Identifying and Diagnosing TDP-43 Neurodegenerative Diseases in Psychiatry

Abstract

Neuropsychiatric symptoms (NPS) are common manifestations of neurodegenerative disorders and are often early signs of those diseases. Among those neurodegenerative diseases, TDP-43 proteinopathies are an increasingly recognized cause of early neuropsychiatric manifestations. TDP-43-related diseases include frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE). The majority of TDP-43-related diseases are sporadic, but a significant proportion is hereditary, with progranulin (GRN) mutations and C9orf72 repeat expansions as the most common genetic etiologies. Studies reveal that NPS can be the initial manifestation of those diseases or can complicate disease course, but there is a lack of awareness among clinicians about TDP-43-related diseases, which leads to common diagnostic mistakes or delays. There is also emerging evidence that TDP-43 accumulations could play a role in late-onset primary psychiatric disorders. In the absence of robust biomarkers for TDP-43, the diagnosis remains primarily based on clinical assessment and neuroimaging. Given the association with psychiatric symptoms, clinical psychiatrists have a key role in the early identification of patients with TDP-43-related diseases. This narrative review provides a comprehensive overview of the pathobiology of TDP-43, resulting clinical presentations, and associated neuropsychiatric manifestations to help guide clinical practice.

Keywords: Frontotemporal dementia; amyotrophic lateral sclerosis; differential diagnosis; limbic predominant age related TDP‐43 encephalopathy (LATE); neuropsychiatric symptoms.

FIGURE 1.

Pathological and genetic distribution in FTD and ALS. Visual representation of the continuum of clinical syndromes from FTD to ALS (bottom). The prevalence of pathological subtypes is depicted in pie charts with FTD on the left and ALS on the right. The most common genetic mutations are listed above the pie charts. ALS, amyotrophic lateral sclerosis; ALS-bi, ALS with behavioral impairment; ALS-cbi, ALS with combined cognitive and behavioral impairment; ALS-ci, ALS with cognitive impairment; FTD, frontotemporal dementia; MND, motor neuron disease.

FIGURE 2.

Clinical trials for FTD-GRN and FTD)/ALS-C9orf72. The table lists the drug, target disease, mechanism of action, status, and registration number. The Venn diagram at the bottom provides a visual representation of the drug distributions based on target disease and mutation. AAV, adeno-associated virus; ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia; mAb, monoclonal antibody.