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|Year : 2021 | Volume
| Issue : 5 | Page : 1144-1152
Frontotemporal Dementia – Current Concepts
Goutham Kumar Puppala, Shankar Prasad Gorthi, Vijay Chandran, Gautham Gundabolu
Department of Neurology, Kasturba Hospital, Manipal, Udupi, Karnataka, India
|Date of Submission||18-Jul-2018|
|Date of Decision||25-Sep-2018|
|Date of Acceptance||03-Dec-2018|
|Date of Web Publication||30-Oct-2021|
Shankar Prasad Gorthi
Department of Neurology, Kasturba Hospital, Neurology OPD, Manipal, Udupi - 576 104, Karnataka
Source of Support: None, Conflict of Interest: None
Frontotemporal dementia (FTD) is an entity that includes a group of neurodegenerative disease with symptoms predominantly pertaining to deficits in behavior, executive function (or) language. FTD is one of the most common type of dementia before 65 years of age and is one of the most underdiagnosed dementia as most often the symptoms overlap with psychiatric manifestations. Based on the clinical features, FTD is further subdivided into behavioral variant FTD (Bv-FTD) and primary progressive dementia (PPA). We searched PubMed, MEDLINE, and Google Scholar for articles about FTD disease published in English between January 1, 1975 till 2018. We used the search terms “frontotemporal dementia,” “Fronto temporal dementia-motor neuron disease,” “dementia,” “cognition,” “behavioral variant,” and “primary progressive aphasia.
Keywords: Behavior, frontotemporal dementia, language, primary progressive aphasia
Key Message: Frontotemporal dementia (FTD) are a group of neurodegenerative disorders resulting in progressive deterioration of behavior, executive function (or) language with an associated pathology in the frontal and temporal lobes. These include Behavioral variant FTD (bvFTD) Semantic variant PPA (svPPA), Non-fluent agrammatic PPA (nfPPA), FTD-MND, PSP and CBS. FTD is one of the most common type of dementia before 65 years of age and is one of the most underdiagnosed dementia as most often the symptoms overlap with psychiatric manifestations. There are no specific treatment options available for FTD, most often the treatment is aimed at educating the patient caregivers about the disease condition and symptomatic pharmacotherapy.
|How to cite this article:|
Puppala GK, Gorthi SP, Chandran V, Gundabolu G. Frontotemporal Dementia – Current Concepts. Neurol India 2021;69:1144-52
Frontotemporal dementia (FTD) has an insidious onset and slowly progressive course, which is characterized by progressive impairment in behavior, language, and functions associated with execution. It is considered as the third most common cause of dementia and one of the most common cause of early onset dementia.
| » History|| |
First case of FTD was described in 1892 by Arnold pick in a patient who presented with slowly progressive aphasia with frontal and temporal atrophy. Later in 1911, Alois Alzheimer identified an association of this entity with pick's bodies and labeled it as Pick's disease. The diagnosis is challenging as most of the symptoms overlap with psychiatric symptoms. Here, we review the epidemiology, nomenclature, pathophysiology, genetics, subtypes, clinical features, neuropsychological testing, differential diagnosis, diagnosis, and treatment of various variants of FTD.
| » Epidemiology|| |
The prevalence of dementia is increasing day by day due to increase in patient's awareness and increase in diagnostic modalities. In 2013, a meta-analysis was conducted, which has analyzed 73 studies of early onset dementia and was found to have FTD as the second most prevalent of this category with a prevalence ranging from 3% to 26%. The number can be still more as the disease is underdiagnosed (or) diagnosed as psychiatric illness. It has been found that in India, there is an epidemiological transition in which the percentage of aged people is rising, and also, these people are at a higher risk for noncommunicable diseases such as cardiovascular diseases and stroke, which might be secondary to vascular risk factors as the age advances. The major challenge in Indian setting is coexistence of vascular dementia with primary degenerative dementia. In the recent past, published Indian data on Dementia are rising; however, there is still unmet need. According to the WHO, by 2025, of the estimated 1.2 billion people of age ≥60, ~75% will reside in developing countries. It is predicted that population having dementia will double every 20 years to 42.3 million in 2020 and 81.1 million in 2040. This rapid rise is highest in India (around 336%) followed by China and South Asia. In a clinic-based study from South India, FTD (18.7%) was found to be one of the major causes of primary dementias, surpassed only by Alzheimer's disease (38.3%) and vascular dementia (25.4%). A study from East India on Early onset dementia (age: <65 years) has projected a higher frequency of possible AD (30%) followed by FTD (27%).
| » Nomenclature|| |
First description of FTD was given by Mesulam in 1982 who studied six patients with progressive aphasia and labeled it as slowly progressive aphasia without generalized dementia. Later, in 1988, Neary and Snowden termed this group as dementia of frontal type and in 1990, Gustafon and Brun termed this group as frontal lobe dementia of non-Alzheimer type.
| » Neuropathology|| |
FTD is characterized predominantly by gliosis, neuronal loss, and microvacuolar changes, which were predominantly seen in anterior temporal lobe, frontal lobe, insular cortex, and anterior cingulate cortex with initial changes occurring in anterior cingulate cortex in most of the cases. In these areas, there are specialized neurons situated in layer 5 termed as von economo neurons that mediate high-speed connections necessary for initiative, judgment, and emotional responsiveness. Early onset of degeneration in these neurons may be possible pathology in FTD. Either TAR DNA-binding protein 43 (TDP-43) (or) microtubule-associated protein Tau (MAPT) (or) Fused in sarcoma (FUS) protein account for almost all cases of FTLD. Based on this, the FTD was sub categorized into FTLD-TDP, FTLD-Tau, FTLD-FUS.
Around 50% cases of FTLD accounts for FTLD-TDP., On the basis of patterns of internuclear or cytoplasmic or cortical association, they are subclassified into A, B, and C subtypes.,
Approximately 36%–50% of FTLD patients accounts for FTLD-Tau.,, The most common subtype in this entity include corticobasal degeneration (35%), progressive supranuclear palsy (31%). and Pick's disease (30%) in the decreasing order of frequency.,,
Nearly 10% cases of FTLD accounts for FTLD-Fus. Most often, these patients present with early onset psychosis, disinhibition, and other behavioral abnormalities without any motor deficits, and they demonstrate the presence of FUS-immuno reactive inclusions predominantly in dentate gyrus.
| » Genetics|| |
Around 40% of patients with FTLD have family history, of which mutations involving GRN, MAPT, and C9orf72 (chromosome 9 open reading frame 72) accounts for 60% of all inherited FTLD. MAPT mutations were the first to be identified as the cause of inherited FTD. These mutations lead to microtubule instability with increased propensity of Tau self-aggregation which may lead to neurodegeneration. Progranulin (GRN) is involved in modulation of inflammation, axonal growth, and wound repair. Any mutations involving GRN may lead to loss of functional progranulin levels in cerebrospinal fluid and serum. MAPT encodes for 17q21.1 and GRN encodes for 17q21.32. C9orf72 gene mutation is the most common cause of frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) spectrum, and it constitutes for about 25% of familial cases of FTLD due to expansion of noncoding GGGGCC hexanucleotide repeat.,
Apart from the aforementioned mutations, the other mutations involving TAR DNA-binding protein, FUS, valocin containing protein (VCP), charged multivesicular body protein 2b (CHMP2B) are also involved with familial FTD.,,,
| » Classification|| |
Based on pattern of atrophy on magnetic resonance imaging (MRI) and on autopsy section and clinical presentation FTD is further divided into
I) Behavioral variant FTD (Bv-FTD).
ii) Primary progressive aphasia (PPA).
PPA can be either of the two types, such as agrammatic (nonfluent) variant (or) semantic variant (svPPA). The semantic variant can be of left-svPPA (or) right-svPPA.
This spectrum of FTD is dominated by behavioral symptoms. Cardinal features of Bv-FTD are apathy, loss of empathy, hyperorality, and social disinhibition. Disinhibition may manifest as increased sexual desire, use of inappropriate language. Apathy may present as loss of interest in which the patient may lie starring at the walls (or) repetitive behaviors which may be simple (or) complex and may include collecting scrap material, etc., and hyperorality which may be associated with increased consumption of sugar-rich diet.
2. Agrammatic variant of PPA
The predominant deficit noted is impairment in language structure and praxis. Characteristic deficits include Apraxia of speech (or) Agrammatism (omission of closed class words such as a, the), nonfluent speech (halting or hesitant speech). Apraxia of speech is due to loss of connections between frontal operculum and supplemental motor area.
3. Semantic PPA
Both types of semantic dementia have deficits of semantic knowledge but with preserved speech fluency, symptoms will differ whether it is left-svPPA (or) right-svPPA. Symptoms are related to early atrophy of anterior temporal lobe.,,. Early features of L-svPPA include word finding difficulties especially for verbs; in the critical stages, patient substitutes specific words with superordinate categories (e.g., vehicles for car) as the disease advances loss of word meaning increases and have trouble recognizing what is shown to them. But, in R-svPPA, early features are behavioral, while language problems occur late in the disease course., The early behavioral problems are due to involvement of right anterior temporal lobe and orbitofrontal cortex., As the disease progresses, it may involve visual temporal association area and posterior temporal association area and may develop prosopagnosia and visual agnosia. Main differences between various types of FTD are depicted in [Table 1].
Motor symptoms of FTD
Motor symptoms are most commonly seen with Bv-FTD. Around 40% of patients with Bv-FTD may have motor neuron disease in which they may present either with lower motor neuron signs or upper motor neuron signs. Around 20% of patients with Bv-FTD may present with early Parkinsonism More Details. Bv-FTD may be sometimes associated with corticobasal syndrome or progressive supranuclear palsy in which earlier may be associated with alien limb phenomenon, asymmetrical Parkinsonism, and dystonia.
In a tertiary care hospital from south India, in a span of 1 year, 52 patents were analyzed who are diagnosed to have dementia, out of which 10 patients were found to have FTD. Among the 10 patients who were diagnosed to have FTD, 8 were falling in to BV-FTD group and 2 patients in to agrammatic variant of PPA. The clinical characteristics of those patients were mentioned in [Table 2].
Neurocognitive assessment in patients with Bv-FTD demonstrates defective executive tasks with minimal or no involvement of visuospatial domains and memory. [Figure 1] demonstrates the impaired motor luria test in a patient with possible FTD. [Figure 2] demonstrates defective executive functions in clock drawing in patients with possible Bv-FTD. Neuroimaging may show predominant atrophy of right temporal or frontal lobe and the atrophic patterns may vary between different mutations (discussed later in neuro-imaging).
|Figure 1: Demonstrates the impaired motor luria test in a patient with possible FTD|
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|Figure 2: Depicting defective executive functions in two patients of possible Bv-FTD by clock drawing test|
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Patients with svPPA exhibit single word comprehension deficit, and the production of speech while describing a picture may reflect near normal word output but interspersed with frequent filler words. Patients may have a different pattern of episodic memory deficit in which they recall recent events, with difficulty in recalling remote memory. This pattern of episodic memory loss is different from Alzheimer's disease in which there is more deficit in recalling recent events. Neuroimaging may show dominant anterior temporal lobe atrophy which is typically asymmetric at the time of onset.
In patients with Agrammatic PPA, there is reduced speech production with word finding difficulties, circumlocutions, and grammatical errors. Imaging in these patients may be associated with atrophy of dominant inferior frontal lobe.
FTD-Motor neuron disease
Approximately 30% patients who are diagnosed with amyotrophic lateral sclerosis were found to have coexistent symptoms of FTD, most often associated with C9orf72 mutation, which is due to expansion of noncoding GGGGCC hexanucleotide repeat.
The differential diagnosis of FTD requires enquiry in to the family history and history of progression of behavioral changes, neuropsychological testing, imaging, and behavioral changes. Hematological work up including kidney and liver function tests, thyroid function tests, vitamin B12 assessment, and complete blood count to be considered to rule out treatable causes of dementia. Other reversible causes of dementia such as toxic (metals and drugs) and infectious causes should be kept in the differentials before arriving a diagnosis of FTD. Most often FTD has overlap of symptoms with Alzheimer's disease (AD) but the later has prominent deficits in memory, near-normal neurological examination and neuro imaging may show atrophy of brain which is generalized rather than focal. [Table 3] differentiates between AD and FTD. FTD and dementia with Lewy body (DLB) may have a set of common symptoms such as hallucinations and executive dysfunction but DLB may have predominant Parkinsonism features and shows fluctuation in cognition. History of dysphagia, postural instability with early falls, and pseudobulbar features help in differentiating progressive supranuclear palsy (PSP) from FTD. However, PSP and Corticobasal degeneration (CBD) may present as nfvPPA or bvFTD in the initial stages.
Last, most of the FTD patients are treated by psychiatrists in the early course of illness because of an overlap of symptoms between the two; more often bvFTD is misdiagnosed as psychiatric illness. Symptoms such as emotional withdrawal and apathy may be confused with depressive illness, but the lack of sadness which is typical of true depression lacks in patients with FTD. Mutations affecting C9orf72 have been found to have affiliation with bipolar disorders and Schizophrenia.,,
- Clinical diagnosis
A patient is suspected to be a possible case of bvFTD if he has any three of the following features like early behavioral disinhibition, early lack of empathy, early apathy/inertia, early perseverations and stereotypes, changes in dietary habits, and executive predominant deficits with spared memory on testing. Probable diagnosis of bvFTD is made if he has, in addition to possible criteria, a significant decline per Clinical Dementia Rating Scale or Functional Activities Questionnaire; or imaging (frontal and/or anterior temporal) to support the diagnosis. Definite diagnosis of bvFTD requires either histopathological evidence or genetic testing showing presence of pathogenic mutation in addition to previous criteria.
Clinical diagnosis of nfvPPA is made if impairment in language functions predominate like agrammatism (effortful, halting speech) or at least two of the features, such as impaired comprehension of sentences with complex syntax, with sparing of single word comprehension, and spared object knowledge. Imaging features (in left posterior frontoinsular) in addition to above features make diagnosis probable. Histopathological evidence or presence of pathogenic genetic mutation along with probable criteria makes diagnosis definite.
svPPA is suspected clinically if patient has impaired confrontation naming and impaired single word comprehension in addition to any three of the following – impaired object knowledge, surface dyslexia with spared repetition, and spared grammar and motor speech production. Involvement of anterior temporal lobe as evidenced on imaging in addition to above features makes svPPA a probable diagnosis. Histopathological evidence or presence of pathogenic genetic mutation makes diagnosis definite.
- Biomarkers in dementia
A Biomarker is an indicator of biological and pathological processes that can be objectively measured, and also indicates pharmacologic responses to a therapeutic intervention.
In dementia, the following biomarkers are useful:
- Neuroimaging biomarkers.
- Fluid biomarkers
- Gene-specific biomarkers.
I. Neuroimaging biomarkers
The various neuroimaging biomarkers used for diagnosis of FTD is based on either structural changes in brain or by functional changes in brain.
1. Structural changes in brain
A. Gray matter changes
Most of the imaging studies in FTD are based on T1-weighted MRI to detect changes in gray matter. The following variables are measured, such as brain volume, rate of brain atrophy, and volume of specific brain regions of interest., Semiquantitative atrophy using visual rating scales helps in distinguishing between FTD from Alzheimer's disease with a specificity of 81% if performed by experienced dementia experts. In a cluster analysis study, around four subtypes of Bv-FTD have been identified, such as temporal dominant, frontal dominant, frontotemporal, and frontotemporoparietal., [Figure 3] demonstrating the asymmetrical frontal and temporal atrophy in a patient with FTD (L > R). In the PPA syndromes L-svPPA predominantly have asymmetrical left-sided anteroinferior temporal lobe atrophy and in nfvPPA predominantly left-sided inferior frontal and insula involvement is present., In the genetic forms of FTD, asymmetrical frontotemporal parietal atrophy predominantly seen in FTD associated with GRN mutations, and symmetrical involvement of anteromedial temporal and orbitofrontal lobes is seen in MAPT mutation-associated FTD.,,
|Figure 3: Demonstrating the asymmetrical frontal and temporal atrophy in a patient with FTD (L>R)|
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B. White matter changes
Diffuse tensor imaging (DTI) is the technique used for assessing white matter connections of brain. The white matter diffusibility abnormalities are found to appear before the occurrence of gray matter changes in FTD.,, DTI not only helpful in differentiating between subtypes of FTD but it also helps in detection of early changes before disease onset and can also differentiate between individuals with and without dementia. The uncinate fasciculus, cingulum bundle, and genu of corpus callosum are predominantly involved in bvFTD., Left orbitofrontal and anterior temporal white matter (superior longitudinal fasciculus) predominantly affected in nfvPPA., SV PPA shows asymmetric inferior temporal white matter (predominantly left sided)., The white matter changes detected by DTI enable the detection of pathological changes before the onset of clinical symptoms in FTD and thus serves as a promising biomarker for early diagnosis of FTD. Evidence has shown that DTI can differentiate between FTD and Alzheimer's disease with a sensitivity of 78% and specificity of 68%.
2. Functional changes
Functional brain imaging studies such as SPECT can provide information, which may assist us in initial diagnosis of dementia and also in differentiating between other dementing illnesses. SPECT with Tc-99m Ethylcysteinate dimer (Tc-99m ECD) is the compound, which is essential in differentiating FTD from Alzheimer's disease.
According to McNeill et al., SPECT provides 80% sensitivity and 65% specificity in distinguishing FTD from Alzheimer's disease. However, Tripathi et al. reported a sensitivity of 96% and specificity of 98% for SPECT in detection of FTD with a positive predictive value of 96% and negative predictive value of 98%.
FDG-PET detects the alteration in brain metabolism that may occur before the appearance of gray matter atrophy.,,, Asymmetrical low glucose metabolism in orbitofrontal cortex, dorsolateral frontal cortex, and anterior temporal poles is highly specific for Bv-FTD with a sensitivity and specificity of 80%–95%.,,,. This may vary between different subtypes of PPA, such as asymmetrical bilateral temporal hypometabolism seen in SV PPA, whereas in nfvPPA, left inferior frontal gyrus, dorsolateral fontal cortex, and anterior cingulate cortex hypometabolism are seen.,,
3. Arterial spin labeling
Arterial spin labeling (ASL) measures brain perfusion noninvasively in which water protons in arterial blood are magnetically labeled. It has several advantages over FDG-PET in that it is noninvasive, no radiation effects, widely available, and low cost. ASL may show hypoperfusion in amygdala, insula, and medial frontal lobes in FTD.,, The brain perfusion measured by ASL can be used as an early biomarker in preclinical stage of genetic FTD, such as decrease in cerebral blood flow can be seen in pre symptomatic individual who carry GRN or MAPT mutation.
4. Resting state functional magnetic resonance imaging
Intrinsic functional connectivity between different brain regions can be measured by resting state functional magnetic resonance imaging (RS-f MRI). In FTD, there is decreased connectivity between anterior cingulate cortex and frontoinsular region. In SV PPA, there is reduced connectivity of temporal lobe is seen, In GRN, mutations left frontal connectivity is reduced.
5. Amyloid and Tau PET tracers
These tracers can be used to differentiating between FTD and Alzheimer's disease, such as PET with amyloid tracer (Pittsburgh compound) can detect amyloid beta deposits with high sensitivity which may indicate Alzheimer's disease pathology, whereas various types of FTD are Pittsburgh compound B negative. In FTD patients with MAPT mutations associated with 3-repeat and 4-repeat Tau pathology, there is increased uptake of F-Av-1451 Ligand (Flortaucipir) seen in temporal cortex and frontal cortex.
II. Fluid bio markers
1. CSF amyloidβ and tau
There is no definite CSF biomarker for the diagnosis of FTD, but the CSF biomarkers are used to differentiate FTD from other closest differentials such as Alzheimer's disease. Elevated levels of total-tau (t-tau), phospho-tau (p-tau), and decreased levels of Aβ1–42 are found in Alzheimer's disease, which were found to be normal in FTD.
2. Neuro filament proteins
Neuro filaments (NFLs) are major components of neuro axonal cytoskeleton, which play important role in synapse and axonal transport. The increased level of NFL in blood and CSF reflects axonal damage and serves as a promising biomarker in the monitoring and prognosis of FTD patients. Among the subgroups of FTD, levels of NFL are highly elevated in GRN mutations, varied levels in C9orf72 expansions and low levels are seen in patients with MAPT mutations.
III. Gene-specific biomarkers
Progranulin is a protein component which has important role in neurite outgrowth and inflammation. The mutations that effect GRN reduce the blood and CSF levels of progranulin to 25%–40% of normal levels., The blood and CSF levels of progranulin enables the discrimination of presymptomatic and symptomatic GRN mutation carriers from noncarriers with high sensitivity (96%–100%) and specificity (93%–100%).,
2. Diapeptide repeat proteins (DPR) translated from C9orf 72 repeat expansions.
Glycine-proline-repeating protein is a DPR protein and its levels are found to be elevated in patients with C9orf72 expansions.
| » Treatment|| |
There are no specific treatment options available for FTD; most often the treatment is aimed at educating the patient caregivers about the disease condition and symptomatic pharmacotherapy. Current pharmacotherapy is based on the modification of neurotransmitter systems, such as Selective Serotonin Reuptake Inhibitors, such as Citalopram and Trazodone, used in behavioral symptoms, such as agitation and disinhibition. When psychosis and aggression are presenting symptoms, neuroleptic medications can be tried but the randomized controlled trials for the efficacy of these drugs in FTD is lacking. [Table 4] demonstrates the various medical options available for FTD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]