With the exception of occasional genetic causes, there is no single diagnostic test that can diagnose FTD with certainty. The diagnosis of FTD requires a thorough history, verified by a caregiver, and a neurological examination. Neary et al (1998) published consensus criteria for the clinical diagnosis of FTD, and more specific criteria for the behavioral variant of FTD were developed in 2011. Like other degenerative diseases, there is insidious onset and progression over time. When the diagnosis is uncertain, referral to a neurologist with an interest in cognition/behavior and/or a geriatric neuropsychologist is indicated (see below). Blood work should be done to exclude alternative causes of cognitive symptoms, including a basic metabolic panel, CBC, RPR, ESR, B12 level and thyroid studies.
All patients should be screened for obstructive sleep apnea (OSA), as executive dysfunction and behavior changes are common in OSA. If the classic features of OSA are present (e.g., loud disruptive snoring, snorts and apneic pauses while sleeping, crowded oropharynx, excessive daytime sleepiness, repetitive desaturations on overnight oximetry), then referral to a sleep medicine specialist and polysomnography is indicated. Vascular risk factors should be assessed. Infections (including HIV), immune based dementias and neoplastic/paraneoplastic etiologies are occasionally causative or significant contributors, and should be considered. When a family history is positive, genetic testing can be undertaken. It is recommended that the individual see a genetic counselor first, to be sure they understand the implications of this testing. (www.genetests.org; www.nsgc.org). An educational resource for patients and families on the genetics of FTD is available through AFTD.
A full neuropsychological testing evaluation should be used to better assess the pattern of cognitive loss in a suspected FTD case and to help rule out psychiatric etiologies for an individual’s symptoms. Screening neuropsychological testing takes several hours and is done by a neuropsychologist (or sometimes under direction of a neuropsychology technician). It provides additional supportive evidence for the FTD diagnosis, keeping in mind that some patients perform within normal limits when features are mild. When PPA is suspected, a comprehensive evaluation by a speech/language pathologist is warranted.
Brain imaging is indicated in all individuals with symptoms of FTD to rule out structural causes. MRI scanning will identify small vessel ischemia, subdural hematomas, strategically placed tumors and hydrocephalus. Additionally, the pattern of brain atrophy can support the diagnosis. Severe “knife-edge atrophy” of the frontal and/or anterior temporal lobes may be seen. Often this is asymmetrical. There is often relative sparing of the posterior head regions. However, new research indicates that atrophy of the parietal lobe is found in many genetic cases. The MRI is more sensitive for assessing vascular changes and subtle patterns of atrophy, but it requires an individual to lie still for 15 to 30 minutes. If the individual is unable to tolerate this, or if they are severely claustrophobic, a CT scan may be more realistic. If the MRI or CT scan does not show atrophy, and the diagnosis remains unclear, a fluorodeoxyglucose positron emission tomography (FDG-PET ) scan or SPECT (single proton emission CT) scan may be considered. FDG-PET scans are more specific, but are costly. They show functional changes in brain glucose metabolism, and are often positive earlier than MRIs. The SPECT scan is less costly, but it reflects blood flow more than metabolic change, and is felt to be less sensitive for FTD.
Lumbar puncture is another test that can be used to rule out mimicking conditions (infection, immune etiologies, carcinomatous and paraneoplastic syndromes). Measurement of CSF phospho-tau, total tau and Beta-amyloid can sometimes support the diagnosis of FTD over Alzheimer’s disease.
Electrophysiologic testing is sometimes warranted in patients with possible FTD. The pattern of change in electroencephalography is nonspecific in FTD; often the test is normal. It may be used to rule out nonepileptic seizures and other systemic (hyperammonemia) or infectious (prion) disorders. Although nonspecific, this testing is easily obtained at many hospitals, is less costly, and it is relatively noninvasive. Electromyography is uncomfortable, but may be indicated in cases where concurrent motor neuron disease is suspected.
THE ROLE OF SPECIALISTS
Many primary care physicians are uncomfortable making the diagnosis of FTD. Given the uncommon nature of the condition, and the implications of an incorrect diagnosis, it is reasonable to refer those suspected of having FTD to a specialty center in cognitive disorders. Most of these are directed by neurologists, though an interested geriatric psychiatrist or geriatrician may also be appropriate. Psychiatrists are helpful when behavioral or emotional problems are predominant. Geriatricians are desirable in older FTD patients with concurrent medical comorbidities.
Some individuals seek rehabilitation services. These are appropriate when there are functional disabilities in communication (speech therapy), mobility (physical therapy) or self-care (occupational therapy). Cognitive therapies are sometimes appropriate when specific tasks need to be learned. A referral for behavioral management strategies can also be helpful for caregivers since most individuals with FTD are more functional in a structured, consistent environment.
There are no medications which are FDA-approved for the management of FTD-related features. In some instances such as when behavioral dyscontrol or marked irritability is present, medications can decrease these features. Management of problematic FTD features is challenging, and establishing a working relationship between a primary care physician and a cognitive/behavioral neurologist or psychiatrist, along with a neuropsychologist with expertise in non-pharmacologic modes of behavior management, is strongly advised.
IMPORTANCE OF PATHOLOGY
A definitive diagnosis of FTD can only be made post-mortem via autopsy of the brain. Confirmation of diagnosis is important for families, and in the advancement of research. Autopsy evaluation of a patient with FTD can be daunting to a general pathologist. Bigio (2013) provides a step-wise histochemical and immunohistochemical approach to investigation for the general pathologist conducting an autopsy on a decedent with FTD.
Chow TW and Alobaidy A. Incorporating new diagnostic schemas, genetics, and proteinopathy into the evaluation of frontotemporal degeneration . In press for April 2013. Dementia Issue, American Academy of Neurology Continuum Series. http://www.ncbi.nlm.nih.gov/pubmed/23558488
Manoochehri M, Huey ED. Diagnosis and management of behavioral issues in frontotemporal dementia. Curr Neurol Neurosci Rep. 2012 Oct;12(5):528-36
Whitwell JL, Josephs KA. Recent advances in the imaging of frontotemporal dementia. Curr Neurol Neurosci Rep. 2012 Dec;12 (6):715-23.
FTD Genetics and Genetic Counseling
Goldman JS, Rademakers R, Huey ED, et al. An algorithm for genetic testing of frontotemporal lobar degeneration. Neurology. 2011 Feb 1: 76(5); 475-83.
Goldman JS. New approaches to genetic counseling and testing for Alzheimer’s disease and frontotemporal degeneration. Curr Neurol Neurosci Rep. 2012 Oct;12(5):502-10.
Bigio EH. Making the diagnosis of frontotemporal lobar degeneration. Arch Pathol Lab Med. 2013 Mar; 137(3):314-25.
UCSF Primer on Frontotemporal Dementia
The UCSF Memory and Aging Center provides information for physicians and a downloadable document, Primer on Frontotemporal Dementia, that describes a recommended work up and points UCSF physicians consider in making a differential diagnosis.
NEJM – FTD Clinicopathological Conference
Two members of AFTD’s Medical Advisory Council, Bradford C. Dickerson, M.D. and Bruce Miller, M.D. presented a Clinicopathological Conference at Massachusetts General Hospital to demonstrate a differential diagnostic process in neurodegenerative disease. Case 9-2015 – A 31-Year-Old Man with Personality Changes and Progressive Neurologic Decline, was published in the NEJM on March 19, 2015. This case can be used as an educational tool with colleagues and students to demonstrate when a diagnosis of FTD should be considered. Access it here.