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Saccade Abnormalities in Autopsy-Confirmed Frontotemporal Lobar Degeneration and Alzheimer Disease

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Saccade Abnormalities in Autopsy-Confirmed Frontotemporal Lobar Degeneration and Alzheimer Disease ORIGINAL CONTRIBUTION Saccade Abnormalities in Autopsy-Confirmed Frontotemporal Lobar Degeneration and Alzheimer Disease Adam L. Boxer, MD, PhD; Siobhan Garbutt, PhD; William W. Seeley, MD; Aria Jafari, BS; Hilary W. Heuer, PhD; Jacob Mirsky, MS; Joanna Hellmuth, MD, MHS; John Q. Trojanowski, MD, PhD; Erik Huang, MD, PhD; Steven DeArmond, MD; John Neuhaus, PhD; Bruce L. Miller, MD Background: Deficits in the generation and control of Participants: A total of 28 subjects with autopsy- saccades have been described in clinically defined fron- confirmed FTD, 10 subjects with autopsy-confirmed AD, totemporal dementia (FTD) and Alzheimer disease (AD). and 27 age-matched normal controls. Objective: To determine the saccade abnormalities as- Results: All subjects with FTD or AD were impaired rela- sociated with autopsy-defined cases of frontotemporal lo- tive to normal controls on the antisaccade task. How- bar degeneration (FTLD) and of AD, because clinical FTD ever, only FTLD-tau and AD cases displayed reflexive vi- syndromes can correspond to a number of different un- sually guided saccade abnormalities. The AD cases derlying neuropathologic FTD and non-FTD diagnoses. displayed prominent increases in horizontal saccade la- tency that differentiated them from the FTD cases. Im- Design: An infrared eye tracker was used to record vi- pairments in velocity and gain were most severe in in- sually guided saccades to 10° targets and antisaccades dividuals with progressive supranuclear palsy but were in subjects with autopsy-confirmed FTD and subjects also present in other tauopathies. By using vertical and with autopsy-confirmed AD, a mean (SE) of 35.6 (10.0) months prior to death, and age-matched normal con- horizontal saccade velocity and gain as our measures, trols. Twelve subjects with FTD had an FTLD–TAR we were able to differentiate patients with progressive DNA-binding protein 43 pathology, 15 had an FTLD- supranuclear palsy from other patients. Vertical saccade tau pathology, and 1 subject showed an FTLD–fused in velocity was strongly correlated with dorsal midbrain sarcoma protein pathology. Receiver operating curve volume. statistics were used to determine the diagnostic value of the oculomotor variables. Neuroanatomical correlates Conclusion: Decreased visually guided saccade veloc- of oculomotor abnormalities were investigated using ity and gain are suggestive of underlying tau pathology voxel-based morphometry. in FTD, with vertical saccade abnormalities most diag- nostic of progressive supranuclear palsy. Setting: Memory and Aging Center, Department of Neu- rology, University of California, San Francisco. Arch Neurol. 2012;69(4):509-517 Author Affil RONTOTEMPORAL DEMENTIA in clinical phenomenology, at autopsy, the and Aging C (FTD) describes a group of same pathological diagnosis may be asso- of Neurology Garbutt, See common neurodegenera- ciated with a variety of clinical syn- Hellmuth, an 7,8 tive dementias that in- dromes during life. and Mr Mirs cludes 3 core syndromes, be- From a molecular perspective, 2 FTD for Integrativ havioral variant FTD (bvFTD), semantic neuropathologic subtypes predominate: Department F Garbutt and dementia, and a progressive nonfluent those associated with insoluble deposits aphasia.1 Patients with these core FTD syn- of tau protein (frontotemporal lobar de- Department Laboratory M dromes often develop features of amyo- generation with tau pathology [hereafter 2 Huang and D trophic lateral sclerosis (FTD-ALS), cor- referred to as FTLD-tau]) and those asso- Department ticobasal degeneration syndrome (CBDS), ciated with insoluble deposits of the TAR and Biostatis and progressive supranuclear palsy syn- DNA-binding protein 43 (TDP-43; here- University o drome (PSPS, also know as Richardson after referred to as FTLD-TDP).9,10 A third, Francisco; an syndrome3),4,5 with individual patients ini- less common pathology related to depo- Neurodegen Research, De tially meeting clinical criteria for one syn- sition of the fused in sarcoma protein Pathology an drome but subsequently developing symp- (FUS) is identified in most remaining cases Medicine, Un 11 Author Affiliations are listed at toms and signs of one or more additional (hereafter referred to as FTLD-FUS). Cer- Pennsylvania the end of this article. syndromes.6 Consistent with this overlap tain clinical syndromes strongly associ- Trojanowski ARCH NEUROL / VOL 69 (NO. 4), APR 2012 WWW.ARCHNEUROL.COM 509 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 ate with a single molecular pathology, whereas others may CLINICAL DIAGNOSES be associated with one or more pathologies. For ex- ample, semantic dementia and FTD-ALS usually pre- Subjects underwent clinical evaluations and magnetic reso- dict FTLD-TDP pathology at autopsy, whereas progres- nance imaging within 3 months of an eye movement evalua- sive nonfluent aphasia and PSPS most often reflect FTLD- tion and were categorized as having AD, semantic dementia, tau pathology.12 PSPS, CBDS, or bvFTD or as normal controls. At the time of Despite our improved understanding of the molecular assessment, all subjects with FTD met the criteria of Neary et al1 for semantic dementia, progressive nonfluent aphasia, or underpinnings of FTD, there are currently no effective treat- 13 bvFTD; the National Institute of Neurological Disorders and ments. New agents that specifically target tau have be- Stroke–Society for PSP criteria for probable PSP22; or the cri- gun to enter human clinical trials, increasing the impor- teria for CBDS4 as described in Garbutt et al.16 Normal con- tance of early accurate prediction of underlying pathology trols had normal neurological and neuropsychological exami- in patients with FTD syndromes. Abnormalities in the con- nations and had clinical dementia rating (CDR) scores of 0.23 trol of eye movements are frequently observed in FTD and Subjects with AD met the National Institute of Neurological are useful diagnostically in differentiating clinical FTD syn- and Communicative Diseases and Stroke–Alzheimer Disease and dromes from each other as well as from Alzheimer disease Related Disorders Association probable criteria.24 (AD).14-16 We previously found that, although most clini- cal FTD syndromes were impaired in the voluntary con- AUTOPSY-DEFINED GROUPS trol of saccades and smooth pursuit eye movements, clini- cal syndromes with predicted FTLD-tau pathology, For group analyses, subjects with FTLD were subdivided by including PSPS and CBDS, displayed relatively specific and underlying neuropathology into 1 of 4 groups: (1) FTLD-TDP severe abnormalities in visually guided (reflexive) sac- pathology (type 1, 2, or 3; n=12); (2) PSP (n=8); (3) CBD (n=4); cades.16 We reasoned that such saccade abnormalities might (4) Pick disease (n=2) or FTD and parkinsonism linked to chro- mosome 17 (FTDP-17; n=1); and (5) AD (n=10). The sub- be useful diagnostically in identifying FTD cases with un- jects with Pick disease and those with an FTDP-17 pathology derlying tau pathology during life. However, because clini- were combined on the basis of having similar saccade abnor- cal CBDS often corresponds to other non–FTLD-tau pa- malities. One subject had a diagnosis of FTLD-FUS pathology thology diagnoses, including AD, at autopsy,4 and PSP (eTable 2) and was excluded from the group analyses but used pathology is found in a variety of clinical syndromes, in- in the neuroimaging and receiver operating characteristic (ROC) cluding individuals who present with bvFTD or with curve analyses. CBDS,17-19 the utility of using saccade measurements to iden- tify FTLD-tau pathology would need to be evaluated in FTD NEUROPATHOLOGICAL ANALYSIS cases with autopsy-confirmed diagnoses. Therefore, the goals of our study were to (1) determine the saccade ab- Autopsies were performed at the University of California, San normalities associated with autopsy-confirmed FTD as com- Francisco, or at the University of Pennsylvania, according to pared with AD and (2) determine the ability of saccade ab- standard protocols.25 normalities to differentiate FTLD-tau from FTLD-TDP and AD during life. EYE MOVEMENT RECORDINGS Two-dimensional movements of the right eye were measured METHODS using the Fourward Technologies Generation 6.1 Dual Pur- kinje Image Eye Tracker as described previously.16 Targets were NOMENCLATURE 0.1° bright spots presented on a large analog oscilloscope at a viewing distance of 80 cm. We use the acronym FTD to refer to the following clinically defined syndromes: semantic dementia, CBDS, progressive non- OCULOMOTOR PARADIGMS fluent aphasia, PSPS, and bvFTD. We use the acronym FTLD to refer to the following neuropathologically defined syn- Reflexive, visually guided (prosaccade) trials consisted of ran- dromes: FTLD-tau pathology, FTLD-TDP pathology, and FTLD- domly interleaved 5° and 10° targets presented up, down, left, FUS pathology, and to the following diagnoses: CBD, Pick dis- or right of a central fixation point. Each trial began with illu- ease, and PSP.20 Subjects with AD met the National Institute 21 mination of a central fixation spot for 1000 milliseconds. When on Aging–Reagan Institute criteria for high likelihood AD. the fixation light was extinguished, targets appeared either im- mediately (overlap condition) or after a 200-millisecond gap SUBJECTS (gap condition). The eccentric target remained illuminated for 1000 milliseconds. A blank screen interval of 1000 millisec- All subjects with autopsy-confirmed FTD or with autopsy-
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