Approach
Diagnosing FTD remains a challenge, and it is thought to be underdiagnosed, in part because of symptom overlap between behavioral variant FTD (bvFTD) and a number of psychiatric disorders.[24][58]
A full history and clinical exam are the first steps toward diagnosis. Caregiver reports of changes in behavioral and psychologic symptoms are the main source of information for clinicians, and should be assessed through caregiver interviews.[59] When a generalist suspects FTD in an adult <70 years of age, or whenever there is a family history of dementia, referral should be made to a memory assessment specialist or service for a comprehensive assessment.[60]
History
A full history should be obtained independently from a person who was familiar with the patient before disease onset. A thorough account is required of any changes in the patient's social interpersonal conduct, regulation of personal conduct (e.g., disinhibition), emotions (e.g., apathy, empathy), cognitive abilities, and awareness about their illness, as well as enduring aspects of temperament, character, attitudes, and habits.[59]
Common features at onset are:
Insidious onset of coarsened personality, and changes in social behavior and habits
Gradually progressive loss of language fluency or comprehension
Progressive self-neglect and abandonment of work, activities, and social contacts.
It is essential to establish a chronology of symptoms. In FTD, changes in personality, language, habits, and activity generally precede the development of memory impairment, disorientation, or apraxias. FTD may also be associated with falls and parkinsonian symptoms. Such features are suggestive of FTD with parkinsonism, corticobasal degeneration, and progressive supranuclear palsy. FTD can also be associated with muscle wasting and weakness, which is suggestive of amyotrophic lateral sclerosis (ALS).
A full family history is required if FTD is suspected. The Goldman score is a measure of strength of family history that takes account of degree of relativity within families.[61] A positive family history should extend beyond FTD and young-onset dementia to include Parkinson disease and related disorders, ALS, and unexplained late-onset psychiatric disorders.[24]
The physician should ask about previous episodes with symptoms of mental disturbance (whether treated or untreated) such as recurring mania or depression, which may point to a primary psychiatric disorder rather than FTD. Distressing compulsions are also unlikely to be due to FTD.
The possibility of conditions such as hyperthyroidism should be explored (by inquiring about, for example, heat intolerance, weight loss despite excessive eating, tremulousness, and palpitations) because features of hyperthyroidism, such as irritability, restlessness, increased eating (with decreased satiation), and distractibility, may result in a presentation that mimics FTD.
The careful documentation of disability forms the basis for treatment planning. Disabilities include disorientation, impaired communication, failures of self-care and socialization, loss of bladder and bowel control, and inability to dress.
Examination
Patients with FTD may have no neurologic abnormality or cognitive impairment at disease onset. Some patients present with subtle motor signs and/or have executive cognitive deficits at disease onset. Subtle signs suggestive of frontal lobe dysfunction arise as the disease progresses, including one or more of glabellar, snout, sucking, rooting, or grasp reflexes. Many patients manifest parkinsonism, with some combination of tremor at rest, hypophonia, slowness of movement, narrowed range of facial expression, stooped posture, and unsteady gait. ALS, when present, is characterized by progressive asymmetric weakness of spinal or bulbar muscles, which may be accompanied by pharyngeal weakness.
Cognitive testing
Cognitive test performance should be recorded at initial assessment and then every 6 months. It is not unusual for cognitive test scores to be in the non-impaired range for up to 1 year after presentation and to decline steadily for about 3 to 4 years before the patient becomes untestable.
The mini-mental state examination (MMSE) remains the most widely used (and best understood) simple cognitive test. However, patients with FTD can score above the cut-off score of 24/30 even if they have significant cognitive impairment, so it is of limited usefulness for detecting FTD. The Montreal cognitive assessment (MOCA) can be used to assess for decline in cognition over time, and some subsets may give information about poor frontal lobe functioning.[62]
The frontal assessment battery, a bedside test that can be administered in 10 minutes, is helpful for screening and identifying frontal lobe dysfunction.[63]
The Executive Interview (EXIT) is another useful bedside screening tool for detecting possible frontal lobe dysfunction. It comprises a short screen of 25 items, and takes approximately 15 minutes.[64] The Quick EXIT is an abridged, 14-item version of the original EXIT that was developed by omitting 11 items that were assessed to fit the scale less well.[65]
Poor emotional processing is detectable in patients with all 3 FTD subtypes and is an important clinical feature in bvFTD and semantic dementia.[66] Emotional responses often confound interpretation of cognitive test results, so careful longitudinal evaluations are needed to support diagnosis.
Formal test batteries (e.g., the Delis-Kaplan Executive Function System [D-KEFS], or selected items from the Wechsler Adult Intelligence Scale [WAIS]) are helpful if diagnosis is still uncertain. These are given by specialists and neuropsychologists, and assist in the diagnosis by documenting a predominance of deficits in the executive and/or language domains of cognition, with relative sparing of memory, orientation, and praxis. Neurobehavioral scales may also be of use in differentiating from other forms of dementia.[67]
The course of FTD differs from that of most other forms of dementia largely because memory problems are not severe in early stages. Most dementia rating scales are biased toward detection of worsening in Alzheimer disease. The frontotemporal rating scale (FRS) was developed specifically for FTD, and can detect functional deterioration over 12 months.[68] The degree of dementia severity is more accurately estimated by the FRS than by conventional dementia rating scales.
Laboratory evaluation
Routine screening tests that should be done at presentation to exclude other diseases include the following:
CBC
CRP
Thyroid-stimulating hormone
Free T4
Metabolic panel
Renal function tests
Hepatic function tests
Serum vitamin B12 levels
Serum folate levels
Serologic testing for syphilis
Serologic testing for Lyme disease (enzyme-linked immunosorbent assay)
Serologic testing for HIV.
Results of hematologic, serologic, and biochemical tests are generally normal.
Cerebrospinal fluid markers
Cerebrospinal fluid (CSF) markers are an area of increasing interest, and may be of some diagnostic value. A marked elevation of CSF neurofilament light chain (NfL) protein may be indicative of FTD.[69][70] Higher levels of NfL or amyloid (Aβ42/Aβ38 and Aβ42/Aβ40), and lower levels of amyloid precursor protein (sAPPβ), in CSF may help to distinguish FTD from Alzheimer disease.[71] Neuronal pentraxin 2 (NPTX2) in CSF is reduced in a genetic variant of FTD and is another potential biomarker. NPTX2 is located in synapses and its levels are correlated with disease progression, so decreases in levels probably reflect synaptic dysfunction or loss.[72]
Brain imaging
Structural brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) and functional imaging (positron emission tomography [PET] or single-photon emission computed tomography [SPECT]) are diagnostically useful in differentiating patients with bvFTD from healthy people and patients with other neurodegenerative diseases.[73] Characteristic regional atrophy and hypometabolism are apparent, predominantly in the frontal and/or temporal lobes, that often shows left-right asymmetry.[73][74]
bvFTD is typically associated with atrophy on structural MRI and hypometabolism on fluorodeoxyglucose (FDG)-PET in the prefrontal cortex and anterior temporal lobes, with relative sparing of more posterior regions of the brain, such as the occipital lobe. Disruption in the structural connectivity of the brain, measured using diffusion tensor imaging (DTI), is also a feature.
Semantic dementia is associated with characteristic patterns of atrophy on structural MRI, and hypometabolism in temporal lobes is evident on FDG-PET.
Primary progressive aphasia is associated with relatively focal patterns of atrophy on MRI, and hypometabolism in the left posterior frontal lobe is evident on FDG–PET.
MRI or CT (MRI is preferred) should be ordered whenever a diagnosis of FTD is suspected. If MRI/CT results are normal or indeterminate, FDG-PET should be used, followed by SPECT if results are still unclear.[75] FDG-PET imaging is also indicated in the assessment of progressive dementia and of neurodegeneration in patients with mild cognitive impairment.[76]
Advanced MRI methods (e.g., voxel-based morphometry, resting-state functional MRI, DTI, and arterial spin labeling and anteroposterior index) may differentiate between FTD and Alzheimer disease, with a reported sensitivity of 60-83% and specificity of 63-93%.[73][77]
Studies of the fine structure of the adult neuronal networks and specific sub-regional network "hubs" are likely to provide normative benchmarks in the differential diagnosis of common dementias including FTD.[78] Broadly, in FTD, white matter disruption is more severe than gray matter damage.[79]
Genetic testing
Genetic tests to identify a known relevant mutation are not generally available in routine clinical genetic services. The clinical context is rarely straightforward; a clinical diagnosis of the subtype of dementia is often provisional, and neuropathology is lacking for affected family members. If genetic testing is undertaken, the clinical genetic team requires sufficient laboratory resources to distinguish between subtypes of dementia.[80]
Family history of FTD is a good indicator of whether genetic testing is appropriate. Mutations in the GRN and MAPT genes are present almost exclusively in patients with a strong family history, whereas C9orf72 expansion can occur in apparently sporadic disease. Based on clinical experience and available evidence, genetic testing is desirable for all patients with probable or possible bvFTD, and in patients with suspected bvFTD with strong psychiatric features and at least one affected family member. Screening for C9orf72 mutations should take place for all patients with suspected FTD with prominent psychiatric symptoms or family history of late-onset primary psychiatric disorder (even if full diagnostic criteria are not met).[24] Genetic testing (for MAPT, GRN, and C9orf72) should also be performed if the results could contribute to decisions about pregnancy.
Genetic testing should be considered within the context of a clinical genetic service with the capacity to provide educational and psychological support for affected families.
Brain tissue examination
Neuropathologic exam is the standard for definitive diagnosis. Specimens may be obtained by brain biopsy, but this is generally not recommended. Therefore, pathologic confirmation is typically obtained at the end of life, and is particularly valuable in the characterization of familial dementia.
The neuropathologic diagnosis is based on formal criteria.[81][82] On gross exam, regional atrophy predominantly affecting the frontal and/or temporal lobes is found. Molecular neuropathology allows most cases of FTD to be placed into one of three molecular subgroups: frontotemporal lobar degeneration with tau (30% to 50% of cases), TAR DNA binding protein (TDP-43), or FET protein accumulation.[46]
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