eMedicine Specialties > Neurology > Behavioral Neurology and Dementia

Frontotemporal Lobe Dementia: Differential Diagnoses & Workup

Author: Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center
Contributor Information and Disclosures

Updated: Feb 11, 2009

Differential Diagnoses

Pick Disease

Workup

Laboratory Studies

  • Routine testing (eg, blood, cerebrospinal fluid) in frontotemporal dementia is usually unrevealing.
  • The genetic test for apoE4 is less useful in frontotemporal dementia than in Alzheimer disease. A study by Mesulam et al found no association between frontotemporal dementia and the apoE4 genotype.16 Other studies have had somewhat different results, but, in general, apoE4 correlates much better with Alzheimer disease than with frontotemporal dementia.

Imaging Studies

  • Routine brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is usually remarkable only for cerebral atrophy.
    • Some patients show impressive localized atrophy in the frontal or temporal lobe on one or both sides.
    • On MRI, temporal lobe atrophy is especially easy to detect in the coronal projections. Cases differ as to the relative degree of atrophy in the frontal or temporal lobe and on the left versus right side. Research studies using voxel-based morphometry have provided more precise maps of the areas of focal atrophy.
    • Patients with frontal lobe neurobehavioral disorders (behavioral variant frontotemporal lobe dementia) often have bilateral frontal atrophy, especially involving the medial frontal cortex, sometimes with anterior temporal lobe atrophy as well.
    • Whitwell et al reported in 2006 that cases associated with motor neuron disease have more paracentral atrophy by voxel-based morphometry on MRI.12
    • Patients with progressive nonfluent aphasia tend to have perisylvian, left hemisphere atrophy, involving both the frontal and temporal lobes.
    • Patients with semantic dementia typically have temporal lobe atrophy, sometimes bilaterally.
    • Patients with the related tauopathy progressive supranuclear palsy have midbrain tegmentum and superior cerebellar peduncle atrophy, and those with corticobasal degeneration have frontoparietal atrophy. 
  • Functional imaging techniques, particularly single photon emission computed tomography (SPECT) and positron emission tomography (PET), detect focal lobar hypometabolism or hypoperfusion with great sensitivity.
    • The Hammersmith PET facility in London published early studies by Tyrell et al, demonstrating that left temporal hypometabolism was observed in virtually all early cases of primary progressive aphasia.17
    • More advanced cases also showed hypometabolism in the left frontal lobe and, occasionally, a lesser degree of hypometabolism in the right hemisphere.
  • These patterns of cortical involvement have been confirmed in many subsequent studies.
  • The pattern of frontal and/or temporal involvement is distinct from that of Alzheimer disease, in which both parietal lobes tend to show the earliest hypometabolism.
  • New ligands used to bind to amyloid protein deposits (eg, Pittsburgh Compound B) are helpful in the diagnosis of Alzheimer disease but not frontotemporal lobe dementia.

Other Tests

  • The most specific tests for evaluating frontotemporal dementia, other than brain imaging studies, are neuropsychological testing and evaluation by a speech/language pathologist with standardized language batteries.
    • Such studies assess the specific pattern of language abnormality and the presence of other cognitive and memory deficits.
    • Preservation of many of these functions distinguishes frontotemporal dementia and primary progressive aphasia syndromes from Alzheimer disease.
  • The EEG findings are commonly abnormal in frontotemporal dementia, often showing focal slowing of electrical activity over one or both frontal or temporal lobes. These findings are not sufficiently specific to be clinically useful, and, in general, EEG is less useful than functional brain imaging with PET and even lobar atrophy on MRI.

Histologic Findings

Various pathologic findings have been reported in patients with primary progressive aphasia and frontotemporal lobe dementia. The central theme of these reports is that these syndromes have a non-Alzheimer pathology.

Considering first the cases of primary progressive aphasia, Pick disease was the first pathologic disease associated with this syndrome. This was reported with a description of the language syndrome in 1892. The neuropathological features of Pick disease are focal, lobar atrophy of the frontal and/or temporal lobes of one or both hemispheres, prominent gliosis associated with swollen neurons, and/or argentophilic inclusions (Pick bodies). In the current era, several groups have reported cases of pathologically proven Pick disease. Holland et al18 , Wechsler et al19 , and Graff-Radford et al20 have reported patients with pathologically proven Pick disease and progressive language deterioration. All patients described in these reports had slowly progressive language symptoms, with naming involved early. In all cases, enough cognitive functions were spared initially to make the disorder easily distinguishable from typical Alzheimer disease.

Many reported cases do not have Pick bodies but have the less specific findings of lobar atrophy, neuronal loss, gliosis, and microvacuolization. These cases were previously referred to as dementia without specific histological features, but this term was used before the newer histological stains for tau and ubiquitin proteins entered routine use. This nonspecific pattern of neuronal loss, gliosis, and microvacuolization was reported in 2 cases as a pathologic underpinning of primary progressive aphasia.21

Similar changes have also been reported by Morris et al22 under the term hereditary dysphasic dementia and by English authors Neary, Snowden, and colleagues under the term frontal lobe dementia. As noted in Causes, most non-Alzheimer disease pathologies can be divided into those with positive staining for tau proteins, including those linked to chromosome 17, and those with ubiquitin staining (FTLD-U), leaving only rare cases with truly nonspecific pathology.23 Among the tau-positive patients, some develop symptoms and show pathologic criteria for corticobasal degeneration and others show overlap with the progressive supranuclear palsy pathology. Cases with ubiquitin staining have been divided into 3 subtypes, as discussed earlier, and these include both the motor neuron disease and frontotemporal lobe dementia cases (FTLD-MND) and the patients with a progranulin mutation on chromosome 17.

Alzheimer disease, the most common dementing illness, can mimic almost any of the frontotemporal lobe dementia variants when it presents with focal symptoms. Only a few cases of pathologically confirmed Alzheimer disease have been reported that presented with isolated nonfluent aphasia, but more have been described with the syndromes of semantic dementia (though other cases of semantic dementia have the FTLD-U pathology) and with the logopenic variant of primary progressive aphasia.

Kertesz et al have suggested the term Pick complex to include these various non-Alzheimer pathologies, with or without Pick inclusion bodies and with or without motor neuron disease.24

More on Frontotemporal Lobe Dementia

Overview: Frontotemporal Lobe Dementia
Differential Diagnoses & Workup: Frontotemporal Lobe Dementia
Treatment & Medication: Frontotemporal Lobe Dementia
Follow-up: Frontotemporal Lobe Dementia
Multimedia: Frontotemporal Lobe Dementia
References
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Further Reading

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Keywords

frontotemporal dementia, frontal dementia, semantic dementia, nonspecific dementia, Pick's disease, Pick disease, primary progressive aphasia, FTD, PPA, tauopathy, motor neuron disease, Alzheimer disease, Alzheimer's disease, AD, fluent aphasia, nonfluent aphasia

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Contributor Information and Disclosures

Author

Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center
Howard S Kirshner, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Heart Association, American Medical Association, American Neurological Association, American Society of Neurorehabilitation, National Stroke Association, Phi Beta Kappa, and Tennessee Medical Association
Disclosure: Boehringer Ingelheim Honoraria Speaking and teaching; BMS/Sanofi Honoraria Speaking and teaching; Novartis Honoraria Speaking and teaching

Medical Editor

Robert A Hauser, MD, MBA, Professor of Neurology, Molecular Pharmacology and Physiology, Director, Parkinson's Disease and Movement Disorders Center, University of South Florida; Clinical Chair, Signature Interdisciplinary Program in Neuroscience
Robert A Hauser, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Society of Neuroimaging, and Movement Disorders Society
Disclosure: Allergan Sales, LLC Honoraria Speaking and teaching; Bayer Shering Pharma AG Honoraria Consulting; Boehringer Ingelheim France Honoraria Consulting; Centapharm Honoraria Speaking and teaching; Genzyme Corporation Honoraria Consulting; GlaxoSmithKline Honoraria Consulting; IMPAX Laboratories, Inc.  Consulting; Kyowa Pharmaceuticals, Inc. Honoraria Consulting; Novartis Pharmaceuticals Corp. Honoraria Consulting; Prestwick Pharmaceuticals, Inc. Honoraria Consulting

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Richard J Caselli, MD, Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale
Richard J Caselli, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, American Neurological Association, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Howard A Crystal, MD, Professor, Departments of Neurology and Pathology, State University of New York Downstate; Consulting Staff, Department of Neurology, University Hospital and Kings County Hospital Center
Howard A Crystal, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association
Disclosure: Medivations Honoraria Consulting

 
 
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