Frontotemporal Lobe Dementia

Etiology

Frontotemporal dementia is mainly a sporadic disease. Genetics also plays a key role where approximately 40% of cases are familial in origin.[7] Among them, 13.4% of cases have an autosomal dominant inheritance. Mutations in over 20 genes have been identified in the possible development of FTD. Commonly involved genes are microtubules associated protein tau located on chromosome 17q21.32, granulin on chromosome 17q21.32, and hexanucleotide repeat expansion of the chromosome 9 open-reading-frame 72 (C9orf72) on chromosomal location 9p21.2 (responsible for cytoskeleton organization).[8][9][10] It is also postulated that C9orf72 gene mutation is a continuum between FTD and amyotrophic lateral sclerosis and is responsible for the occurrence of both entities. Head trauma and thyroid disease have been linked with the development of FTD with a 3.3-fold higher risk and 2.5-fold higher risk, respectively.

Epidemiology

The incidence is 2.2/100,000 between age 40-49, 3.3/100,000 between 50-59, and peaks to 8.9/100,000 between age 60-69.[6][8] Although the age at onset varies, the mean age at presentation is 58. Overall prevalence is 15-22 persons /100,000 population. Behavior variant (bvFTD) and semantic variant (svPPA) are more prevalent in men, while nfvPPA predominantly occurs in women. The average survival time is 7.5 years.

Pathophysiology

Frontotemporal dementia has three distinct clinical syndromes based on the underlying pathologic mechanism 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. Abnormal aggregates of transactive DNA-binding protein TDP-43 account for 50% of cases, microtubules-associated tau protein for 45%, and in 5% to 10% cases, tumor-associated protein fused in sarcoma has been found.[5] The abnormal tau protein aggregates have been identified as the main culprit in patients with both sporadic and familial types of FTD except in the svPPA, in which TDP-43 aggregates predominate.[6][7]

History and Physical

The diagnosis of frontotemporal dementia is challenging. The initial clinical presentation may be mistaken for psychiatric disorders or a stroke.[11] 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.[2][4][12]

Behavior variant type FTD (bvFTD): It is the most common phenotype. Patients suffering from bvFTD may present with a cluster of altered behavior and personality changes earlier in the disease process, which include disinhibition, loss of emotional reactivity and disease insight, apathy, impaired abstract thinking, and executive function that gradually worsens over time. Additionally, it may demonstrate a change in dietary behavior and loss of fundamental emotions and empathy but with intact memory until late in the disease.[5][10]

Semantic variant FTD: In this form of FTD, patients manifest language difficulties characterized by 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.[5] Their speech is fluent but doe not make any sense. Memory is affected late in the disease.

Non-fluent variant Primary Progressive Aphasia (nfvPPA): Patients with this type of FTD present clinically with effortful halted speech and paraphasia (jumbled words), difficulty in understanding complex sentences and naming objects.[5] Their memory, abstract thinking, and calculating abilities are spared earlier in the disease course.

 Various bedside tests can be performed if clinical suspicion for FTD is high.

• Go-no-go test: In this test, the patient is asked to perform an action in response to a particular stimulus and inhibit that action in response to different stimuli.
• Letter fluency test: In this test, the patient is asked to say as many words (except proper nouns), starting with a single letter in one minute.
• Attention test: It is used to evaluate the attention span. It is done either by serial seven subtractions from 100 or spells the word “world” backward.
• Similarities and differences: It is done to evaluate abstract thinking. The patient is instructed to compare items (table and chair, apple, and orange).

Evaluation

Patients with frontotemporal dementia should be evaluated as follows:

Laboratory: Neural and axonal cytoskeletons are mainly composed of neurofilaments, which are further made up of small subunits called neurofilament light chains. Neurofilament light chain, among other biomarkers, can be increasingly seen in blood and cerebrospinal fluid of patients with FTD.

Radiographic tests: Magnetic resonance imaging, computed tomography scan, or single-photon emission tomography can be used to demonstrate atrophy and hypoperfusion in the frontal and temporal lobes. However, the findings are not specific. Imaging may aid in the diagnosis or to rule out other etiologies.[4][9]

Electroencephalography (EEG): It is not very helpful for FTD as it is for Alzheimer’s disease; however, in comparison to the healthy group, a typical EEG pattern was observed in several patients with FTD and was marked by the reduction of fast activities (alpha, beta1- beta3), but no difference in slow activities (delta & theta waves).[5]

Neurocognitive exams: Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment, and Functional Cognitive Assessment. For primary care, the Cochrane dementia and cognitive improvement group supports the utilization of two tests; MMSE (the most commonly used test in primary care) and the Informant Questionnaire for Cognitive Disorders in the Elderly. MMSE assesses different domains of dementia, including but not limited to memory, cognition, language, attention/orientation, and executive functions.[13][14]

Treatment / Management

A multidimensional approach is required to manage patients suffering from FTD. Genetic counseling, in terms of genetic testing and recommendations, should be provided to patients and their families.

Non-Pharmacologic Treatment

It includes an interprofessional approach, such as social support services, physical therapy & occupational therapy, speech therapy, cognitive behavior therapy, rehabilitation services, and caregivers' education. Regular monitoring of the behavior of both the patient and caregiver for assessing activities of daily living, such as financial account managing, driving, environmental modification, and eating, is mandatory.[5]

Pharmacological Treatment

Acetylcholinesterase inhibitors and N-methyl-D-aspartate inhibitors have no proven benefit. Similarly, selective serotonin reuptake inhibitors (SSRIs) have a limited role. They can improve certain behaviors, but not cognition. Antipsychotics have mixed results but comes with a price of severe extrapyramidal side effects to which the patients with FTD are susceptible; therefore, they are not approved by the US food and drug administration as a treatment for FTD. Selective dopaminergic antagonists can improve motivation and apathy. Several disease-modifying drugs like salsalate (tau acetylation inhibitor) and gosuraneb (anti-tau monoclonal antibodies) targeting different biomarkers are being studied, but no recommendations yet have been made. Several other promising disease-modifying drugs are currently under clinical trials.[15][16](B3)

Differential Diagnosis

Frontotemporal dementia syndrome overlap can occur and may be confused with other psychiatric disorders. Therefore, a comprehensive history and a thorough physical examination are required to distinguish each clinical entity. The neurological exam plays an essential role in assessing the condition. Ruling out of other causes of the decline in cognitive functioning such as endocrine and metabolic disorders should also be considered.[4][5][6]

• Alzheimer disease
• Vascular dementia
• Lewy body dementia
• Parkinsonism
• Supranuclear palsy
• Alcoholism
• Bipolar disorders
• Schizophrenia
• Borderline personality disorder
• Obsessive-compulsive disorder

Prognosis

The presentation at a younger age may cause a delay in the diagnosis of FTD, resulting in significant detrimental emotional, financial, and social impact on patients, family, and their caregivers. The mortality risk associated with FTD is six-fold as compared to Alzheimer's disease, which has a four-fold risk.[6][10] The average survival time is 7.5 years.

Complications

According to survey-based studies, sleep, or nighttime behavior disturbance is demonstrated by 33%-76% of patients with FTD. these are more likely to be reported in patients with PPA than bvFTD. Similar is the case in the caregivers of PPA patients. All sleep disorders require sleep hygiene and routine maintenance. Also, there is a risk of an overlapping syndrome with FTD, such as FTD-motor neuron disease, FTD-progressive supranuclear palsy, and FTD-amyotrophic lateral sclerosis. All require both pharmacologic and non-pharmacologic approaches as well as treatment of underlying disease.

• Insomnia: reported in 48% of cases
• Sleep-disordered breathing: reported in 68% of cases[17]
• Excessive daytime sleepiness: reported in 64% of cases
• Restless leg syndrome: reported in 8% of cases
• Risk of falls[18]
• Hypersexuality
• Eating disorders, (such as hyperphagia/binge eating, lack of appetite, a particular food preference)[19]