Frontotemporal Dementias

Abstract

Purpose of review: This article reviews the common behavioral and cognitive features of frontotemporal dementia (FTD) and related disorders as well as the distinguishing clinical, genetic, and pathologic features of the most common subtypes.

Recent findings: Advances in clinical phenotyping, genetics, and biomarkers have enabled improved predictions of the specific underlying molecular pathology associated with different presentations of FTD. Evaluation of large international cohorts has led to recent refinements in diagnostic criteria for several of the FTD subtypes.

Summary: The FTDs are a group of neurodegenerative disorders featuring progressive deterioration of behavior or language and associated pathology in the frontal or temporal lobes. Based on anatomic, genetic, and neuropathologic categorizations, the six clinical subtypes of FTD or related disorders are: (1) behavioral variant of FTD, (2) semantic variant primary progressive aphasia, (3) nonfluent agrammatic variant primary progressive aphasia, (4) corticobasal syndrome, (5) progressive supranuclear palsy, and (6) FTD associated with motor neuron disease. Recognition and accurate diagnoses of FTD subtypes will aid the neurologist in the management of patients with FTD.

Figure 5-2

Example of amyloid (Pittsburgh compound B [PiB]) and fluorodeoxyglucose positron emission tomography (FDG-PET) scans demonstrating typical patterns of diffuse amyloid deposition and temporal and parietal hypometabolism in Alzheimer disease (A) in contrast to the absence of amyloid deposition and presence of frontal hypometabolism in a patient with frontotemporal dementia–motor neuron disease, confirmed on autopsy to have frontotemporal lobar degeneration (FTLD) with TDP-43 inclusions (B). AD = Alzheimer disease; DVR = distribution volume ratio; neg = negative; pos = positive; SUVR = standardized uptake value ratio. Modified with permission from Rabinovici GD, et al, Neurology. www.neurology.org/content/77/23/2034.full. © 2011 American Academy of Neurology.

Figure 5-1

T2-weighted axial MRI shows bifrontal and temporal atrophy in the patient in Case 5-1 with sporadic behavioral variant of frontotemporal dementia.

Figure 5-3

Imaging of the patient in Case 5-2. A, Axial fluid-attenuated inversion recovery (FLAIR) MRI demonstrating left temporal pole atrophy suggestive of semantic variant primary progressive aphasia. B, With disease progression, severe atrophy is observed in the left temporal pole as well as significant atrophy in the right temporal pole on axial FLAIR MRI.

Figure 5-4

Imaging of the patient in Case 5-3 who presented with nonfluent agrammatic variant primary progressive aphasia. Axial fluid-attenuated inversion recovery (FLAIR) MRI demonstrating left posterior frontal and frontoinsular atrophy (circled in red).

Figure 5-5

Handwriting sample and attempt at clock drawing of the patient in Case 5-3 with corticobasal syndrome including symptoms of the nonfluent agrammatic variant primary progressive aphasia. The handwriting sample demonstrates spelling and grammatical errors, as well as difficulty forming and spacing letters. Visual construction deficits are apparent on the clock drawing.

Figure 5-6

Midbrain atrophy in progressive supranuclear palsy. Midsagittal MRI in a patient with progressive supranuclear palsy demonstrating thinning of the rostral midbrain resulting in the hummingbird sign. Modified with permission from Boeve B, Parkinsonism Relat Disord. www.sciencedirect.com/science/article/pii/S1353802011700608. © 2011 Elsevier Ltd.

Figure 5-7

Neuropathologic classification of frontotemporal lobar degeneration. aFTLD-U = atypical frontotemporal lobar degeneration; AGD = argyrophilic grain disease; ALS = amyotrophic lateral sclerosis; BIBD = basophilic inclusion body disease; CBD = corticobasal degeneration; CTE = chronic traumatic encephalopathy; DLDH = dementia lacking distinctive histology; FTLD = frontotemporal lobar degeneration; FTD-3 = frontotemporal dementia associated with chromosome 3; FTLD-FUS = frontotemporal lobar degeneration with fused in sarcoma proteinopathy; FTLD-ni = frontotemporal lobar degeneration with no inclusions; FTLD-tau = frontotemporal lobar degeneration with tauopathy; FTLD-TDP = frontotemporal lobar degeneration with TDP-43 proteinopathy; FTLD-UPS = frontotemporal lobar degeneration with involvement of the ubiquitin proteasome system; MSTD = multiple system tauopathy with dementia; NIFID = neuronal intermediate filament inclusion dementia; PiD = Pick disease; PSP = progressive supranuclear palsy; TPSD = tangle predominant senile dementia; Ub = ubiquitin; WMT-GGI = white matter tauopathy with globular glial inclusions; 3R = 3 microtubule-binding repeats; 4R = 4 microtubule-binding repeats; ?-opathies = subtype without a hallmark protein aggregate identified to date; + = inclusions present; − = inclusions absent. ^a Unclassifiable and MAPT related: 3R, 4R, or both. Reprinted with permission from Bigio EH, Arch Pathol Lab Med. www.archivesofpathology.org/doi/abs/10.5858/arpa.2012-0075-RA. © 2013 College of American Pathologists.

Figure 5-8

Pathologic features in frontotemporal lobar degeneration with tauopathy. A, Pick bodies in the temporal cortex of a patient with Pick disease; B, tufted astrocyte in a patient with progressive supranuclear palsy; C, a globose tangle in a case with progressive supranuclear palsy; D, astrocytic plaque as a hallmark lesion of corticobasal degeneration; E, neuronal and glial tau pathology in the frontal cortex of a patient with MAPT gene mutation. Panels A, C, and D are tau immunohistochemistry; Panels B and E are Gallyas-Braak silver stain. Scale bars: 50 mm. Reprinted with permission from Neumann M, et al, Expert Rev Mol Med. journals.cambridge.org/action/displayAbstract?fromPage=online&aid=5988276&fileId=S1462399409001136. © 2009 Cambridge University Press.

Figure 5-9

Types of TDP-43 pathology in frontotemporal lobar degeneration. A, Type A is characterized by compact neuronal cytoplasmic inclusions and short neurites and is most commonly associated with behavioral variant of frontotemporal dementia, progressive nonfluent aphasia, and GRN mutations. B, Type B is characterized by compact and granular cytoplasmic inclusions and is associated with frontotemporal dementia–motor neuron disease, behavioral variant of frontotemporal dementia, and C9ORF72 expanded repeats. C, Type C is characterized by long neurites and is found in semantic variant primary progressive aphasia. D, Type D is characterized by numerous neuronal intranuclear inclusions and is found in patients with VCP mutations. Reprinted with permission from Neumann M, et al, Expert Rev Mol Med. journals.cambridge.org/action/displayAbstract?fromPage=online&aid=5988276&fileId=S1462399409001136. © 2009 Cambridge University Press.