Frontotemporal dementia (FTD) - An overview

Contents

Introduction

Clinically and pathologically heterogeneous group of non-Alzheimer dementias characterised collectively by relatively selective, progressive atrophy involving the frontal or temporal lobes, or both.

History:

In 1892, Arnold Pick, a Czech neurologist, provided the first known description of a patient with FTD. He depicted a patient with progressive deterioration of language associated with left temporal lobe atrophy, a process that would presently be classified as svPPA. Histologic analysis of Pick’s clinical cases, performed by Alois Alzheimer in 1911, showed silver staining argyrophilic cytoplasmic inclusions within neurons. In 1923, Gans described “Pick’s atrophy” to characterize unique cases with atrophy in the frontal and temporal lobes. By 1926, Pick’s students Onari and Spatz expanded on Alzheimer’s pathologic description by delineating Pick’s bodies from Pick’s cells identifying “Pick’s disease” as a neuropathological entity.

Aetiology

Genetic causes:
Genetics plays a key role where approximately 40% of cases are familial in origin.

C90RF72 gene mutation (M/C): Results in a hexanucleotide repeat expansion

Frontotemporal Dementia Gene Mutations | Finger E. C. (2016). Frontotemporal Dementias. Continuum (Minneapolis, Minn.), 22(2 Dementia), 464–489. https://doi.org/10.1212/CON.0000000000000300

Classification

Clinical classification:
There are three main clinical syndromes of FTD, defined on the basis of leading features at presentation.

Behavioral variant FTD (bvFTD) (M/C, 50% cases): Behavioral changes
Primary progressive aphasia (PPA) (language decline):
- Progressive non-fluent aphasia (nfvPPA): Impaired speech production
- Semantic dementia (svPPA): Impaired word comprehension and semantic memory

Bedside clinical assessment of the progressive aphasias: a simple algorithm (informed by current consensus criteria for progressive aphasia) for syndromic diagnosis of patients presenting with progressive language decline. The clinical syndromic diagnosis should be supplemented by neuropsychological assessment, brain magnetic resonance imaging, and ancillary investigations including cerebrospinal fluid examination (see text) | Warren, J. D., Rohrer, J. D., & Rossor, M. N. (2013). Clinical review. Frontotemporal dementia. BMJ (Clinical research ed.), 347, f4827. https://doi.org/10.1136/bmj.f4827

Pathophysiology

Frontotemporal lobar degeneration (FTLD):
FTD is characterized by intracellular deposition of abnormal proteins aggregates in the frontal and temporal lobes resulting in the degeneration of neurons, microvacuoles formation, and astrocytosis; hence the term frontotemporal lobar degeneration.

Molecular pathologies and phenotypic correlations in frontotemporal dementia (FTD): The schematic shows major genes causing frontotemporal dementia, histopathological substrates, and clinical phenotypes. Neuroanatomical profiles are shown as coronal magnetic resonance imaging sections (left hemisphere displayed on the right) abutting the corresponding pathological substrates, with regions of predominant regional atrophy demarcated by white rectangles. Genetic bases for pathological substrates and phenotypic associations of tissue pathologies are shown as intersecting (for example, mutations in the progranulin gene (GRN) are associated with TDP-43 type A (TDP-A) pathology, which may be associated with clinical syndromes of behavioural variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA), corticobasal syndrome (CBS), and frontotemporal dementia with motor neurone disease (FTD-MND)). Group functional neuroimaging studies have demonstrated involvement of intrinsic, large scale brain networks in FTD syndromes: a medial paralimbic network (including anterior cingulate, orbital frontal, and frontoinsular cortices) in bvFTD; an anterior temporal and inferior frontal network in semantic dementia; and dorsally directed dominant hemisphere language networks in PNFA. However, the network correlates of particular molecular pathologies are less well established. This scheme arranges diseases according to whether they produce damage that is relatively more restricted to anterior (toward left of figure) areas or extends posteriorly (toward right of figure) within each cerebral hemisphere; whether damage within a hemisphere is more focally restricted to the temporal lobes (toward bottom of figure) or more distributed (toward top of figure); and according to the degree of asymmetry of involvement between the two hemispheres (more asymmetrical diseases shown more centrally) | Warren, J. D., Rohrer, J. D., & Rossor, M. N. (2013). Clinical review. Frontotemporal dementia. BMJ (Clinical research ed.), 347, f4827. https://doi.org/10.1136/bmj.f4827

Molecular classification:

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. | Bigio EH, Arch Pathol Lab Med.56 www.archivesofpathology.org/doi/abs/10.5858/arpa.2012-0075-RA. © 2013 College of American Pathologists.

Neuropathology:

Abnormal accumulations of tau or TDP-43 (M/C, 90%)
FUS inclusions (remaining 10%)

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. | Neumann M, et al, Expert Rev Mol Med.57 journals.cambridge.org/action/displayAbstract?fromPage=online&aid=5988276&fileId=S1462399409001136. © 2009 Cambridge University Press.

Clinical features

The diagnosis of frontotemporal dementia is challenging. The initial clinical presentation may be mistaken for psychiatric disorders or a stroke. Therefore, a thorough history and physical examination, especially from the caregivers, are pertinent. FTD has a wide range of presentations in relation to the areas involved. In all forms of FTD, functional ability and activities of daily living are compromised.

Paintings made by a 53 year old male with FTLD that had both language and behavioral symptoms. He developed compuslions for painting as one of his early symptoms and it is postulated that as his right temporal lobe become more involved that the faces in his work became less detailed and began to have a more generic smile with teeth. | Olney, N. T., Spina, S., & Miller, B. L. (2017). Frontotemporal Dementia. Neurologic clinics, 35(2), 339–374. https://doi.org/10.1016/j.ncl.2017.01.008

Behavioral-variant frontotemporal dementia (bvFTD):
Changes in social behavior and personality predominate, reflecting the orbitobasal frontal lobe focus of the pathology.

Characterised by progressive decline in interpersonal and executive skills, with altered emotional responsivity and emergence of a variety of abnormal behaviours including apathy, disinhibition, obsessions, rituals, and stereotypies
Change in dietary behavior and loss of fundamental emotions and empathy but with intact memory until late in the disease

svPPA (semantic variant primary progressive aphasia):
Marked, often asymmetric (left > right) anterior and inferior temporal atrophy

Language difficulties:
- Paraphasia (impaired word-finding ability or loss of vocabulary)
- Difficulty in understanding the meaning of words, impaired comprehension, and difficulty in recognizing unfamiliar objects or faces.
Speech is fluent but not making any sense
Memory is affected late in the disease.

Nonfluent variant PPA (nfvPPA):
Predominant left posterior fronto-insular atrophy

Language difficulties:
- Non-fluent, effortful, halting speech that is dominated by obvious word-finding difficulties and agrammatism
- Language production is simplified, phonematic paraphasias are frequent.
- Oral apraxia is observed in most patients, dysarthria occurs less frequently.
In contrast to svPPA, memory, abstract thinking, and calculating abilities are spared earlier in the disease course.

Complications

Insomnia: reported in 48% of cases
Sleep-disordered breathing: reported in 68% of cases
Excessive day time sleepiness: reported in 64% of cases
Restless leg syndrome: reported in 8% cases
Risk of falls
Hypersexuality
Eating disorders, (such as hyperphagia/binge eating, lack of appetite, a particular food preference)

Diagnosis

Clinical tests:

Go-no-go test: Patient asked to perform an action in response to a particular stimulus and inhibit that action in response to different stimuli.
Letter fluency test: Patient asked to say as many words (except proper nouns), starting with a single letter in one minute.
Attention test: Evaluate the attention span by serial seven subtractions from 100 or spelling the word “world” backward.
Similarities and differences: To evaluate abstract thinking by comparing items (table and chair, apple, and orange).

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. | Finger E. C. (2016). Frontotemporal Dementias. Continuum (Minneapolis, Minn.), 22(2 Dementia), 464–489. https://doi.org/10.1212/CON.0000000000000300

Structural (MRI) brain imaging

T1-weighted structural MRI in patients with behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia and nonfluent variant primary progressive aphasia: (A) Behavioural variant frontotemporal dementia (B) semantic variant frontotemporal dementia and (c) nonfluent variant primary progressive aphasia. Images are in radiological view (right hemisphere is on the left side of the image). | Bott, N. T., Radke, A., Stephens, M. L., & Kramer, J. H. (2014). Frontotemporal dementia: diagnosis, deficits and management. Neurodegenerative disease management, 4(6), 439–454. https://doi.org/10.2217/nmt.14.34

Fluorodeoxyglucose positron emission tomography (FDG-PET):

Hypometabolism in the frontotemporal lobes

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. | Rabinovici GD, et al, Neurology.12 www.neurology.org/content/77/23/2034.full. © 2011 American Academy of Neurology.

Management

There are currently no therapies specifically approved for FTD. Thus, education and supportive management of safety and behavioral issues for the patient and caregiver are essential in supporting patients with FTD.

Pharmacological management:
Current treatment approaches are limited to symptomatic treatments that employ off-label uses of medications modulating neurotransmitter systems, usually to modify difficult behaviors.