Geriatric Psychiatry and the Future of Dementia Care: Diagnosing TDP-43 Neurodegenerative Disease

Over a century ago, Arnold Pick, a Czech neuropsychiatrist, laid out an initial case series of patients exhibiting profound changes in behavior, personality, and language who, on autopsy, were found to have frontal lobe degeneration. 1 Kertesz A Frontotemporal Dementia/Pick's disease. Arch Neurol. 2004; 61: 969-971https://doi.org/10.1001/archneur.61.6.969 Crossref PubMed Scopus (17) Google Scholar A few years after these initial case descriptions, another neuropsychiatrist, Alois Alzheimer, described ovoid, argyrophilic neuronal inclusions in similar cases with circumscribed atrophy, which he termed “Pick bodies.” 2 Pearce JM Pick's disease. J Neurol Neurosurg Psychiatry. 2003; 74: 169https://doi.org/10.1136/jnnp.74.2.169 Crossref PubMed Scopus (7) Google Scholar A distinct dementia syndrome would eventually be proposed, coined Pick's disease, in honor of its initial description. Nearly 50 years later, the term frontal lobe degeneration of non-Alzheimer type, 3 Gustafson L Frontal lobe degeneration of non-Alzheimer type. II. Clinical picture and differential diagnosis. Arch Gerontol Geriatr. 1987; 6: 209-223https://doi.org/10.1016/0167-4943(87)90022-7 Crossref PubMed Scopus (399) Google Scholar would be introduced, setting off decades of subsequent refinement in the clinical, pathologic, anatomic, and genetic categorization of the disease. Today what is known as frontotemporal dementia (FTD) encompasses a diverse array of clinical syndromes, including the behavioral variant of frontotemporal dementia (bvFTD), two language variants (semantic dementia and non-fluent primary progressive aphasia), two subtypes of atypical Parkinsonism (progressive supranuclear palsy and corticobasal syndrome) and subtypes of amyotrophic lateral sclerosis (ALS) among others. 4 Boeve BF Boxer AL Kumfor F et al. Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations. Lancet Neurol. 2022; 21: 258-272https://doi.org/10.1016/S1474-4422(21)00341-0 Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Recently, transactive response DNA-binding protein 43 (TDP-43) has emerged as a core pathological protein in nearly 50% of bvFTD cases and up to 98% of ALS cases. 5 Ducharme S PY Rohrer J Huey E et al. Identifying and diagnosing TDP-43 neurodegenerative diseases in psychiatry. Am J Geriatr Psychiatr. 2024; 32: 98-113 Abstract Full Text Full Text PDF Scopus (1) Google Scholar This is particularly relevant as trials of disease-modifying therapies for patients with FTD and TDP-43 pathology are expanding with encouraging early results. 5 Ducharme S PY Rohrer J Huey E et al. Identifying and diagnosing TDP-43 neurodegenerative diseases in psychiatry. Am J Geriatr Psychiatr. 2024; 32: 98-113 Abstract Full Text Full Text PDF Scopus (1) Google Scholar When Pick and Alzheimer set down their initial descriptions of FTD, they may not have imagined the kinds of scientific advancements that would drive the current revolution in dementia care – but they understood that neurodegenerative illness exists at the intersection of where changes in the brain manifest psychiatric phenomena. In their review titled “Identifying and Diagnosing TDP-43 Neurodegenerative Diseases in Psychiatry,” Ducharme et al. 5 Ducharme S PY Rohrer J Huey E et al. Identifying and diagnosing TDP-43 neurodegenerative diseases in psychiatry. Am J Geriatr Psychiatr. 2024; 32: 98-113 Abstract Full Text Full Text PDF Scopus (1) Google Scholar describe how modern geriatric psychiatrists can use their diagnostic and clinical acumen to identify early cases like those first described by Pick and Alzheimer, directing a subset of patients to disease-modifying clinical trials, offering a ray of hope against a relentless and debilitating illness.