Clinically and pathologically heterogeneous group of non-Alzheimer dementias characterised collectively by relatively selective, progressive atrophy involving the frontal or temporal lobes, or both.
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.
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
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
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
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
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.
Treatment Approaches for Behavioral Symptoms in Frontotemporal Dementia | Finger E. C. (2016).
Frontotemporal
Dementias. Continuum (Minneapolis, Minn.), 22(2 Dementia), 464–489. https://doi.org/10.1212/CON.0000000000000300