Management of frontotemporal dementia: targeting symptom management in such a heterogeneous disease requires a wide range of therapeutic options

Abstract

There are no US FDA-approved therapies for the management of frontotemporal dementia (FTD). Evidence-based medicine that would support a FDA indication for the treatment of FTD requires large-scale, randomized, double-blind, placebo-controlled trials that do not currently exist. Progress in obtaining approval and therapeutic indications for FTD has been severely hampered by the heterogeneity of clinical and pathological phenotypes seen in various FTD disease states. These issues are often misinterpreted by clinicians, caregivers and patients suggesting that potential treatment options are nonexistent for this devastating disease. This article discusses these issues in the context of recent studies and publications investigating therapeutic options in FTD, and further suggests a rationale for individualized therapy in FTD. Targeting the myriad of symptoms seen in FTD requires recognition of such symptoms that may play primary or secondary roles in the spectrum of deficits that lead to functional disability in FTD, and the availability of a wide range of therapeutic options that may be helpful in alleviating such symptomatology. Fortunately, agents targeting the many cognitive, behavioral, psychiatric and motor symptoms that can be seen in FTD are readily available, having been previously developed and approved for symptomatic benefit in other disease states. In contrast to the widespread belief that beneficial treatments are not available for FTD today, our therapeutic armament is stocked with pharmacological tools that may improve quality of life for those suffering from this devastating and incurable class of degenerative diseases.

Figure 1

Coronal view of frontal and temporal lobes depicting neuroanatomic subdivisions and clinical phenotypes associated with select involvement of these areas.

Figure 2. Gross pathology and histopathological findings in frontotemporal dementia

Frontotemporal dementias (FTDs) are devastating neurological diseases with characteristic gross and microscopic pathological features. Gross photographs from FTD cases (medial aspect (A) and inferior aspect (B)) demonstrate the dramatic atrophy of the anterior portions of the cerebral neocortex – the frontal and anterior temporal cortices. A hemisected brain viewed from the midline (A) demonstrates atrophy in the frontal gyri (black arrow), along with atrophy of the genu of the corpus callosum (red arrow) in contrast to the relatively spared posterior cortex and splenium of the corpus collusum (blue arrow). Green arrows (A & B) show the markedly atrophic anterior portion of the temporal lobes. Immunohistochemical stains ((C–F), with nuclei counterstained with hematoxylin) can show diagnostic features that help discriminate between FTD subtypes. Tauopathies (C & D) can show divergent features. In progressive supranuclear palsy (C), anti-phospho-tau antibody labels both neurons (black arrow) and fine ‘tufted astrocytes’ (red arrows) in the striatum. In Pick’s disease (D), anti-tau antibody highlights roughly spherical ‘Pick body’ inclusions within the cytoplasm of hippocampal dentate granule cells. Relatively newly defined histopathological features associated with FTDs include aberrant immunohistochemical staining with TDP-43 (e) and FUS (F). TDP-43 protein (e) is normally present in the cell nuclei (relatively normally stained cell indicated with black arrow). However, in FTD, amyotrophic lateral sclerosis and hippocampal sclerosis dementia, cells display aberrant intracytoplasmic TDP-43 inclusions (red arrow) and aberrant background staining of neurites. Similarly, aberrant anti-FUS (F) staining labels neurites (red arrow) and intracytoplasmic inclusions (black arrow) in some FTD brains. Scale bars = (C) 50 μm, (D) 100 μm, (e) 50 μm and (F) 30 μm. FUS: Fused in sarcoma; PSP: Progressive supranuclear palsy; TDP: Tar DNA-binding protein.

Figure 3. A clinically plausible algorithm for empiric evaluation of potential symptomatic therapies for the treatment of frontotemporal dementia

SSRI: Selective serotonin reuptake inhibitor.