Eye movement abnormalities are sensitive markers of neurological disease and are useful in the differential diagnosis of a variety of clinical neurological syndromes (Leigh and Kennard, 2004
). Prominent eye movement abnormalities have been described in corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) (Vidailhet et al.
; Rottach et al.
; Rivaud-Pechoux et al.
), and are useful for diagnosing these disorders and differentiating them from each other as well as other neurodegenerative diseases (Litvan et al.
; Leigh and Riley, 2000
). CBS and PSP are clinically, genetically and pathologically related to frontotemporal lobar degeneration (FTLD), a common cause of dementia in individuals with disease onset at ages <65 (Boeve et al.
; Boxer and Miller, 2005
; Cairns et al.
; Kertesz et al.
). However, it is not known to what extent CBS- and PSP- related oculomotor abnormalities are present in FTLD, or whether such findings can differentiate FTLD from CBS, PSP or Alzheimer's disease.
FTLD comprises three core clinical dementia syndromes, a behavioural and dysexecutive (or frontal) variant called frontotemporal dementia (FTD), and two forms of primary progressive aphasia, a temporal lobe variant, also called semantic dementia (SD), and a progressive non-fluent apahasia (PA) (Neary et al.
). Diagnosis of each of the FTLD clinical syndromes relies mainly on the identification of a combination of progressive behavioural and neuropsychological impairments and the exclusion of others. In contrast, the presence of oculomotor abnormalities is a core diagnostic feature of PSP (Litvan et al.
). Although CBS is associated with oculomotor abnormalities that are distinct from PSP (Leigh and Riley, 2000
), such findings do not constitute core diagnostic criteria for this syndrome (Boeve et al.
). Instead, most clinical CBS criteria rely on the presence of atypical Parkinsonism, cortical signs and cognitive impairments. Like FTLD, clinical research criteria for Alzheimer's disease are primarily based on the presence of progressive cognitive and functional deficits (McKhann et al.
CBS and PSP display prominent visually guided saccade abnormalities, including increased saccade latency in CBS and decreased saccade velocity and gain in PSP (Steele et al.
; Rebeiz et al.
; Vidailhet et al.
; Rottach et al.
). Consistent with the overlapping cognitive and behavioural features of CBS and PSP with FTLD, FTLD variants with frontal lobe damage are similarly impaired to PSP patients in their ability to withhold visually guided (reflexive) saccades on the anti-saccade task (Meyniel et al.
; Boxer et al.
). Two of the core clinical FTLD syndromes, FTD and PA, are associated with abnormalities in voluntary saccades and smooth pursuit, however visually guided (reflexive) saccades are relatively normal (Boxer et al.
). Increased latency, decreased spatial accuracy and impaired ability to control the initiation of saccades, as well as decreased smooth pursuit gain have been described in Alzheimer's disease (Hutton et al.
; Fletcher and Sharpe, 1986
; Currie et al.
; Moser et al.
; Shafiq-Antonacci et al.
; Mosimann et al.
; Crawford et al.
; Boxer et al.
). In this regard, the oculomotor abnormalities in Alzheimer's disease are similar to what has been described for CBS, but there have been no direct comparisons between these disorders.
Complicating the comparison of oculomotor features between CBS, PSP and FTLD are the overlapping molecular pathologies identified at autopsy in all three groups. Most clinically diagnosed cases of FTLD are found to have protein deposits that stain for the proteins tau or ubiquitin (FTLD-U) in different patterns (Cairns et al.
). Depending on the reported pathological series, there are approximately equal percentages of both types of molecular pathology found at autopsy in clinically diagnosed FTD cases (Forman et al.
; Josephs et al.
), whereas most SD cases are associated with FTLD-U pathology (Davies et al.
). As classically described, both corticobasal degeneration [CBD; the autopsy finding first described in association with CBS (Rebeiz et al.
)] and PSP are associated with tau deposition (in different patterns), and most clinically diagnosed cases of PA are also found to have CBD or PSP pathology at autopsy (Josephs et al.
). Less commonly, clinical FTD cases may also be associated with CBD- or PSP-type pathology at autopsy (Josephs et al.
) and conversely FTLD-U pathology may be associated with clinical oculomotor abnormalities similar to PSP (Paviour et al.
). Thus, if the clinical oculomotor features of CBS and PSP predict tau deposition at autopsy, it would be expected that similar oculomotor abnormalities should be detected in FTLD cases with tau deposition, particularly PA, but also a significant proportion of FTD cases.
The goal of this study was to directly compare the oculomotor abnormalities associated with CBS, PSP, FTLD and Alzheimer's disease, and to investigate the ability of oculomotor measurements to differentiate these syndromes. Given the similarities between autopsy findings in CBS, PSP and FTLD we hypothesized that the characteristic oculomotor features of CBS and PSP would also be present in FTLD. Since oculomotor function is less sensitive to language or limb motor impairments than traditional neuropsychological tests, we hypothesized that eye movements would be superior to neuropsychological tests in diagnosing the clinical syndromes with the most profound oculomotor impairments.