AUTHOR=Aiello Edoardo Nicolò , Feroldi Sarah , De Luca Giulia , Guidotti Lucilla , Arrigoni Eleonora , Appollonio Ildebrando , Solca Federica , Carelli Laura , Poletti Barbara , Verde Federico , Silani Vincenzo , Ticozzi Nicola 

TITLE=Primary progressive aphasia and motor neuron disease: A review

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=14

YEAR=2022

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2022.1003792

DOI=10.3389/fnagi.2022.1003792

ISSN=1663-4365

ABSTRACT=<sec><title>Background</title><p>This study aims at reviewing, within the framework of motor neuron disease-frontotemporal degeneration (MND-FTD)-<italic>spectrum</italic> disorders, evidence on the co-occurrence between primary progressive aphasia (PPA) and MND in order to profile such a complex at pathological, genetic and clinical levels.</p></sec><sec><title>Methods</title><p>This review was pre-registered (<ext-link ext-link-type="uri" xlink:href="http://osf.io/ds8m4" xmlns:xlink="http://www.w3.org/1999/xlink">osf.io/ds8m4</ext-link>) and performed in accordance with the 2020 PRISMA guidelines. Case reports/series and group studies were included if addressing (1) progressive non-fluent aphasia (PNFA) or semantic dementia (SD) with MND or (2) MND patients with co-morbid PNFA/SD.</p></sec><sec><title>Results</title><p>Out of 546 initial records, 56 studies were included. As to case reports/series (<italic>N</italic> = 35), which included 61 PPA-MND patients, the following findings yielded: (1) PNFA is more frequent than SD in PPA-MND; (2) in PPA-MND, the most prevalent motor phenotypes are amyotrophic lateral sclerosis and predominant-upper MND, with bulbar involvement being ubiquitous; (3) extrapyramidal features are moderately frequent in PPA-MND; (4) PPA-MND patients usually display frontotemporal, left-greater-than-right involvement; (5) TDP-43-B is the typical pathological substrate of PPA-MND; (6) <italic>TBK1</italic> mutations represent the most frequent genetic risk factors for PPA-MND.</p><p>As to group studies, including 121 patients, proportional meta-analytic procedures revealed that: (1) the lifetime prevalence of MND in PPA is 6%; (2) PPA occurs in 19% of patients with co-morbid MND and FTD; (3) MND is more frequent in PNFA (10%) than in SD patients (3%).</p></sec><sec><title>Discussion</title><p>Insights herewith delivered into the clinical, neuropathological and genetic features of PPA-MND patients prompt further investigations aimed at improving clinical practice within the MND-FTD <italic>spectrum</italic>.</p></sec>