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Deficits in the generation and control of saccades have been described in clinically-defined frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses, we sought to determine the saccade abnormalities associated with autopsy-defined cases of FTLD and AD.
An infrared eye tracker was used to record visually guided saccades to ten degree targets and antisaccades in 28 autopsy-confirmed FTD and 10 AD subjects, an average of 35.6 ± 10 months prior to death and 27 age-matched normal controls (NC). 12 FTD subjects had FTLD-TDP pathology, 15 had FTLD-tau pathology and one showed FTLD-FUS pathology. Receiver operating curve (ROC) statistics were used to determine diagnostic value of oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry (VBM).
All FTD and AD subjects were impaired relative to NC on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually-guided saccade abnormalities. AD cases displayed prominent increases in horizontal saccade latency that differentiated them from FTD cases. Impairments in velocity and gain were most severe in individuals with Progressive Supranuclear Palsy (PSP) but were also present in other tauopathies. Vertical and horizontal saccade velocity and gain were able to differentiate PSP cases from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume.
Decreased visually-guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of PSP.
Frontotemporal dementia (FTD) describes a group of common neurodegenerative dementias that includes three core syndromes, a behavioral variant (bvFTD), semantic dementia (SD) and a progressive nonfluent aphasia (PNFA) 1. Patients with these core FTD syndromes often develop features of amyotrophic lateral sclerosis (FTD-ALS),2 corticobasal degeneration syndrome (CBDS), and Progressive Supranuclear Palsy syndrome (PSPS; Richardson’s syndrome3), 4–5 with individual patients initially meeting clinical criteria for one syndrome but subsequently developing symptoms and signs of one or more additional syndromes.6 Consistent with this overlap in clinical phenomenology, at autopsy the same pathological diagnosis may be associated with a variety of clinical syndromes during life. 7–8
From a molecular perspective, two FTD neuropathologic subtypes predominate: those associated with insoluble deposits of tau protein (frontotemporal lobar degeneration with tau pathology [FTLD-tau]) and those associated with insoluble deposits of the TAR DNA Binding Element Protein 43 kDa (TDP-43; FTLD-TDP) 9–10 A third, less common, pathology related to deposition of the fused in sarcoma protein (FUS) is identified in most remaining cases (FTLD-FUS).11 Certain clinical syndromes strongly associate with a single molecular pathology, while others may be associated with one or more pathologies. For example, SD and FTD-ALS usually predict FTLD-TDP at autopsy, whereas PNFA and PSPS most often reflect FTLD-tau. 12
Despite improved understanding of the molecular underpinnings of FTD, there are currently no effective treatments.13 New agents that specifically target tau have begun to enter human clinical trials, increasing the importance of early accurate prediction of underlying pathology in patients with FTD syndromes. Abnormalities in the control of eye movements are frequently observed in FTD and are useful diagnostically in differentiating clinical FTD syndromes from each other as well as from Alzheimer’s disease (AD).14–16 We previously found that while most clinical FTD syndromes were impaired in the voluntary control of saccades and smooth pursuit eye movements, clinical syndromes with predicted FTLD-tau pathology, including PSPS and CBDS displayed relatively specific and severe abnormalities in visually-guided (reflexive) saccades. 16 We reasoned that such saccade abnormalities might be useful diagnostically in identifying FTD cases with underlying tau pathology during life. However, since clinical CBDS often corresponds to other non-FTLD-tau diagnoses, including AD, at autopsy4, and PSP pathology is found in a variety of clinical syndromes including individuals who present with bvFTD or CBDS17–19, the utility of using saccade measurements to identify FTLD-tau pathology would need to be evaluated in FTD cases with autopsy-confirmed diagnoses.
The goals of this study were therefore to 1) determine the saccade abnormalities associated with autopsy confirmed FTD as compared to AD, and 2) determine the ability of saccade abnormalities to differentiate FTLD-tau from FTLD-TDP and AD during life.
We use the abbreviation FTD to refer to the clinically-defined syndromes bvFTD, SD, CBDS, PNFA and PSPS; and FTLD to refer to the neuropathologically-defined syndromes, FTLD-tau, FTLD-TDP and FTLD-FUS; and diagnoses, CBD, Pick’s and PSP. 20 AD subjects met NIA-Reagan criteria for high likelihood AD.21
All autopsy-confirmed FTD and AD subjects as of December, 2010 (n= 38) from a larger series of clinically-diagnosed FTD patients reported previously16 and 27 age-matched normal controls (NC) were enrolled. All subjects were evaluated at the University of California, San Francisco (UCSF) and gave informed consent to participate in the experimental procedures. An additional group of 50 clinically-diagnosed FTD subjects were used for the neuroimaging analysis only (Supplementary Table S1). All aspects of the study were approved by the UCSF Institutional Review Board.
Subjects underwent clinical evaluations and MRI scans within 3 months of eye movement evaluation and were categorized as bvFTD, SD, PSPS, CBDS, or NC. At the time of assessment, all FTD subjects met criteria of Neary et al. 1 for bvFTD, SD or PNFA, NINDS-Society for PSP criteria for probable PSP,22 or criteria for CBS 4 as described.16 NC subjects had normal neurological and neuropsychological examinations, and clinical dementia rating (CDR) scores of 0. 23 AD subjects met NINCDS-ADRDA probable criteria. 24
For group analyses, FTLD subjects were subdivided by underlying neuropathology into one of four groups: 1) FTLD-TDP (Type 1, 2 or 3; n = 12); 2) PSP (n = 8); 3) CBD (n = 4); 4) Pick’s disease (n = 2) or FTDP-17 (n = 1); and 5) AD (n = 10). The Pick’s and FTDP-17 subjects were combined based on similar saccade abnormalities. One subject had a pathologic diagnosis of FTLD-FUS (Supplementary Table S2) and was excluded from the group analyses but used in the neuroimaging and ROC curve analyses.
Autopsies were performed at UCSF or at the University of Pennsylvania according to standard protocols. 25
Two-dimensional movements of the right eye were measured using the Fourward Technologies (Gallatin, MO) Generation 6.1 Dual Purkinje Image Eye Tracker as described previously. 16 Targets were 0.1 deg bright spots presented on a large analog oscilloscope at a viewing distance of 80 cm.
Reflexive visually-guided (prosaccade) trials consisted of randomly interleaved 5 and 10 degree targets presented up, down, left, or right of a central fixation point. Each trial began with illumination of a central fixation spot for 1000 ms. When the fixation light was extinguished targets appeared either immediately (overlap condition) or after a 200 ms gap (gap condition). The eccentric target remained illuminated for 1000 ms. A blank screen interval of 1000 ms occurred between trials. At least seven responses were recorded for each stimulus in each direction. Only the 10 degree overlap data were analyzed.
Antisaccade (AS) trials began with illumination of the central fixation point for 1000 ms. After a 200 ms gap, targets appeared 10 degrees to the right or left and remained illuminated for 1000 ms. Subjects were given instructions to “look away from the target that appears on the side at the corresponding spot on the other side of the fixation point, and if you make a mistake try to correct yourself.” Responses to at least 18 AS trials were recorded in each direction.
Saccade latencies were computed as the duration from the appearance of an eccentric target to the onset of the first eye movement (Figure 1A). First gains were computed as the difference in eye position between fixation and the end of the first movement. End gains were computed as the difference in eye position between fixation and the final eye position for the trial. AS responses were considered to be correct if the first eye movement after target onset had an amplitude >3 degrees and was in the opposite direction from the target.
MRI scans were obtained on a 1.5-T Magnetom VISION system (Siemens Inc., Iselin, N.J.) as described in a previous report 26. 3D T1-weighted scans (MP-RAGE) were used for analyses. Voxel-based morphometry (VBM) images were pre-processed and statistically analyzed using the SPM5 software package (http://www.fil.ion.ucl.ac.uk/spm), using standard procedures as described in previously.15 An analysis of covariance, controlling for total intracranial volume, age and sex, was used to investigate the brain structure correlates of saccade abnormalities in the autopsy-confirmed FTLD subjects plus an additional 52 clinically diagnosed FTLD subjects (Supplementary Table S2). At the voxel level, statistical threshold of p < 0.05, corrected for multiple comparisons (Family-Wise Error), was used.
Group comparisons of demographic, neuropsychological and eye movement measures between neuropathologically-diagnosed groups used Chi square or analysis of variance along with Tukey or Sidak post hoc statistics. Analyses of oculomotor findings controlled for differences in disease severity at the time of assessment by including CDR- sum of boxes (SOB) as a covariate in ANOVAs. Diagnostic value of oculomotor findings was analyzed using Receiver Operating Curve (ROC) statistics. To control for differences in disease severity, ROC analyses used the residual values from linear regressions of CDR-SOB and oculomotor values of interest. Significance was accepted at the p < 0.05 level. Analyses were performed using SPSS (version 17.0, SPSS, Chicago, IL).
When grouped by pathologic diagnosis, patient groups were comparable in age, gender, disease duration and time to autopsy. Autopsies showed that 15 FTD subjects had FTLD-tau pathology, 12 had FTLD-TDP pathology, and 1 patient had FTLD-FUS pathology; the clinical research diagnoses at the time of oculomotor assessment are shown in Table 1. All groups except PSP were impaired relative to NC on the MMSE. The CBD, Pick’s/FTDP-17 subjects were more impaired than the FTLD-TDP and PSP groups (p < 0.05, ANOVA Tukey post hoc). CDR 27 and CDR-SOB scores were higher in the CBD, PSP and Pick’s group than in the FTLD-TDP group (p < 0.05).
Examples of 10 degree upward saccades (Figure 1) demonstrate the differences in vertical saccade performance between pathologic groups. FTLD-TDP subjects and three out of four CBD subjects displayed visually-guided saccades that were indistinguishable from NC (Figure 1A and 1B). In contrast, the fourth CBD subject, who presented with a classic CBDS, showed abnormalities including increased latency, decreased velocity, and decreased gain as well as occasional macrosaccadic oscillations (Figure 1C and 1H). One of the subjects with Pick’s disease displayed decreased saccade velocity and gain (Figure 1D) as compared to the more severely decreased saccade velocity and gain seen in a PSP subject (Figure 1E). The PSP subjects also exhibited occasional square wave jerks (Figure 1G).
Both horizontal (F[6, 59]= 3.90; p = 0.003; Figure 2A) and vertical saccade latency (F[6, 59]= 6.59; p < 0.001) differed between groups. All group comparisons controlled for disease severity at the time of oculomotor assessment (Table 1) by including CDR-SOB score as a covariate. Post-hoc tests revealed that AD subjects had increased horizontal saccade latencies relative to FTLD-TDP (p = 0.007) and PSP subjects (p = 0.043). Vertical saccade latencies were increased in both AD and PSP as compared to NC and FTLD-TDP subjects (p ≤ 0.05).
Horizontal saccade velocity differed between groups (F[6,59] = 8.26; p < 0.001). PSP subjects had decreased horizontal velocity relative to NC, FTLD-TDP, CBD and AD subjects (p <0.05). Pick’s/FTDP-17 subjects also had lower horizontal velocities than NC, FTLD-TDP and AD subjects (p < 0.05; Figure 2B). Similarly, the group difference seen for vertical velocity (F[6,59]=16.7; p<0.001) was due to slower saccades in the PSP subjects compared to NC, FTLD-TDP, CBD and AD subjects (p<0.01).
PSP subjects also showed decreased horizontal first gains compared to all other subjects (p ≤ 0.025; Figure 2C), but there was not a significant difference in end gain between groups (F[6,59] = 0.716; p =0.638) for horizontal trials, indicating that PSP subjects could attain the ten degree target position through a series of smaller saccadic movements. For vertical eye movements, both first and end gains differed significantly between groups (F[6,59] = 22.4 and F[6,59] = 13.9 respectively; p < 0.001). Again, post-hoc tests revealed that patients in the PSP group had decreased vertical gains compared to all other subject groups (p ≤0.001).
Performance on the antisaccade (AS) task also revealed differences between groups (F[6, 55]=9.47; p < 0.001; Figure 2D). The AS task involves suppression of a visually-guided saccade and generation of a voluntary saccade in the opposite direction. Post-hoc tests showed that the FTLD-TDP, Pick/FTDP-17, PSP and AD groups all had significantly lower percentage correct AS trials than NC subjects (p<0.025), with a trend (p = 0.065) towards worse performance in the CBD group as well. A measure of the ability to self-correct AS errors, the total (correct + self-corrected errors) AS score also differed between groups (F[6,455]=7.09; p < 0.001), with the FTLD-TDP, Pick’s/FTDP-17, PSP and AD groups performing worse than NC (p < 0.02).
Saccade parameters differed between groups, indicating that abnormalities could be diagnostically useful. Receiver operating curve (ROC) statistics were used to determine the diagnostic value of saccade abnormalities in differentiating the autopsy-confirmed FTLD and AD patients (n=38). Horizontal saccade latency, but not other measures, differentiated AD from all FTLD cases (AUC = 0.807; p = 0.01). A variety of saccade parameters differentiated PSP subjects from all other patients, with vertical saccade velocity and both vertical and horizontal first gains most effective (p < 0.001; Table 2). When all subjects with FTLD-tau pathology were combined, horizontal saccade velocity and first gain were best (p < 0.01) able to differentiate this group (n=15) from the non-tau FTLD and AD cases (n = 22).
We investigated the neuroanatomical correlates of the saccade parameters that best differentiated the FTD groups using VBM. At the whole brain level, vertical saccade velocity was correlated with brain volume in the dorsal midbrain white matter in the vicinity of the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF; MNI coordinates = 2, −18, −4; p = 0.028, FWE corrected; Figure 3A). No other brain regions were correlated with vertical saccade velocity even using a lower statistical threshold (p < 0.1, corrected), nor were any other oculomotor variables that differentiated the groups correlated with brain volume. The slowest vertical saccades and lowest volumes were in the PSP and Pick’s subjects (Figure 3B). In the riMLF region, PSP subjects had smaller brain volumes than NC and TDP-43 subjects (p < 0.001; Figure 3C). CBD subjects also showed atrophy compared to NC (p = 0.001) and TDP-43 subjects (p = 0.028) in the vicinity of the riMLF.
We investigated the saccade abnormalities found in autopsy-confirmed FTD and AD cases and found distinctive abnormalities in FTLD cases with underlying tau pathology and in AD. Although all FTD and AD subjects were impaired in their ability to inhibit visually-guided saccades on the antisaccade task, reflexive visually-guided saccades in FTLD-TDP subjects were indistinguishable from NC. PSP subjects had the most severe visually-guided saccade abnormalities, with greater involvement of vertical than horizontal saccades. These abnormalities included elevated latency, decreased velocity and decreased gains. Unexpectedly, other FTLD-tau cases, including an individual with Pick’s disease and one with FTDP-17, also had similar saccade abnormalities, although in these cases the abnormalities were more prominent in the horizontal than the vertical plane. In contrast, AD cases displayed increased saccade latencies as compared to the other patient groups. Consistent with these findings, visually-guided saccade velocity and gain were able to differentiate PSP subjects from all other patients, as well as FTLD-tau subjects from non-FTLD-tau subjects, whereas horizontal saccade latency differentiated AD from FTLD patients, all an average of more than 2.5 years prior to death. The parameter best able to differentiate PSP from other subjects, vertical saccade velocity, was also strongly correlated with dorsal midbrain volume in the vicinity of the riMLF, and FTLD-tau cases were atrophied relative to NC and FTLD-TDP cases in this region. This suggests a potential neuroanatomical basis for the differences we measured in visually-guided saccades; i.e., damage to the brainstem oculomotor network is more severe in FTLD-tau than FTLD-TDP.
These findings extend our previous work which suggested that visually-guided saccades are normal in FTLD-TDP, 16 particularly in individuals with SD who often display enhanced visual talent. 28 Moreover, similar to previous reports based on clinically-diagnosed patients that included PSP, 29–30 the autopsy-confirmed PSP patients in this study had the most severe vertical saccade impairments. Although clinically-diagnosed CBDS has previously been associated with severe alterations in saccade latency and gain, 31 we found that only one of the four autopsy-confirmed CBD subjects had visually-guided saccade abnormalities. These results are similar to a recent clinical-pathological CBDS series which noted oculomotor findings in only approximately 20% of subjects, mainly late in the course of disease. 32 We found that AD patients displayed prominent increases in saccade latency. Since CBDS is known to be pathologically heterogeneous, with some clinically-defined series containing a large percentage of pathological AD subjects,4, 33 we suggest that previous descriptions of increased latency in CBDS may have largely reflected cases with underlying AD pathology16, 31. In the current study, the CBD case with abnormal visually-guided saccades also experienced macrosaccadic oscillations (Figure 1F), a finding not previously described in CBDS or CBD. Although we did not quantify these fixation abnormalities, such findings might also help to identify FTD cases with underlying tau pathology.
Supranuclear gaze palsy and variably decreased saccade velocity have been reported in autopsy confirmed ALS 34–35 and clinically-diagnosed FTD-ALS; 36 however, we found no evidence of decreased saccade velocity in the six pathologically confirmed FTLD-ALS subjects studied here. Since saccade abnormalities in ALS have been closely associated with bulbar-onset cases,37 the lack of such abnormalities in our subjects may reflect the fact that none of our FTLD-ALS cases had bulbar-onset disease.
The visually-guided saccade abnormalities that we observed in our PSP subjects are similar to those described in a previous autopsy-confirmed PSP case 38 as well as in other clinical PSP series.29–30 The current study extends these observations to a series of autopsy-confirmed PSP cases who presented with PSPS. Previous studies have inferred that damage to the riMLF and related structures explained vertical saccade impairments in PSP based on experiments in monkeys coupled with human postmortem data in individuals with vertical saccade palsy or PSP.39–41 We provide direct experimental support for models implicating riMLF and nearby structures as the cause of vertical saccade slowing in PSP through the strong correlation between saccade velocity and dorsal midbrain volume that we quantified (Figure 3), and its severe atrophy in living PSP subjects at the time they experienced slowed saccades. As we have demonstrated in previous studies, the increased saccade latency in AD is likely related to the prominent dorsal parietal lobe involvement in these cases. 16, 28, 42
We found that saccade gain and velocity abnormalities were able to differentiate PSP cases from other FTD syndromes (Table 2). These saccade abnormalities constitute the supranuclear gaze palsy observed at the bedside in PSP and thus our findings are consistent with previous studies that determined that gaze palsy is an effective criterion for differentiating PSP from other neurodegenerative diseases.19,43 Since PSP can present with a frontal lobe dementia,17 the measurement of saccade velocity and gain may be useful diagnostically in identifying clinical FTD cases with underlying PSP or other tau pathology.
Study funding: NIH (R01AG038791, R01AG031278, P50 AG023501, P01AG019724), the John Douglas French Foundation; the Hellman Family Foundation; the Larry L. Hillblom Foundation.