Elsevier

Biological Psychiatry

Volume 75, Issue 7, 1 April 2014, Pages 574-581
Biological Psychiatry

Review
Diagnosis and Management of Behavioral Variant Frontotemporal Dementia

https://doi.org/10.1016/j.biopsych.2013.11.006Get rights and content

Frontotemporal dementia was documented over a century ago. The last decade, however, has seen substantial changes in our conceptions of this increasingly recognized disorder. Different clinical variants have been delineated, the most common of which is the behavioral variant (bvFTD). Updated diagnostic criteria have been established. New histopathological findings and genetic etiologies have been discovered. Research continues to uncover molecular mechanisms by which abnormal proteins accumulate in degenerating brain tissue. Novel neuroimaging techniques suggest that functional networks are diminished in bvFTD that might be relevant to empathy and social behavior. Despite rapid advances in our understanding of bvFTD, the disease is still under-recognized and commonly misdiagnosed. The result is inappropriate patient care. Recognizing the various presentations of bvFTD and its histological and genetic subtypes might further diagnosis, treatment, and research.

Section snippets

Epidemiology

The incidence of FTD seems to peak during the 6th and 7th decades of life, at 2.2, 3.3, and 8.9/100,000 person-years at 40–49, 50–59, and 60–69, respectively. Mean age at onset varies somewhat across FTD subtypes, with bvFTD having the earliest onset, followed by svPPA and then nvfPPA (18). The average survival time from diagnosis to death ranges from 3 years for bvFTD patients with motor neuron disease to approximately 12 years in patients with semantic variant PPA (19). The mean age at

Clinical Presentations

In 2011 an international consortium developed revised criteria for the diagnosis of bvFTD (24) (Table S2 in Supplement 1). The new criteria were designed to increase diagnostic sensitivity compared with previous criteria by Neary et al. (25). In a comparison of the new criteria with histological evidence of FTLD, the sensitivity was 85% and specificity was 95% for probable bvFTD (26).

People with bvFTD frequently have limited insight into their illness, making an informant critically important

Clinicopathological Correlation: Histopathology and Genetics

Behavioral variant FTD involves atrophy of the orbitofrontal, anterior cingulate, anterior insular, and anterior temporal cortices, particularly within the right hemisphere (37). Functional studies have increasingly demonstrated network connectivity disruption in addition to modular and structural atrophy. Different degenerative diseases have been associated with unique networks that might explain particular symptoms. For example, AD has been tied to changes in the default mode network,

Tau

Tau is important in the pathogenesis of a variety of neurodegenerative conditions, including AD and FTD. Tau protein normally helps to maintain microtubular structure. There are six isoforms of tau, three of which have three microtubule binding repeats, and three of which have four repeats. Approximately half of all patients with bvFTD have tau aggregates: three microtubule binding repeats tau in Pick’s disease, and four microtubule binding repeats tau in PSP and CBD (Figures S1–S3 in

Trans-Activator Regulatory DNA Binding Protein 43

The TDP-43 protein is found in approximately half of bvFTD cases on histological examination and is seen in all cases of FTD-ALS. There are three major patterns of TDP-43 pathology: Type A, Type B, and Type C, which correlate with different forms of FTD. The FTLD TDP-43 type A is characterized by inclusions that occur with progranulin mutations but can be seen in other patients with bvFTD or nfvPPA in whom progranulin mutations are absent. Type B is typical for FTD with motor neuron disease,

Differential Diagnosis

A careful history, combined with laboratory studies and neuroimaging, can usually exclude reversible mimics of FTD such as neurological infections, metabolic disorders, vascular disease, and paraneoplastic conditions.

Patients with bvFTD might exhibit symptoms suggestive of obsessive-compulsive disorder, bipolar disorder, depression, or schizophrenia. An onset of symptoms in patients in middle age should lead to consideration of the inclusion of bvFTD in the differential diagnosis (17). Other

Diagnosis of Frontotemporal Dementia

A diagnosis of FTD is made primarily by clinical assessment. Despite potential diagnostic pitfalls, the presence of abnormal social conduct, change of eating habits, stereotyped behaviors, and apathy in the relative absence of memory or visuospatial deficit will usually lead to the correct diagnosis (24).

A short neuropsychological battery to compare different cognitive domains can be an efficient way of aiding the differential diagnosis. Neuropsychological evaluation should show primarily

Treatment

The proper treatment of FTD requires an individually tailored approach. Because no treatment is yet available that changes the course of the neurodegenerative disease, the focus of medical therapy is on symptomatic relief (76). The difficult behaviors typical for bvFTD can place a great deal of stress on caregivers. Education and counseling about the neurological basis of the disease can offer some relief to frustrated friends and family. Resources such as The Association for Frontotemporal

Conclusions

Frontotemporal dementia is increasingly recognized as not only a common cause of early-onset dementia but also a cause of manic, depressive, obsessive-compulsive, or psychotic symptoms. The syndrome of bvFTD can result from a number of different proteinopathies, and some cases have a genetic etiology. Recognizing the core features of bvFTD as well as the variety of possible presentations can avoid misdiagnosis. This will permit the appropriate selection of symptomatic therapies and might

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