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 (), 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 (), 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 (). 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.