What is Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions?

From the Guidelines

Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions is a neurodegenerative disorder characterized by abnormal accumulation of ubiquitinated proteins in brain cells, and the most recent evidence suggests that treatment focuses on symptom management, with medications such as selective serotonin reuptake inhibitors (SSRIs) and non-pharmacological approaches being equally important. This condition typically affects the frontal and temporal lobes of the brain, causing progressive changes in behavior, personality, and language abilities. The most common protein involved is TDP-43, though other proteins like FUS can also be implicated.

According to the study published in Brain in 2020 1, the diagnostic dilemma between genetic FTD and primary psychiatric disorders (PPD) is best illustrated by C9orf72 mutations, which is the most common genetic cause of FTD. The study also highlights the importance of genetic testing, particularly for family members, as approximately 40% of cases have a hereditary component, involving genes like C9orf72, GRN, and MAPT.

The study published in the Journal of Neurology, Neurosurgery and Psychiatry in 2021 1 provides consensus recommendations for speech and language therapy in the management of functional communication, swallowing, cough, and related disorders. The study suggests that traditional treatment approaches used for developmental and neurological articulatory disorders may be effective, and that non-pharmacological approaches, such as establishing routine, providing environmental cues, and speech therapy for language difficulties, are equally important.

The most recent and highest quality study, published in 2021 1, recommends a multidisciplinary approach to the management of FTLD, including speech and language therapy, occupational therapy, and genetic testing. The study also highlights the importance of establishing a clear timeline of symptoms, including the age at onset, predominant early symptoms, and progression over time, as well as exploring both neurological and psychiatric symptoms.

In terms of treatment, the study published in Brain in 2020 1 suggests that medications such as SSRIs, like sertraline (50-200 mg daily) or citalopram (20-40 mg daily), may help manage behavioral symptoms, while antipsychotics such as quetiapine (25-200 mg daily) might be used for severe agitation, though with caution due to increased stroke risk. Non-pharmacological approaches, including establishing routine, providing environmental cues, and speech therapy for language difficulties, are equally important.

Overall, the management of FTLD with ubiquitin-positive inclusions requires a comprehensive and multidisciplinary approach, including symptom management, genetic testing, and non-pharmacological interventions.

Some key points to consider in the management of FTLD include:

• Establishing a clear timeline of symptoms, including the age at onset, predominant early symptoms, and progression over time
• Exploring both neurological and psychiatric symptoms
• Considering genetic testing, particularly for family members, as approximately 40% of cases have a hereditary component
• Using medications such as SSRIs and antipsychotics, as needed, to manage behavioral symptoms
• Implementing non-pharmacological approaches, such as establishing routine, providing environmental cues, and speech therapy for language difficulties.

From the Research

FTLD and Ubiquitin

• Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous disorder 2.
• FTLD with ubiquitin-positive inclusions (FTLD-U) is a subtype of FTLD characterized by the presence of ubiquitin-positive inclusions in the brain 2.
• TDP-43 is a major ubiquitinated disease protein in FTLD-U, and its presence is associated with distinct clinical and neuropsychological features 2.

Clinical Phenotype of FTLD-U

• Patients with FTLD-U/TDP-43 have shorter survival, difficulty with object naming, and substantial executive deficits 2.
• The clinical phenotype of FTLD-U is distinct from other forms of FTLD, with prominent obsessionality, repetitive behaviors, and rituals 3.
• FTLD-U is associated with a distinct clinical form of frontotemporal dementia, potentially allowing identification of such patients in life with a high degree of precision 3.

Treatment of FTLD

• Selective serotonin reuptake inhibitors (SSRIs) have been shown to improve behavioral symptoms in patients with FTLD, including disinhibition, depressive symptoms, carbohydrate craving, and compulsions 4, 5.
• Memantine treatment has been shown to be well-tolerated in patients with FTLD, but its effectiveness in improving cognitive and behavioral symptoms is unclear 6.

Pathological Features of FTLD-U

• FTLD-U is characterized by the presence of ubiquitin-positive inclusions in the brain, which are negative for TDP-43 and immunostain positive for the Fused in Sarcoma protein (FUS) 3.
• The pathological features of FTLD-U are distinct from other forms of FTLD, with a characteristic distribution of ubiquitin-positive inclusions in the brain 2.