Clinical and Pathological Continuum of Multisystem TDP-43 Proteinopathies

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Abstract
Frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions (FTLD-U) or “ubiquitin-only dementia” is characterized by degeneration of the neocortex and hippocampus with ubiquitin-positive but tau- and α-synuclein–negative inclusions. Using ubiquitin or novel monoclonal antibodies generated from FTLD-U brains, at least 4 distinct morphological subtypes of FTLD-U have been described.1-3 Subtype 1 is characterized by frequent long neuritic profiles predominantly in the superficial cortical layers; subtype 2, by neuronal cytoplasmic inclusions in superficial and deep cortical layers; and subtype 3, by an abundance of small neuritic profiles and neuronal cytoplasmic inclusions (often ring shaped) predominantly in the superficial cortical layers.1 Subtype 4 refers to the unique neuropathology found in FTLD with valosin-containing protein gene mutations featuring mainly numerous neuronal intranuclear inclusions and no dentate gyrus inclusions.2 The cardinal clinical features of all FTLDs are progressive changes in executive function and behavior often with disinhibition and language difficulties. Frontotemporal lobar degeneration is the second most common cause of early-onset dementia after Alzheimer disease. Notably, the neuropathology underlying FTLD is a tauopathy in approximately 45% of patients, while in about 50% of patients, the underlying pathology is FTLD-U. When FTLD-U is associated with amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND) either clinically or pathologically, the term FTLD-MND is used.2 Further, ALS may be associated with cognitive impairments characteristic of FTLD, and it has been speculated that ALS and FTLD are different manifestations of a single disorder.4 However, the presence of additional clinical features has usually led to the exclusion of a diagnosis of classic ALS and instead is regarded as an ALS-Plus syndrome according to El Escorial clinical diagnostic criteria.5 Thus, the association of typical ALS followed by progressive cognitive impairments culminating in dementia often is referred to as ALS plus dementia (ALS-D).

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