible. We provide several examples of potential global, composite, and individual cognitive measures, as well as behavioral measures promising for FTD trials. Development and application of appropriate trial outcomes is critically important to success in advancing new treatments for FTD patients.06/2014; 3:12. DOI:10.1186/2047-9158-3-12