EDITORIAL
Antisaccades and Executive Dysfunction in PD: Two Sides of the Same Coin? Paresh A. Malhotra, PhD, MRCP and Adolfo M. Bronstein, PhD, FRCP* Division of Brain Sciences, Imperial College, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, United Kingdom
Over recent decades, the fact that, in addition to its cardinal motor features, Parkinson’s disease (PD) is undoubtedly associated with both cognitive impairment1 and abnormalities of eye movements2 has become increasingly clear. With respect to the former, dementia is increasingly recognized in PD and is associated with increased morbidity and mortality. It appears to be very closely linked to increasing age but is also more likely to occur in those individuals with akinetic-rigid presentations, whereas patients with a tremor-dominant form of the disease show less cognitive impairment and are less likely to develop dementia.3,4 However, cognitive impairment in the context of PD, particularly in the early stages, is not always immediately obvious with a tool such as the MiniMental State Examination, often requiring more targeted or detailed neuropsychological assessment before it is identified.5 Similarly, abnormalities of eye movements in idiopathic PD tend not to be obvious on standard clinical assessment and are more likely to be revealed with eye-tracking equipment in the research setting, where patients’ saccades can become hypometric, typically during specific “higher-order” stimuli paradigms.6 An increasing body of evidence links these two sets of findings, showing that eye movements and visual task performance are more affected in those individuals with PD who have cognitive impairment.7 In particular, saccadic latency has been found to correlate with executive dysfunction rather than motor severity,8 PD patients with cognitive impairment are more likely to make errors on visuospatial tasks than patients without cognitive impairment,9 and, most pertinent to the current study, increased antisaccade latencies correlate with reduced working memory performance.10 However, these studies have been con-
-----------------------------------------------------------*E-mail: [email protected]
Relevant conflicts of interest/financial disclosures: Dr Paresh Malhotra receives research funding from the Higher Education Council for England. Professor Adolfo Bronstein’s research is funded by the Medical Research Council (UK). Received: 3 February 2015; Accepted: 8 February 2015 Published online 15 March 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/mds.26211
founded to some extent by the effects of long-term dopaminergic treatment, making determination of the exact relationship between eye movement abnormalities, cognitive deficits, and motor symptom progression in PD particularly difficult. In this issue, Antoniades and colleagues describe their findings from a detailed examination of cognition and oculomotor function in 19 drug-na€ıve patients with Parkinson’s disease.11 These individuals, all with an akinetic-rigid rather than a tremor-dominant presentation, showed no evidence of any abnormality of standard prosaccadic (ie, making saccades toward a visible target) latencies as compared with 20 healthy volunteers, and no correlation was seen between latencies and Unified Parkinson’s Disease Rating Scale III score. However, when patients were tested with an antisaccade protocol, where they were instructed to look away from a newly appeared target stimulus, they made almost twice as many errors as control subjects. These errors correlated with Unified Parkinson’s Disease Rating Scale III, and even more strongly with switch cost on the trails test and performance on a rule-finding task, both of which are measures of executive function. The authors, citing evidence from imaging studies and neurophysiological work in primates, propose that these impairments in eye movement control and flexible cognitive behavior are likely to be secondary to effects on prefrontal cortex, and because they found no abnormality of verbal fluency, even though these processes also appear to involve prefrontal regions, they suggest that fluency tasks are more insensitive to small degrees of dysfunction. Antisaccade tasks have been used to probe cognition in a number of diseases, including Alzheimer’s disease and schizophrenia, and have been shown to be particularly sensitive to frontal damage and dysfunction.12 As well as reflecting inhibitory processes, accurate performance on antisaccade paradigms requires intact spatial working memory and attention, although the patients in the current study were not formally tested in these cognitive domains. The results described by Antoniades et al. provide further strong evidence linking eye movement abnormalities and cognitive impairments in PD, with the
Movement Disorders, Vol. 30, No. 6, 2015
745
M A L H O T R A
A N D
B R O N S T E I N
recruitment of a drug-na€ıve cohort making them particularly compelling. A further point to draw from the findings is that drug-na€ıve patients appear to manifest no abnormalities of latencies for prosaccades to a peripheral target, although whether this finding extends to saccades made during visual exploration or completion of a cognitively demanding task remains to be seen. Although the authors’ account focuses on the prefrontal cortex, they suggest that its operation is being impacted by basal ganglia changes, and as this implies, it is likely that both anti-saccades and these aspects of executive function are dependent on intact fronto-striatal networks,13 and dysfunction of any part of the circuit thus may lead to impaired performance in both these domains. Antoniades and colleagues state that they plan to follow this patient group longitudinally to ascertain whether saccadometry and executive function tasks may predict future characteristics of the disease process. One further aspect of any such longitudinal study that will be of particular interest will be the effect of commencing dopaminergic therapy, and we look forward to their findings.
References 1.
746
Lees AJ, Smith E. Cognitive deficits in the early stages of Parkinson’s disease. Brain 1983;106:257-270.
Movement Disorders, Vol. 30, No. 6, 2015
2.
Leigh RJ, Zee DS. The Neurology of Eye Movements. In: Contemporary Neurology Series 70, 4th ed. New York: Oxford University Press, 2006: 762 p.
3.
Zetusky WJ, Jankovic J, Pirozzolo FJ. The heterogeneity of Parkinson’s disease: clinical and prognostic implications. Neurology 1985;35:522-526.
4.
Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA. Heterogeneity of Parkinson’s disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005;76:343-348.
5.
Hoops S, Nazem S, Siderowf AD, et al. Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease. Neurology 2009;73:1738-1745.
6.
Bronstein AM, Kennard C. Predictive ocular motor control in Parkinson’s disease. Brain 1985;108:925-940.
7.
Mosimann UP, Muri RM, Burn DJ, Felblinger J, O’Brien JT, McKeith IG. Saccadic eye movement changes in Parkinson’s disease dementia and dementia with Lewy bodies. Brain 2005;128: 1267-1276.
8.
Perneczky R, Ghosh BC, Hughes L, Carpenter RH, Barker RA, Rowe JB. Saccadic latency in Parkinson’s disease correlates with executive function and brain atrophy, but not motor severity. Neurobiol Dis 2011;43:79-85.
9.
Archibald NK, Hutton SB, Clarke MP, Mosimann UP, Burn DJ. Visual exploration in Parkinson’s disease and Parkinson’s disease dementia. Brain 2013;136:739-750.
10.
van Stockum S, MacAskill M, Anderson T, Dalrymple-Alford J. Don’t look now or look away: two sources of saccadic disinhibition in Parkinson’s disease? Neuropsychologia 2008;46:3108-3115.
11.
Antoniades CA, Demeyere N, Kennard C, Humphreys GW, Hu MT. Antisaccades and executive dysfunction in early drug-naive Parkinson’s disease: the discovery study. Mov Disord 2015;30:843-847.
12.
Hutton SB, Ettinger U. The antisaccade task as a research tool in psychopathology: a critical review. Psychophysiology 2006;43:302313.
13.
Robbins TW, Cools R. Cognitive deficits in Parkinson’s disease: a cognitive neuroscience perspective. Mov Disord 2014;29:597-607.
Antisaccades and Executive Dysfunction in PD: Two Sides of the Same Coin? Paresh A. Malhotra, PhD, MRCP and Adolfo M. Bronstein, PhD, FRCP* Division of Brain Sciences, Imperial College, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, United Kingdom
Over recent decades, the fact that, in addition to its cardinal motor features, Parkinson’s disease (PD) is undoubtedly associated with both cognitive impairment1 and abnormalities of eye movements2 has become increasingly clear. With respect to the former, dementia is increasingly recognized in PD and is associated with increased morbidity and mortality. It appears to be very closely linked to increasing age but is also more likely to occur in those individuals with akinetic-rigid presentations, whereas patients with a tremor-dominant form of the disease show less cognitive impairment and are less likely to develop dementia.3,4 However, cognitive impairment in the context of PD, particularly in the early stages, is not always immediately obvious with a tool such as the MiniMental State Examination, often requiring more targeted or detailed neuropsychological assessment before it is identified.5 Similarly, abnormalities of eye movements in idiopathic PD tend not to be obvious on standard clinical assessment and are more likely to be revealed with eye-tracking equipment in the research setting, where patients’ saccades can become hypometric, typically during specific “higher-order” stimuli paradigms.6 An increasing body of evidence links these two sets of findings, showing that eye movements and visual task performance are more affected in those individuals with PD who have cognitive impairment.7 In particular, saccadic latency has been found to correlate with executive dysfunction rather than motor severity,8 PD patients with cognitive impairment are more likely to make errors on visuospatial tasks than patients without cognitive impairment,9 and, most pertinent to the current study, increased antisaccade latencies correlate with reduced working memory performance.10 However, these studies have been con-
-----------------------------------------------------------*E-mail: [email protected]
Relevant conflicts of interest/financial disclosures: Dr Paresh Malhotra receives research funding from the Higher Education Council for England. Professor Adolfo Bronstein’s research is funded by the Medical Research Council (UK). Received: 3 February 2015; Accepted: 8 February 2015 Published online 15 March 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/mds.26211
founded to some extent by the effects of long-term dopaminergic treatment, making determination of the exact relationship between eye movement abnormalities, cognitive deficits, and motor symptom progression in PD particularly difficult. In this issue, Antoniades and colleagues describe their findings from a detailed examination of cognition and oculomotor function in 19 drug-na€ıve patients with Parkinson’s disease.11 These individuals, all with an akinetic-rigid rather than a tremor-dominant presentation, showed no evidence of any abnormality of standard prosaccadic (ie, making saccades toward a visible target) latencies as compared with 20 healthy volunteers, and no correlation was seen between latencies and Unified Parkinson’s Disease Rating Scale III score. However, when patients were tested with an antisaccade protocol, where they were instructed to look away from a newly appeared target stimulus, they made almost twice as many errors as control subjects. These errors correlated with Unified Parkinson’s Disease Rating Scale III, and even more strongly with switch cost on the trails test and performance on a rule-finding task, both of which are measures of executive function. The authors, citing evidence from imaging studies and neurophysiological work in primates, propose that these impairments in eye movement control and flexible cognitive behavior are likely to be secondary to effects on prefrontal cortex, and because they found no abnormality of verbal fluency, even though these processes also appear to involve prefrontal regions, they suggest that fluency tasks are more insensitive to small degrees of dysfunction. Antisaccade tasks have been used to probe cognition in a number of diseases, including Alzheimer’s disease and schizophrenia, and have been shown to be particularly sensitive to frontal damage and dysfunction.12 As well as reflecting inhibitory processes, accurate performance on antisaccade paradigms requires intact spatial working memory and attention, although the patients in the current study were not formally tested in these cognitive domains. The results described by Antoniades et al. provide further strong evidence linking eye movement abnormalities and cognitive impairments in PD, with the
Movement Disorders, Vol. 30, No. 6, 2015
745
M A L H O T R A
A N D
B R O N S T E I N
recruitment of a drug-na€ıve cohort making them particularly compelling. A further point to draw from the findings is that drug-na€ıve patients appear to manifest no abnormalities of latencies for prosaccades to a peripheral target, although whether this finding extends to saccades made during visual exploration or completion of a cognitively demanding task remains to be seen. Although the authors’ account focuses on the prefrontal cortex, they suggest that its operation is being impacted by basal ganglia changes, and as this implies, it is likely that both anti-saccades and these aspects of executive function are dependent on intact fronto-striatal networks,13 and dysfunction of any part of the circuit thus may lead to impaired performance in both these domains. Antoniades and colleagues state that they plan to follow this patient group longitudinally to ascertain whether saccadometry and executive function tasks may predict future characteristics of the disease process. One further aspect of any such longitudinal study that will be of particular interest will be the effect of commencing dopaminergic therapy, and we look forward to their findings.
References 1.
746
Lees AJ, Smith E. Cognitive deficits in the early stages of Parkinson’s disease. Brain 1983;106:257-270.
Movement Disorders, Vol. 30, No. 6, 2015
2.
Leigh RJ, Zee DS. The Neurology of Eye Movements. In: Contemporary Neurology Series 70, 4th ed. New York: Oxford University Press, 2006: 762 p.
3.
Zetusky WJ, Jankovic J, Pirozzolo FJ. The heterogeneity of Parkinson’s disease: clinical and prognostic implications. Neurology 1985;35:522-526.
4.
Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA. Heterogeneity of Parkinson’s disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005;76:343-348.
5.
Hoops S, Nazem S, Siderowf AD, et al. Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease. Neurology 2009;73:1738-1745.
6.
Bronstein AM, Kennard C. Predictive ocular motor control in Parkinson’s disease. Brain 1985;108:925-940.
7.
Mosimann UP, Muri RM, Burn DJ, Felblinger J, O’Brien JT, McKeith IG. Saccadic eye movement changes in Parkinson’s disease dementia and dementia with Lewy bodies. Brain 2005;128: 1267-1276.
8.
Perneczky R, Ghosh BC, Hughes L, Carpenter RH, Barker RA, Rowe JB. Saccadic latency in Parkinson’s disease correlates with executive function and brain atrophy, but not motor severity. Neurobiol Dis 2011;43:79-85.
9.
Archibald NK, Hutton SB, Clarke MP, Mosimann UP, Burn DJ. Visual exploration in Parkinson’s disease and Parkinson’s disease dementia. Brain 2013;136:739-750.
10.
van Stockum S, MacAskill M, Anderson T, Dalrymple-Alford J. Don’t look now or look away: two sources of saccadic disinhibition in Parkinson’s disease? Neuropsychologia 2008;46:3108-3115.
11.
Antoniades CA, Demeyere N, Kennard C, Humphreys GW, Hu MT. Antisaccades and executive dysfunction in early drug-naive Parkinson’s disease: the discovery study. Mov Disord 2015;30:843-847.
12.
Hutton SB, Ettinger U. The antisaccade task as a research tool in psychopathology: a critical review. Psychophysiology 2006;43:302313.
13.
Robbins TW, Cools R. Cognitive deficits in Parkinson’s disease: a cognitive neuroscience perspective. Mov Disord 2014;29:597-607.
