Measuring progression in frontotemporal dementia - Implications for therapeutic interventions

Department of Clinical Neurosciences, University of Cambridge, UK.
Neurology (Impact Factor: 8.29). 06/2008; 70(22):2046-52. DOI: 10.1212/01.wnl.0000313366.76973.8a
Source: PubMed


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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Available from: Peter J Nestor, Apr 11, 2014
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    • "Notably, this profile of white matter change was observed regardless of the metric used, and indicates a particularly early and rapidly progressive pathological change. The widespread and rapidly progressive white matter changes over time in bvFTD are consistent with the shorter life expectancy (Garcin et al., 2009; Onyike, 2011) and faster cognitive decline (i.e., ACE-R or frontotemporal dementia rating scale) generally reported in these patients compared to the other FTD subtypes (Kipps et al., 2008; Piguet et al., 2011). In contrast, the longitudinal white matter changes found in PNFA were not as dramatic as those observed in bvFTD. "
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    ABSTRACT: Frontotemporal dementia is a degenerative brain condition characterized by focal atrophy affecting the frontal and temporal lobes predominantly. Changes in white matter with disease progression and their relationship to grey matter atrophy remain unknown in FTD. This study aimed to establish longitudinal white matter changes and compare these changes to regional grey matter atrophy in the main FTD subtypes. Diffu-sion and T 1 -weighted images were collected from behavioral-variant FTD (bvFTD: 12), progressive non-fluent aphasia (PNFA: 10), semantic dementia (SD: 11), and 15 controls at baseline and 12 months apart. Changes in white matter integrity were established by fractional anisotropy, mean, axial and radial diffusivity measure-ments using tract-based spatial statistics. Patterns of cortical grey matter atrophy were measured using voxel-based morphometry. At baseline, bvFTD showed severe cross-sectional changes in orbitofrontal and anterior temporal tracts, which progressed to involve posterior temporal and occipital white matter over the 12-month. In PNFA, cross-sectional changes occurred bilaterally in frontotemporal white matter (left > right), with longitudinal changes more prominent on the right. Initial white matter changes in SD were circum-scribed to the left temporal lobe, with longitudinal changes extending to bilateral frontotemporal tracts. In contrast, progression of grey matter change over time was less pronounced in all FTD subtypes. Mean diffu-sivity was most sensitive in detecting baseline changes while fractional anisotropy and radial diffusivity revealed greatest changes over time, possibly reflecting different underlying pathological processes with dis-ease progression. Our results indicate that investigations of white matter changes reveal important differences across FTD syndromes with disease progression. Hum Brain Mapp 00:000–000, 2013. V C 2013 Wiley Periodicals, Inc.
    Full-text · Article · Jul 2014 · Human Brain Mapping
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    • "Similarly, the Clinician Global Impressions scales should also be considered, as they have already been implemented in several trials and have documented sensitivity to change [7]. The ACE-R, which incorporates the MMSE as well as further assessment of attention, memory, verbal fluency, language and visuospatial function has also shown sensitivity to change in bvFTD [42]. "
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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.
    Full-text · Article · Jun 2014 · Translational Neurodegeneration
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    • "To date, clinical trials in FTD have relied on assessment measures developed and standardized for the assessment of AD (Freedman 2007; Kipps et al. 2008). Yet it is clear that FTD is clinically distinct from AD in terms of cognitive, behavioral, psychiatric, and motor signs and symptoms (Allain et al. 2003; Arvanitakis 2010; Bei et al. 2010; Boxer and Boeve 2007; Chow 2005; Galariotis et al. 2005a; Graff-Radford and Woodruff 2007; Kaye et al. 2010; Mendez 2009; Chow et al. 2009; Kertesz et al. 2000; Lindau et al. 2003; Mathuranath et al. 2000a; Mioshi et al. 2007; Perry and Hodges 2000; Robles et al. 1999; Salmon et al. 2008). "
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    ABSTRACT: There are no currently Food and Drug Administration-approved or proven off-label treatments for the frontotemporal dementias (FTD). Clinicians, caregivers, and patients struggle regularly to find therapeutic regimens that can alleviate the problematic behavioral and cognitive symptoms associated with these devastating conditions. Success is "hit or miss" and the lessons learned are largely anecdotal to date. Drug discovery in this area has been largely hampered by the heterogeneous clinical presentations and pathological phenotypes of disease that represent significant obstacles to progress in this area. Biologically, plausible treatment strategies include the use of antidepressants (selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitor and monoamine oxidase inhibitors), acetylcholinesterase inhibitors, N-methyl-D-aspartic acid antagonists, mood stabilizers, antipsychotics, stimulants, antihypertensives, and agents that may ameliorate the symptoms of parkinsonism, pseudobulbar affect, and motor neuron disease that can often coexist with FTD. These medications all carry potential risks as well as possible benefits for the person suffering from FTD, and a clear understanding of these factors is critical in selecting an appropriate therapeutic regimen to maximize cognition and daily functions, reduce behavioral symptoms, and alleviate caregiver burden in an individual patient. The role of the caregiver in tracking and reporting of symptoms and the effects of individual therapeutic interventions is pivotal in this process. This manuscript highlights the importance of establishing an effective therapeutic partnership between the physician and caregiver in the medical management of the person suffering from FTD.
    Preview · Article · Jun 2011 · Journal of Molecular Neuroscience
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