Primary progressive aphasia and the FTD-MND spectrum disorders: clinical, pathological, and neuroimaging correlates

Abstract

Objective: Behavioral variant frontotemporal dementia (bvFTD), is commonly considered the cognitive presentation of the frontotemporal dementia-motor neuron disease (FTD-MND) spectrum disorder. We evaluated the prevalence of primary progressive aphasia in a series of pathologically confirmed cases of FTD-MND spectrum. Methods: Pathologically confirmed cases of frontotemporal lobar degeneration-motor neuron disease (FTLD-MND) were obtained from the UCSF brain bank. Cases were analyzed for presence of language impairment via retrospective chart review of research visits that include neurologic exam, in-depth cognitive testing and magnetic resonance imaging (MRI) imaging. Forty one cases were included. Thirty two were diagnosed with FTD-MND, while nine cases were diagnosed as MND-only from clinical evaluation. Results: Ten FTLD-MND cases (31%) presented with prominent or isolated language involvement consistent with a diagnosis of primary progressive aphasia (PPA), which we called progressive aphasia with motor neuron disease (PA-MND). Of these, three cases that mirrored the non-fluent variant of PPA (nfvPPA) were named nfvPA-MND. The imaging pattern of these nfvPA-MND showed atrophy strictly confined to the frontal and anterior temporal language cortical areas. Another group of seven cases that resembled patients with the semantic variant PPA (svPPA) were named svPA-MND. The group of svPPA-MND on imaging analysis showed selective atrophy of the temporal lobe and orbitofrontal cortex. Conclusions: Language impairment was a frequent phenotype of FTD-MND associated with focal atrophy patterns within the language networks. This data suggest patients with FTD-MND can present quite often with language phenotype of nfvPPA and svPPA, as opposed to exclusive bvFTD symptoms.

Primary Progressive Aphasia: Toward a Pathophysiological Synthesis

“…Clinical and neuropsychological tests may reveal certain clues as to the underlying proteinopathy in PPA: non-verbal episodic memory deficits are associated with Alzheimer pathology [49], whilst Parkinsonism (often evolving into a progressive supranuclear palsy/corticobasal syndrome) and apraxia of speech are typically associated with a tauopathy [22, 23••]. Motor neuron disease features accompanying nfvPPA and svPPA may be under-recognised and predict underlying histopathology [50,51].…”

Moving Toward Patient-Tailored Treatment in ALS and FTD: The Potential of Genomic Assessment as a Tool for Biological Discovery and Trial Recruitment

“…That is: individuals with bvFTD manifest with dysexecutive and behavioral symptoms because neurons within specific regions of the brain underlying executive function and social behavior (e.g., anterior cingulate, frontoinsular, striatum, and amygdala regions) are impacted (Perry et al, 2017); individuals with svPPA manifest semantic loss because neurons within anterior temporal lobe related to semantic knowledge are impacted (Gorno-Tempini et al, 2011). Neuroimaging studies additionally support the notion of ALS and FTD as a continuum showing that motor cortex and anterior cingulate as well as their underlying white matter tracts are impacted in ALS patients, while widespread frontal, anterior cingulate, insular, and temporal lobes are impacted in ALS-FTD and bvFTD patients (Lillo et al, 2012;Crespi et al, 2018;Trojsi et al, 2018;Seeley, 2019;Vinceti et al, 2019). Furthermore, while most forms of ALS are due to pathological inclusions of TDP-43 (with some exceptions, noted in the next section), about half of all bvFTD (Neumann et al, 2006;Perry et al, 2017), most svPPA (Grossman, 2010;Josephs et al, 2011;Borghesani et al, 2020), and a portion of nfvPPA cases are due to TDP-43 (Adams-Carr et al, 2020).…”

“…People with FTD may also experience movement symptoms, such as bradykinesia, dystonia, rigidity, and apraxia, with 12.5% of patients with bvFTD meeting clinical criteria for either corticobasal syndrome (CBS) or progressive supranuclear palsy syndrome (PSPS) ( Ljubenkov and Miller, 2016 ). About 15% of people with bvFTD, 11% of patients with nfvPPA, and 19% of patients with svPPA may also eventually develop motor symptoms consistent with ALS ( Rascovsky et al, 2011 ; Vinceti et al, 2019 ).…”

Cognitive and Behavioral Manifestations in ALS: Beyond Motor System Involvement

“…ALS motor and cognitive manifestations can worsen in parallel, becoming more pronounced when bulbar functions (affecting speech, swallowing, and salivation) are involved [ 8 , 9 ]. Manera et al compared patients according to the lateralization of motor damage and found that spinal patients with symmetric motor impairment had significantly worse cognitive performance than those with lateralized damage [ 10 ].…”

“…These consisted of effortful speech, tongue weakness in nfvPPA-MND, and upper limb weakness with fasciculations in both groups. When looking at the timeline, the nfvPPA-MND cases developed severe motor deficits more rapidly than the svPPA-MND cases [ 9 ].…”