Predictors of survival in frontotemporal lobar degeneration syndromes

Abstract

After decades of research, large-scale clinical trials in patients diagnosed with frontotemporal lobar degeneration (FTLD) are now underway across multiple centres worldwide. As such, refining the determinants of survival in FTLD represents a timely and important challenge. Specifically, disease outcome measures need greater clarity of definition to enable accurate tracking of therapeutic interventions in both clinical and research settings. Multiple factors potentially determine survival, including the clinical phenotype at presentation; radiological patterns of atrophy including markers on both structural and functional imaging; metabolic factors including eating behaviour and lipid metabolism; biomarkers including both serum and cerebrospinal fluid markers of underlying pathology; as well as genetic factors, including both dominantly inherited genes, but also genetic modifiers. The present review synthesises the effect of these factors on disease survival across the syndromes of frontotemporal dementia, with comparison to amyotrophic lateral sclerosis, progressive supranuclear palsy and corticobasal syndrome. A pathway is presented that outlines the utility of these varied survival factors for future clinical trials and drug development. Given the complexity of the FTLD spectrum, it seems unlikely that any single factor may predict overall survival in individual patients, further suggesting that a precision medicine approach will need to be developed in predicting disease survival in FTLD, to enhance drug target development and future clinical trial methodologies.

Primary progressive aphasia and motor neuron disease: A review

“…As to the median survival of PPA-MND patients – i.e., ≈3 years –, it was slightly lower than that of patients with PPA only ( Montembeault et al, 2018 ), this agreeing with the fact that MN involvement represents a risk factor for a shorter survival in PPA patients ( De La Sablonnière et al, 2021 ; El-Wahsh et al, 2021 ). Its high heterogeneity herewith found might be accounted for by the diversities across both PPA and MND phenotypes – since survival is longer in SD than in PNFA ( Tastevin et al, 2021 ), and shorter in classical ALS as compared to atypical MND variants – such as predominant-UMN phenotypes ( Turner and Talbot, 2020 ), which were relatively highly represented (25.5%) among PPA-MND patients.…”

The natural history of primary progressive aphasia: beyond aphasia

“…One of the important results of our study is that despite the relatively benign early presentation, a high proportion of nfvPPA cases developed motor disturbances such as MND, PSP, and CBS and it is conceivable that these syndromes increase mortality risk. Although, only 12 patients deceased in the follow-up and a larger sample size longitudinal study has reported a longer survival in nfvPPA [ 44 ], and a large body of literature has showed a significant shorter survival in FTD patients with motor disturbances [ 45 , 46 ]. The relationship between pyramidal, extrapyramidal symptoms, and nfvPPA have been reported previously [ 11 , 47 – 50 ], and some authors have suggested that apraxia of speech is the clinical marker of progression to PSP and CBS [ 48 ].…”

Pathological manifestation of human endogenous retrovirus K in frontotemporal dementia

“…Amyotrophic lateral sclerosis (ALS; also known as motor neuron disease) is a related neurodegenerative disease characterized by loss of motor neurons leading to physical motor impairment [5][6][7] . bvFTD and ALS exist on a disease spectrum with the majority of cases having the same causal pathogenic protein, trans-activation response (TAR) DNAbinding protein , encoded by TARDBP [8][9][10] . TDP-43 is a DNA/RNA-binding protein that regulates a number of transcriptional and translational processes 11 .…”