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Original Contributions |

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
Arch Neurol. 2012;69(4):509-517. doi:10.1001/archneurol.2011.1021.
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Background Deficits in the generation and control of saccades have been described in clinically defined frontotemporal dementia (FTD) and Alzheimer disease (AD).

Objective To determine the saccade abnormalities associated with autopsy-defined cases of frontotemporal lobar degeneration (FTLD) and of AD, because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses.

Design An infrared eye tracker was used to record visually guided saccades to 10° targets and antisaccades in subjects with autopsy-confirmed FTD and subjects with autopsy-confirmed AD, a mean (SE) of 35.6 (10.0) months prior to death, and age-matched normal controls. Twelve subjects with FTD had an FTLD–TAR DNA-binding protein 43 pathology, 15 had an FTLD-tau pathology, and 1 subject showed an FTLD–fused in sarcoma protein pathology. Receiver operating curve statistics were used to determine the diagnostic value of the oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry.

Setting Memory and Aging Center, Department of Neurology, University of California, San Francisco.

Participants A total of 28 subjects with autopsy-confirmed FTD, 10 subjects with autopsy-confirmed AD, and 27 age-matched normal controls.

Results All subjects with FTD or AD were impaired relative to normal controls on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually guided saccade abnormalities. The AD cases displayed prominent increases in horizontal saccade latency that differentiated them from the FTD cases. Impairments in velocity and gain were most severe in individuals with progressive supranuclear palsy but were also present in other tauopathies. By using vertical and horizontal saccade velocity and gain as our measures, we were able to differentiate patients with progressive supranuclear palsy from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume.

Conclusion Decreased visually guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of progressive supranuclear palsy.

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Figure 1. Examples of upward saccades and fixation abnormalities. Plots of eye position vs time are presented for 3 successive upward saccades to 10° targets for the following individuals: a normal control, which shows intervals for subsequent saccade measurements, including latency, velocity (slope of eye position vs time), and first and end gains (A); a subject with clinical corticobasal degeneration syndrome (CBDS) with a frontotemporal lobar degeneration–TAR DNA-binding protein 43 pathology (B); a subject with clinical CBDS with CBD pathology (C); a subject with the behavioral variant of clinical frontotemporal dementia with Pick disease pathology (D); a subject with clinical progressive supranuclear palsy syndrome (PSPS) with PSP pathology (E); and a subject with clinical Alzheimer disease (AD) with AD pathology (F). Examples of fixation abnormalities in horizontal eye position vs time traces are presented for the following individuals: the same subject with CBDS (C) who had macrosaccadic oscillations (G) and a subject with PSPS with PSP pathology (H).

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Figure 2. Saccade performance of subjects with autopsy-confirmed frontotemporal dementia (FTD) subtypes and Alzheimer disease (AD). The saccade parameters of latency (A), velocity (B), and gain (C) are expressed as mean (SEM) values, with * P < .01 or † P < .05 for comparison with normal controls (NC) and subjects with frontotemporal lobar degeneration associated with insoluble deposits of the TAR DNA-binding protein 43 (TDP). The saccade parameter of antisaccade performance (D) is also expressed as mean (SEM) values, with * P < .01 or † P < .05 for comparison with NC. The error bars indicate SEM. CBD indicates subjects with corticobasal degeneration; Pick/FTDP-17, subjects with Pick disease or with FTD and parkinsonism linked to chromosome 17; and PSP, subjects with progressive supranuclear palsy.

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Figure 3. Correlation between dorsal midbrain volume and vertical saccade velocity. A, The dorsal midbrain region is correlated with vertical saccade velocity from voxel-based morphometric analysis of 77 subjects with frontotemporal lobar degeneration (FTLD; 25 subjects with autopsy-confirmed FTLD and 52 subjects with clinically diagnosed FTLD [displayed at P < .05, familywise error–corrected]). The scale bar indicates t values for the analysis. B, A plot of brain volumes at the peak midbrain voxel with vertical saccade velocity is shown for all subjects with FTLD (the subjects with an autopsy-confirmed diagnosis are indicated by filled symbols). C, The brain volumes of the subjects with autopsy-confirmed FTLD are compared with those of normal controls (NC) at the same voxel as in the plot of brain volumes (B). P values were determined from an analysis of variance, using Tukey post hoc statistics. CBD indicates subjects with corticobasal degeneration; Pick/FTDP-17, subjects with Pick disease or with frontotemporal dementia and parkinsonism linked to chromosome 17; PSP, subjects with progressive supranuclear palsy; and TDP, subjects with FTLD associated with insoluble deposits of the TAR DNA-binding protein 43.

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