TDP-43 in the hypoglossal nucleus identifies amyotrophic lateral sclerosis in behavioral variant frontotemporal dementia.
The hypoglossal nucleus was recently identified as a key brain region in which the presence of TDP-43 pathology could accurately discriminate TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis (ALS). The objective of the present study was to assess the hypoglossal nucleus in behavioral variant frontotemporal dementia (bvFTD), and determine whether TDP-43 in this region is associated with clinical ALS. Twenty-nine cases with neuropathological FTLD-TDP and clinical bvFTD that had not been previously assessed for hypoglossal TDP-43 pathology were included in this study. Of these 29 cases, 41% (n=12) had a dual diagnosis of bvFTD-ALS at presentation, all 100% (n=12) of which demonstrated hypoglossal TDP-43 pathology. Of the 59% (n=17) cohort that presented with pure bvFTD, 35% (n=6) were identified with hypoglossal TDP-43 pathology. Review of the case files of all pure bvFTD cases revealed evidence of possible or probable ALS in 5 of the 6 hypoglossal-positive cases (83%) towards the end of disease, and this was absent from all cases without such pathology. In conclusion, the present study validates grading the presence of TDP-43 in the hypoglossal nucleus for the pathological identification of bvFTD cases with clinical ALS, and extends this to include the identification of cases with possible ALS at end-stage.
Neuroscience Research Australia, Sydney, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia.
Glenda M
GM
Halliday
Brain and Mind Centre, Sydney Medical School, The University of Sydney, Australia.
Matthew C
MC
Kiernan
Discipline of Pathology, Sydney Medical School, The University of Sydney, Australia.
Jillian J
JJ
Kril
Discipline of Pathology, Sydney Medical School, The University of Sydney, Australia.
Remika
R
Mito
Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Japan.
Masami
M
Masuda-Suzukake
Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Japan.
Masato
M
Hasegawa
Neuroscience Research Australia, Sydney, Australia.
Heather
H
McCann
Neuroscience Research Australia, Sydney, Australia.
Lauren
L
Bartley
Neuroscience Research Australia, Sydney, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia.
Carol
C
Dobson-Stone
Neuroscience Research Australia, Sydney, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia.
John B J
JBJ
Kwok
Norwich Medical School, University of East Anglia, Norwich, UK.
Michael
M
Hornberger
Neuroscience Research Australia, Sydney, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia; ARC Centre of Excellence in Cognition and Its Disorders, Sydney, Australia.
John R
JR
Hodges
Neuroscience Research Australia, Sydney, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia. Electronic address: r.tan@neura.edu.au.
Rachel H
RH
Tan
D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000073885:C9orf72 Protein; D002452:Cell Count; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003937:Diagnosis, Differential; D005260:Female; D057180:Frontotemporal Dementia / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007002:Hypoglossal Nerve / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D000077153:Progranulins; D011506:Proteins / Q000235:genetics; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011506:Proteins; C000598624:TARDBP protein, human
Amyotrophic lateral sclerosis; Behavioral variant frontotemporal dementia; Hypoglossal nucleus; TDP-43