JNNP Online First, published on May 29, 2017 as 10.1136/jnnp-2016-314912 PostScript J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2016-314912 on 29 May 2017. Downloaded from

LETTER suggested a possible FTD phenocopy syn- neurologists, 27% from psychiatrists and drome. Importantly, patients with a logo- 11% from general practitioners or other penic profile, likely attributable to physicians. In most patients (95.5%), both Semantic dementia, Alzheimer’s disease, were excluded to FTD and ALS were present at the time of progressive non-fluent avoid artificially inflating the proportion referral. In four patients (4.5%) FTD was aphasia and their association of language syndromes found in FTD diagnosed initially and ALS detected only without ALS. on follow-up. The follow-up period ex- with amyotrophic lateral Presence or absence of ALS was deter- ceeded 3 years in 183 patients with FTD sclerosis mined by clinical neurological examin- and 5 years in 80 patients. ation, supported by neurophysiological Ninety-nine patients have subsequently investigations (except where impracticable). undergone postmortem examination, 13 with INTRODUCTION Neurological examination was repeated ALS and 86 without ALS. All 13 patients The association between amyotrophic throughout follow-up to look for emerging with ALS showed TDP-43 type B pathology, lateral sclerosis (ALS) and frontotemporal signs of ALS. as defined by current nomenclature.5 In dementia (FTD) is well recognised, with We examined subsequent pathological contrast, patients without ALS showed a the majority of reports describing the findings where available. range of pathologies: 39 tau, 3 FUS or behavioural form of FTD (bvFTD).1 We used χ2 analyses to compare fre- FTLD-ni,and44TDP-43(26TDP-A,9 Semantic dementia (SD) and progressive quency of clinical phenotypes in patients TDP-B and 9 TDP-C). Patients with non-fluent aphasia (PNFA) have only with and without accompanying ALS. PNFA showed either tau (5 cases) or rarely been reported alongside ALS. TDP-A (11 cases) pathology, whereas Nevertheless, there have been a number patients with SD (9 cases) all showed of recent reports of language abnormal- RESULTS TDP-C pathology. ities in patients with ALS, with some Seven hundred patients fulfilled the cri- authors arguing that they may be even teria for the study, 360 men and 340 more common than behavioural/executive women, mean onset age 60 (SD 8.6). Of DISCUSSION impairments.23Such findings raise the these, 89 (12.7%) had accompanying The results show that the pure syndromes question of the relationship between SD ALS. There was no significant difference of SD and PNFA occur infrequently and PNFA and ALS. in onset age (t=−1.63(694), p=0.10) alongside ALS. There are sound neurobio- To date, there has been no systematic between patients with (mean=61 years, logical reasons why this might be so. FTD 5 study of the relative prevalence of bvFTD, SD=9.5) and without ALS (mean=60 is pathologically heterogeneous with PNFA and SD in patients with and years, SD=8.5; four missing). There was a almost half of patients having TDP-43 without accompanying ALS. We examined difference in gender distribution between pathology, 45% tau pathology and a small relative frequencies in a large consecutive the groups, with a higher male-to-female percentage with rarer pathological types. cohort of patients with clinical forms of ratio in the ALS-FTD group (1.8:1) than ALS, in contrast, is more homogeneous 2 FTD and suspected frontotemporal lobar the FTD group (1:1; χ =6.50, p=0.012). with almost all patients having specific degeneration pathology. There were differences in clinical pheno- TDP-43 type B pathology, as found in the type (table 1). BvFTD accounted for a current cohort. TDP-B pathology is seen METHODS higher proportion of patients with ALS in some patients with bvFTD but it is not We examined our clinical databases for all than those without. Patients with ALS typically implicated in PNFA or SD. As http://jnnp.bmj.com/ patients referred to a specialist dementia were significantly less likely than those exemplified by the present series, PNFA is clinic within a neuroscience department without to be diagnosed with SD or associated with either tau or TDP-A path- between 1980 and 2016, diagnosed with PNFA. Mixed behavioural language syn- ology, whereas SD is consistently asso- one of the canonical clinical syndromes of dromes did not differentiate the two ciated with TDP-C. FTD: bvFTD, SD or PNFA, or mixed var- groups. Despite the rarity of pure SD or PNFA iants of those syndromes. Clinical classifi- Thirty-seven per cent of patients with syndromes in association with ALS, lan- cations were in line with diagnostic ALS-FTD were referred from a regional guage deficits, including both syntactic criteria for these syndromes published by MND clinic, 25% from general and semantic impairments, have on October 1, 2021 by guest. Protected copyright. Neary et al4 in 1998. Most patients also fulfilled recent criteria, respectively, for bvFTD, semantic variant and non-fluent variants of primary progressive aphasia, Table 1 Clinical classification of patients with and without ALS although the SD classification included FTD only (N=611) ALS/FTD (N=89) patients with right-predominant temporal N (%) N (%) χ2 p Value lobe atrophy in whom face recognition impairments preceded problems in word bvFTD 307 (50.2) 70 (78.7) 25.22 <0.001*** comprehension. Patients were included SD 90 (14.7) 3 (3.4) 8.70 0.004** only if they had undergone a full neuro- PNFA 111 (18.2) 1 (1.1) 16.79 <0.001*** logical examination and comprehensive bvFTD/SD 70 (11.5) 10 (11.2) 0.004 1.00 neuropsychological assessment to support bvFTD/PNFA 31 (5.1) 5 (5.6) 0.047 1.00 the clinical diagnosis. Cases were excluded bvFTD/SD/PNFA† 2 (0.3) 0 (0) – 1.00 if there was diagnostic uncertainty, for **p<0.01 ***p<0.001. example, if a comorbid condition (eg, vas- †Fisher’s exact statistic used as expected cell counts below 5. cular disease, mood disorder) might have ALS, amyotrophic lateral sclerosis; bvFTD, behavioural form of FTD; FTD, ; PNFA, progressive non-fluent aphasia; SD, semantic dementia. affected cognition or lack of progression

J Neurol Neurosurg Psychiatry Month 2016 Vol 0 No 0 1 Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd under licence. PostScript J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2016-314912 on 29 May 2017. Downloaded from been identified as a common feature of Julie S Snowden1,2 the cognitive spectrum accompanying 1Cerebral Function Unit, Manchester Academic Health ALS.23It is interesting in this regard that Sciences Centre, Greater Manchester Neuroscience mixed behavioural/language syndromes Centre, Salford Royal NHS Foundation Trust, Salford, UK were seen as commonly in patients with 2 Faculty of Biology, Medicine and Health, Division of ALS as those without. Thus, language pro- Neuroscience and Experimental Psychology, University permits others to distribute, remix, adapt and build blems are not absent in ALS-FTD. Rather, of Manchester, Manchester, UK upon this work, for commercial use, provided the they are more likely to occur in the Correspondence to Professor Julie S Snowden, original work is properly cited. See: http:// context of the behavioural and executive Cerebral Function Unit, Greater Manchester creativecommons.org/licenses/by/4.0/ syndrome of FTD than in isolation. Neuroscience Centre, Salford Royal Foundation Trust, In this large cohort of 700 patients, Salford M6 8HD, UK; [email protected] 12.7% showed evidence of ALS. This Contributors JAS was involved in data acquisition figure is remarkably similar to the figure and analysis, drafting of the manuscript; JMH was of 12.5% reported in 40 FTD cases.6 In involved in data acquisition, critical review and approval To cite Saxon JA, Harris JM, Thompson JC, et al. J that study, subclinical motor dysfunction of manuscript; JCT, MJ, AMTR, TL and DN were Neurol Neurosurg Psychiatry Published Online First: [please include Day Month Year] doi:10.1136/jnnp- was found in a much larger proportion, involved in acquisition of clinical data, critical review and approval of manuscript; DMAM was involved in 2016-314912 particularly PNFA and bvFTD. The impli- analysis and interpretation of pathological data, critical Received 14 September 2016 cation is that substantially greater numbers review and approval of manuscript; JSS was involved in Revised 22 November 2016 of patients should develop ALS with pro- conception and design, data acquisition, interpretation, Accepted 30 November 2016 revision of manuscript. gression of illness, consistent with the J Neurol Neurosurg Psychiatry 2016;0:1–2. notion of a clinicopathological continuum Funding JAS is funded by the Motor Neurone Disease doi:10.1136/jnnp-2016-314912 between FTD and ALS. Interestingly, Association through a PhD studentship award. The however, the majority of patients in this Manchester brain donation scheme and work of the Manchester Brain Bank is supported by Alzheimer’s REFERENCES study showed signs of both disorders at the Research UK and the Alzheimer’s Society through the fi 1 Phukan J, Pender NP, Hardiman O. Cognitive time of rst clinic referral, and continued Brains for Dementia Research Initiative. impairment in amyotrophic lateral sclerosis. Lancet follow-up elicited few additional ALS Competing interests None declared. Neurol 2007;6:994–1003. cases. A continuum in which all patients 2 Abrahams S. Executive dysfunction in ALS is not the Ethics approval Ethical approval was obtained from whole story. J Neurol Neurosurg Psychiatr with FTD were equally susceptible to ALS ‘ the Newcastle and Tyneside Ethics committee Clinical 2013;84:474–5. might be expected to produce a more ’ data in research into degenerative brain disease Rec 3 Taylor LJ, Brown RG, Tsermentseli S, et al. Is language ‘ ’ equal spread of development of ALS across ref. 09/H0906/53+5, and Manchester Brain Bank Rec impairment more common than executive dysfunction an extended time period. ref. 09/H0906/52+5. in amyotrophic lateral sclerosis? J Neurol Neurosurg – Further study of the nature of the lan- Provenance and peer review Not commissioned; Psychiatr 2013;84:494 8. guage changes found in ALS-FTD will be externally peer reviewed. 4 Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on important in order to attain a greater Data sharing statement Requests for data sharing clinical diagnostic criteria. Neurology 1998;51:1546–54. understanding of the neuropsychological should be made in writing to the corresponding author. 5 Mackenzie IRA, Neumann M, Bigio EH, et al. profile of this condition. Requests will be considered individually at departmental Nomenclature and nosology for neuropathologic research/clinical governance meetings. subtypes of frontotemporal lobar degeneration: an 1,2 1,2 – Jennifer A Saxon, Jennifer M Harris, Open Access This is an Open Access article update. Acta Neuropathol 2010;119:1 4. Jennifer C Thompson,1,2 Matthew Jones,1,2 6 Burrell JR, Kiernan MC, Vucic S, et al. Motor Neuron 1,2 1,2 distributed in accordance with the terms of the Creative Anna M T Richardson, Tobias Langheinrich, Commons Attribution (CC BY 4.0) license, which dysfunction in frontotemporal dementia. Brain http://jnnp.bmj.com/ David Neary,1 David M A Mann,2 2011;134:2582–94. on October 1, 2021 by guest. Protected copyright.

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