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Cognitive dysfunction associated with falls in progressive supranuclear palsy
Gait & Posture 40 (2014) 605–609
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Gait & Posture journal homepage: www.elsevier.com/locate/gaitpost
Cognitive dysfunction associated with falls in progressive supranuclear palsy Sha-Lom Kim, Myung-Jun Lee 1, Myung-Sik Lee * Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history: Received 31 December 2013 Received in revised form 12 June 2014 Accepted 8 July 2014
Background: Attentional and executive dysfunctions are associated with falls in community-dwelling elderly individuals and patients with PD. Frontal cognitive dysfunction and falls are frequent symptoms of PSP. We studied to identify the cognitive domains associated with recurrent falls in patients with PSP. Methods: We performed a battery of neuropsychological tests in 59 individuals with probable PSP. We categorized patients into infrequent fall (one fall during the last 12 months, n = 29) or recurrent fall (two falls during the last 12 months, n = 30) groups. Results: UPDRS subscores for axial deficits were significantly higher in the recurrent fall group than the infrequent fall group, but there were no significant differences in UPDRS total motor scores or subscores for bradykinesia, rigidity, and tremor. There was no difference between groups in MMSE scores. ANCOVA with adjustment for confounding factors showed that, recurrent falls were associated with abnormalities in alternating hand movement, alternating square and triangle, RCFT copying task, and ideomotor apraxia. Group difference of abnormalities in Stroop test was marginal (p = 0.054). However, there were no group differences in the frequency of abnormalities in forward or backward digit span, motor impersistence, fist-edge-palm, contrast programming, go-no-go, Luria loop drawing, or Controlled Oral Word Association Tests. Recurrent falls were not associated with memory or language dysfunction. Conclusions: Recurrent falls in patients with PSP were associated mainly with executive and visuospatial dysfunctions, including (1) impaired coordinated alternating uni- and bimanual motor programming and execution, (2) deficit of attention and decision making in the presence of interference, (3) visuospatial misperception and (4) ideomotor apraxia. ß 2014 Elsevier B.V. All rights reserved.
Keywords: Progressive supranuclear palsy Fall Executive dysfunction Visuospatial dysfunction
1. Introduction Falling is one of the most common and earliest manifestations of progressive supranuclear palsy (PSP) [1,2]. Falls have a significant impact on patients with PSP, leading to physical injury, restricted mobility, hospitalization, and placement in nursing homes [3]. As falls are resistant to medical treatment, they are a major risk factor for mortality in patients with PSP [1]. Many studies report that falls in patients with Parkinson’s disease (PD) are independently associated with cognitive dysfunction, particularly deficits in attentional and executive function [4]. Such frontal cognitive dysfunction is frequent and prominent in
* Corresponding author at: Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul, Republic of Korea. Tel.: +82 22019 3322; fax: +82 23462 5904. E-mail address: [email protected] (M.-S. Lee). 1 Present address at: Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine, Pusan, Republic of Korea. http://dx.doi.org/10.1016/j.gaitpost.2014.07.005 0966-6362/ß 2014 Elsevier B.V. All rights reserved.
patients with PSP [5,6]. Therefore, it is plausible that frontal cognitive dysfunction contributes to early and frequent falls in PSP patients [6]. Searching Medline up to 2013, we found only one study on the relationship between cognitive dysfunction and falling in patients with PSP [7]. In that study, PSP rating scale mental exam subscore (e.g., disorientation, bradyphrenia, emotional incontinence, and grasping/imitative/utilizing behavior) was significantly lower in PSP patients with frequent falls (>one fall/month) compared with those with infrequent falls(one fall/month). However, there was no group difference in cognitive dysfunction as measured by the Mini-Mental State Examination (MMSE) or the Frontal Assessment Battery (FAB). The MMSE and FAB, however, are not adequate for systematic cognitive functional assessment [8]. Furthermore, the previous study included only 26 patients with PSP and did not adjust for confounding factors that may influence the frequency of falls (e.g. severity of axial motor deficits) and the severity of cognitive dysfunction (e.g. age and education level). Here, we performed validated systematic neuropsychological function tests in 59
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untreated patients with a clinical diagnosis of probable PSP. We compared the frequency of attentional, executive, visuospatial construction, visual and verbal memory, and language-related functional abnormalities between PSP patients with infrequent (one fall during the last 12 months, n = 29) and recurrent (two falls during the last 12 months, n = 30) falls. 2. Subjects and methods 2.1. Subjects Subjects were 62 untreated Parkinsonian patients fulfilling the National Institute of Neurological Disorders and Stroke criteria for probable PSP, with disease durations ranging from 1 to 5 years [9]. Clinical diagnoses for all of 62 patients were supported by anatomical evidence from brain magnetic resonance imaging (e.g., prominent midbrain atrophy, dilatation of the third ventricle, and presence of the hummingbird sign). Because low physical activity may reduce the frequency of falls, we excluded three patients who were unable to walk independently [7]. We collected the history of falls from patients and their family members or caregivers. We categorized patients who had fallen no or one time during the last 12 months into the infrequent fall group (n = 29) and those who had fallen two or more times during the last 12 months into the recurrent fall group (n = 30) [3]. Parkinsonian motor deficits were scored using the Unified Parkinson’s Disease Rating Scale (UPDRS). We calculated UPDRS subscores for severity of tremor (items 20 and 21), rigidity (item 22), bradykinesia (items 23–26), and axial motor deficits (items 27, 28, 29, and 30). The present study had been approved by institutional review board of Gangnam Severance Hospital (IRB no. 3-2013-0004). 2.2. Neuropsychological assessment All participants underwent the MMSE for the assessment of global cognitive function. They also underwent a battery of neuropsychological function tests [Seoul Neuropsychological Screening Battery (SNSB)] [10]. The SNSB included forward and backward digit span tests for the assessment of attention and several tests for the measurement of executive function (e.g., motor impersistence, contrast programming, go-no-go test, Luria loop drawing, alternating square and triangle for inhibition of inappropriate response or perseveration, fist-edge-palm test and alternating movements for motor programming and execution, Stroop test for sensitivity to interference, and semantic and phonemic Controlled Oral Word Association Tests for mental flexibility). The SNSB included Rey–Osterrieth Complex Figure Test (RCFT) copying task for the assessment of visuospatial perception. Visuospatial immediate and delayed recall and recognition were
tested using RCFT. Verbal analogs were assessed with the Seoul Verbal Learning Test (SVLT), which included three learning-free recall trials of 12 words, a 20-min delayed recall trial of the 12 target words, and a yes/no recognition test including 12 target and 12 non-target words. The SNSB also included the Korean version of the Boston Naming Test for language function, with the 60 linedrawing pictures adapted for Korean culture. Also, there were several items for the assessment of language-related function (i.e., spontaneous speech, comprehension, repetition, reading, writing, calculation, finger naming, left-right orientation, body part identification, and praxis). MMSE and SNSB scores were compared with scores of 447 age-, sex-, and education level-matched healthy individuals, and those lower than the 16th percentile of the norm were considered abnormal. 2.3. Statistics Group differences in age, disease duration, UPDRS total motor score, and UPDRS subscores were analyzed using Mann–Whitney U-tests. Sex ratios were compared using Chi-square tests. Between-group comparisons of each SNSB items were performed using analysis of covariance (ANCOVA) to examine specific cognitive dysfunction related with recurrent falls. Results were adjusted for duration of disease, UPDRS total motor score, and UPDRS subscores for rigidity, tremor, bradykinesia and axial motor deficits. We did not control age, sex, and education period, because they were already adjusted for norms of neurospychological test. Statistical analyses were performed using SPSS version 20.0. 3. Results 3.1. Characteristics of infrequent and recurrent fall groups (Table 1) There was no significant difference in age between infrequent and recurrent fall group (Mann–Whitney U-test, p = 0.274). Likewise, sex ratios were not significantly different between groups. Both groups had the same median disease duration (3.0 years). Infrequent and recurrent fall group showed no significant differences in UPDRS total motor score or UPDRS subscores for bradykinesia, rigidity, and tremor. Recurrent fall group, however, had a significantly higher UPDRS subscore for axial motor deficits than infrequent fall group (p = 0.049). 3.2. Neuropsychological abnormalities of infrequent and recurrent fall groups (Table 2) Infrequent and recurrent fall group showed no significant difference in global cognitive dysfunction as measured by the MMSE. Also, there was no significant group difference in the frequency of abnormalities in the forward or backward digit span test. Abnormalities in alternating hand movements, alternating square and triangle were more frequent in recurrent fall group than infrequent fall group. Group differences in the abnormal Stroop test was marginal (p = 0.054). However, infrequent and recurrent fall group showed no significant differences in frequency of abnormalities in tests of executive function, including motor impersistence, go-no-go, fist-edge-palm, Luria loop drawing. Also, there were no significant differences in the frequency of abnormalities in the semantic and phonemic Controlled Oral Word Association Tests. Recurrent fall group showed more frequent abnormalities in the RCFT copying task than infrequent fall group, but there were no significant group differences in the frequency of abnormalities in RCFT immediate
Table 1 Comparisons of clinical characteristics between PSP patients with infrequent and recurrent falls.
Age (median; yrs) Sex (male/female) Disease duration (median; yrs) UPDRS score (median) Total Tremor Rigidity Bradykinesia Axial
Infrequent fall group (n = 29)
Recurrent fall group (n = 30)
p
71.0 (45.0–84.0) 19/10 3.0(1.0–5.0)
74.0 (58.0–88.0) 15/15 3.0(1.0–5.0)
0.274a 0.228b 0.981a
29.0 (14.0–64.0) 2.0 (0.0–7.0) 7.0 (1.0–15.0) 10.0 (3.0–28.0) 4.0 (2.0–12.0)
29.0 (14.0–61.0) 2.0 (0.0–7.0) 5.5 (1.0–18.0) 11.0 (5.0–25.0) 6.0 (2.0–14.0)
0.710a 0.478a 0.093a 0.276a 0.049a
Infrequent fall group: fall 1time per year, Recurrent fall group: fall 2 times per year. Abbreviations: PSP, progressive supranuclear palsy; UPDRS, Unified Parkinson’s Disease Rating Scale. Numbers in parentheses = range. a Mann–Whitney test. b Chi-square test,
S.-L. Kim et al. / Gait & Posture 40 (2014) 605–609
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Table 2 Comparisons of frequency of abnormalities in different cognitive domains between PSP patients with infrequent and recurrent falls. Infrequent fall group
Recurrent fall group
% abnormal (n)
% abnormal (n)
F
p
37.9 (11)
50.0 (15)
0.330
0.568
13.8 (4) 17.2 (5)
10.0 (3) 30.0 (9)
5.347 2.789
0.065 0.101
0.0 25.0 21.4 17.8 24.1 14.3 14.3
6.7 43.3 34.5 53.3 53.3 51.7 30.0
(2) (13) (10) (16) (16) (15) (9)
1.136 2.002 0.990 5.520 3.916 4.772 1.665
0.292 0.163 0.325 0.023 0.053 0.034 0.203
44.8 (13) 37.9 (11)
70.0 (21) 53.3 (16)
0.836 0.176
0.365 0.677
44.4 (12) 51.9 (14)
72.0 (18) 67.9 (19)
3.676 3.896
0.062 0.054
18.5 (5)
55.6 (15)
4.868
0.032
51.9 (14) 39.3 (11) 28.6 (8)
60.7 (17) 59.3 (16) 37.0 (10)
1.799 1.244 0.029
0.186 0.270 0.867
37.9 (11) 37.9 (11) 17.2 (5)
50.0 (15) 50.0 (15) 36.7 (11)
0.932 2.156 1.831
0.339 0.148 0.182
41.4 (12)
51.9 (14)
2.440
0.125
10.3 (3) 3.4 (1) 17.2 (5) 0 (0) 7.1 (2) 27.6 (8) 13.8 (4) 6.9 (2) 0 (0)
6.7 3.3 24.1 6.7 20.0 40.0 20.0 13.3 10.0
(2) (1) (7) (2) (6) (12) (6) (4) (3)
0.395 0.052 0.000 0.610 0.002 0.653 0.006 0.259 2.467
0.532 0.820 0.983 0.439 0.965 0.219 0.938 0.613 0.122
21.4 (6) 0 (0)
36.7 (11) 3.3 (1)
4.608 0.704
0.037 0.405
Mini Mental State Examination Seoul Neuropsychological Screening Battery Attention Digit span Forward Backward Executive function Motor impersistence Contrast programming Go-no-go test Alternating hand movement Fist-edge-palm Alternating square and triangle Luria loop drawing COWAT Semantic Animal Supermarket Phonemic Total Stroop test Visuospatial RCFT copy Memory Visuospatial (RCFT) Immediate recall Delayed recall Recognition Verbal (SVLT) Immediate recall Delayed recall Recognition Language and related function Naming Spontaneous speech Fluency Comprehension Repetition Reading Writing Calculation Finger naming Rt. Lt. orientation Body part identification Praxis Ideomotor Buccofacial
(0) (7) (6) (5) (7) (4) (4)
Infrequent fall group: fall 1time per year, recurrent fall group: fall 2 times per year. Abbreviations: COWAT, Controlled Oral Word Association Test; PSP, progressive supranuclear palsy; RCFT, Rey–Osterrieth Complex Figure Test; SVLT, Seoul Verbal Learning Test. recall, delayed recall, and recognition. Ideomotor apraxia was more frequently associated with recurrent fall group. Finally, no significant differences between groups were found in the frequency of abnormalities in verbal memory or languagerelated functions.
4. Discussion The present study showed that global cognitive dysfunction and parkinsoinan motor deficits, except for axial motor deficits, did not contribute to frequent falls in patients with PSP [7,11]. Recurrent falls were not associated with abnormalities in several executive (e.g., forward or backward digit span, motor impersistence, go-nogo test for set shifting, fist-edge-palm test for motor programming, Luria loop drawing), visual and verbal memory, and languagerelated functions. However, recurrent falls in PSP patients were associated with some executive and visuospatial dysfunctions (e.g., alternating hand movements, alternating square and triangle, Stroop test, RCFT copying task, and ideomotor apraxia).
Falls in patients with parkinsonian syndrome have been attributed to (1) lack of anticipatory postural adjustment [12], (2) reduced postural security range (i.e., reduced maximum inclination up to the limit of postural stability) [13], (3) impaired adaptive sensory re-weighting (i.e., increased dependence on visual information) [13], (4) inefficient postural responses (i.e., delayed onset of small amplitude and slow compensatory stepping movements) [12] and (5) gait disturbances (i.e., leg dragging, stride-to-stride variability, and gait freezing) [4,14]. Abnormal axial postural orientation, axial Parkinsonian motor deficits, downgaze palsy, and abnormal otolith-mediated reflexes contribute to frequent falls in patients with PSP [6,7,15]. Cognitive function also plays an important role in the maintenance of dynamic balance, particularly when there are unexpected changes in internal sensory inputs or the external environment. Increasing evidence suggests that even subtle cognitive dysfunctions may increase the risk of falls in patients with PD [13]. Falls are associated with abnormalities in specific
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cognitive domains but not with a global decline in cognitive function [16]. In the present study, recurrent falls in patients with PSP were associated with abnormalities in alternating movements. However, there were no significant differences between groups in UPDRS total motor or UPDRS subscores for bradykineisa, rigidity, and tremor. Furthermore, abnormalities in fist-edge-palm tests were not associated with recurrent falls. Therefore, frequent abnormalities of alternating movements in recurrent fallers were not attributed solely to motor disturbances of the arms. Both fist-edge-palm and alternating movement tests assess sequential motor programming and execution ability [8]. However, alternating movements need additional delicate bimanual coordination. We suspect that impairment in alternating movements share a similar neuronal mechanism with stride-to stride variability in bipedal human walking, which is strongly associated with falls in community-dwelling individuals and patients with PD and Alzheimer’s disease [17–19]. In PD and PSP patients, concomitant cognitive or motor task performance interferes with postural control. Shifting attention to the secondary task, which consequently reduces attention to the primary task (i.e., postural control), reveals postural instability related to basal ganglia dysfunction [20]. Based on these findings, previous studies have emphasized the important role of attention in gait control and postural stability [16,20]. In the present study, there was group difference in alternating square and triangle which is related to perseveration. Selective attention and inhibitory control is needed to control alternative movements and prevent perseveration [21]. The Stroop test also has been used to assess the ability to select and execute proper motor behavior in the presence of interference. Such cognitive functions are needed to inhibit automatic responses to irrelevant stimuli and maintain stability [8,22]. A close relationship has been reported between falls and poor performance in the Stroop test among community-dwelling individuals [23]. In addition, in patients with PD, poor performance in the Stroop test correlates with high stride variability that makes vulnerable to falls [22]. The present study also showed marginal associations between recurrent falls and Stroop test abnormalities. The processing of visual information about one’s surroundings plays an important role in the adjustment of ongoing gait parameters and the maintenance of postural stability [24]. Indeed, recent studies of patients with PD demonstrated that disturbances in postural stability correlate with visuospatial dysfunction but not attentional or executive dysfunction [25]. Visuospatial dysfunction is usually mild but frequent in patients with PSP [5]. In the present study, recurrent falls in patients with PSP were associated with abnormalities in visual perceptual and constructional abilities as measured by the RCFT copying task [26]. This finding supports the importance of visuospatial function to postural stability in patients with PSP. However, we cannot exclude an independent contribution of gaze palsy to RCFT copying task abnormalities and more frequent falls in patients with PSP [5– 7,15]. Finally, ideomotor apraxia was more frequently impaired in recurrent fall group. Left Frontoparietal connection lesion has been thought to main area of the ideomotor apraxia. Ideomotor apraxia can be resulted from spatial and temporal errors that are related to visuospatial and executive dysfunction [27]. Deficits in high level representation of body posture associated with ideomotor apraxia may lead to reduced postural response in PSP patients [28]. A functional brain imaging study of patients with PSP demonstrated an association between falls and reduced cholinergic activity in the thalamus [15]. Thalamic cholinergic inputs arise mainly from the pedunculopontine nucleus (PPN), which is a site of severe neuronal loss in PSP [29]. Animals with PPN lesions exhibit
executive and working memory dysfunction [30]. Also, in patients with PD, deep brain stimulation of the PPN may improve working memory and reduce falls [31,32]. Therefore, the loss of ascending cholinergic projections from the PPN to the thalamus might be a common pathological substrate responsible for cognitive dysfunction and frequent falls in patients with PSP. However, limited effects of cholinergic agents on falls among PSP patients suggest that there may be several underlying mechanisms [11]. Further large and well-designed studies for agents strongly effects for executive and visuospatial function are needed for management of falls in patients with PSP. Some limitations of the present study must be acknowledged. In particular, the cross-sectional design does not allow one to determine a causal relationship between cognitive dysfunctions and recurrent falls. Another shortcoming is the dependence on self-reports of the frequency of falls in the last 12 months, which may limit the reliability of the findings. In summary, recurrent falls in patients with PSP were associated with more errors in complex executive function tests and poorer performance in visuospatial function tests [24]. However, it is uncertain whether such executive and visuospatial dysfunctions were a cause of recurrent falls or epiphenomena of pathologies in subcortical areas involved in the maintenance of postural stability. Conflict of interests The authors have no financial conflicts of interest. Funding The corresponding author has been supported by a faculty grant of Yonsei University College of Medicine (grant number 6-2010-0016). Acknowledgements We appreciate to professor Kyungha Seok (Department of Statistics, Inje Uinversity, Busan, Korea) and professor Sang Jin Kim (Department of neurology, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea) for helping statistical analysis. References [1] Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Burn DJ. Clinical features and natural history of progressive supranuclear palsy: a clinical cohort study. Neurology 2003;60:910–6. [2] Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 2009;8:270–9. [3] O‘Sullivan SS, Massey LA, Williams DR, Silveira-Moriyama L, Kempster PA, Holton JL, et al. Clinical outcomes of progressive supranuclear palsy and multiple system atrophy. Brain 2008;131:1362–72. [4] Latt MD, Lord SR, Morris JG, Fung VS. Clinical and physiological assessments for elucidating falls risk in Parkinson’s disease. Mov Disord 2009;24:1280–9. [5] Cordato NJ, Halliday GM, Caine D, Morris JG. Comparison of motor, cognitive, and behavioral features in progressive supranuclear palsy and Parkinson’s disease. Mov Disord 2006;21:632–8. [6] Williams DR, Watt HC, Lees AJ. Predictors of falls and fractures in bradykinetic rigid syndromes: a retrospective study. J Neurol Neurosurg Psychiatry 2006;77:468–73. [7] Lindemann U, Nicolai S, Beische D, Becker C, Srulijes K, Dietzel E, et al. Clinical and dual-tasking aspects in frequent and infrequent fallers with progressive supranuclear palsy. Mov Disord 2010;25:1040–6. [8] Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a frontal assessment battery at bedside. Neurology 2000;55:1621–6. [9] Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele– Richardson–Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996;47:1–9. [10] Kang Y, Na DL. Seoul neuropsychological screening battery (SNSB). Incheon, South Korea: Human Brain Research & Consulting Co.; 2003. [11] Sidiropoulos C, Lewitt PA. Localizing imbalance in progressive supranuclear palsy: is the thalamus the ‘‘fall guy’’. Neurology 2011;77:92–3.
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Contents lists available at ScienceDirect
Gait & Posture journal homepage: www.elsevier.com/locate/gaitpost
Cognitive dysfunction associated with falls in progressive supranuclear palsy Sha-Lom Kim, Myung-Jun Lee 1, Myung-Sik Lee * Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history: Received 31 December 2013 Received in revised form 12 June 2014 Accepted 8 July 2014
Background: Attentional and executive dysfunctions are associated with falls in community-dwelling elderly individuals and patients with PD. Frontal cognitive dysfunction and falls are frequent symptoms of PSP. We studied to identify the cognitive domains associated with recurrent falls in patients with PSP. Methods: We performed a battery of neuropsychological tests in 59 individuals with probable PSP. We categorized patients into infrequent fall (one fall during the last 12 months, n = 29) or recurrent fall (two falls during the last 12 months, n = 30) groups. Results: UPDRS subscores for axial deficits were significantly higher in the recurrent fall group than the infrequent fall group, but there were no significant differences in UPDRS total motor scores or subscores for bradykinesia, rigidity, and tremor. There was no difference between groups in MMSE scores. ANCOVA with adjustment for confounding factors showed that, recurrent falls were associated with abnormalities in alternating hand movement, alternating square and triangle, RCFT copying task, and ideomotor apraxia. Group difference of abnormalities in Stroop test was marginal (p = 0.054). However, there were no group differences in the frequency of abnormalities in forward or backward digit span, motor impersistence, fist-edge-palm, contrast programming, go-no-go, Luria loop drawing, or Controlled Oral Word Association Tests. Recurrent falls were not associated with memory or language dysfunction. Conclusions: Recurrent falls in patients with PSP were associated mainly with executive and visuospatial dysfunctions, including (1) impaired coordinated alternating uni- and bimanual motor programming and execution, (2) deficit of attention and decision making in the presence of interference, (3) visuospatial misperception and (4) ideomotor apraxia. ß 2014 Elsevier B.V. All rights reserved.
Keywords: Progressive supranuclear palsy Fall Executive dysfunction Visuospatial dysfunction
1. Introduction Falling is one of the most common and earliest manifestations of progressive supranuclear palsy (PSP) [1,2]. Falls have a significant impact on patients with PSP, leading to physical injury, restricted mobility, hospitalization, and placement in nursing homes [3]. As falls are resistant to medical treatment, they are a major risk factor for mortality in patients with PSP [1]. Many studies report that falls in patients with Parkinson’s disease (PD) are independently associated with cognitive dysfunction, particularly deficits in attentional and executive function [4]. Such frontal cognitive dysfunction is frequent and prominent in
* Corresponding author at: Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul, Republic of Korea. Tel.: +82 22019 3322; fax: +82 23462 5904. E-mail address: [email protected] (M.-S. Lee). 1 Present address at: Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine, Pusan, Republic of Korea. http://dx.doi.org/10.1016/j.gaitpost.2014.07.005 0966-6362/ß 2014 Elsevier B.V. All rights reserved.
patients with PSP [5,6]. Therefore, it is plausible that frontal cognitive dysfunction contributes to early and frequent falls in PSP patients [6]. Searching Medline up to 2013, we found only one study on the relationship between cognitive dysfunction and falling in patients with PSP [7]. In that study, PSP rating scale mental exam subscore (e.g., disorientation, bradyphrenia, emotional incontinence, and grasping/imitative/utilizing behavior) was significantly lower in PSP patients with frequent falls (>one fall/month) compared with those with infrequent falls(one fall/month). However, there was no group difference in cognitive dysfunction as measured by the Mini-Mental State Examination (MMSE) or the Frontal Assessment Battery (FAB). The MMSE and FAB, however, are not adequate for systematic cognitive functional assessment [8]. Furthermore, the previous study included only 26 patients with PSP and did not adjust for confounding factors that may influence the frequency of falls (e.g. severity of axial motor deficits) and the severity of cognitive dysfunction (e.g. age and education level). Here, we performed validated systematic neuropsychological function tests in 59
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untreated patients with a clinical diagnosis of probable PSP. We compared the frequency of attentional, executive, visuospatial construction, visual and verbal memory, and language-related functional abnormalities between PSP patients with infrequent (one fall during the last 12 months, n = 29) and recurrent (two falls during the last 12 months, n = 30) falls. 2. Subjects and methods 2.1. Subjects Subjects were 62 untreated Parkinsonian patients fulfilling the National Institute of Neurological Disorders and Stroke criteria for probable PSP, with disease durations ranging from 1 to 5 years [9]. Clinical diagnoses for all of 62 patients were supported by anatomical evidence from brain magnetic resonance imaging (e.g., prominent midbrain atrophy, dilatation of the third ventricle, and presence of the hummingbird sign). Because low physical activity may reduce the frequency of falls, we excluded three patients who were unable to walk independently [7]. We collected the history of falls from patients and their family members or caregivers. We categorized patients who had fallen no or one time during the last 12 months into the infrequent fall group (n = 29) and those who had fallen two or more times during the last 12 months into the recurrent fall group (n = 30) [3]. Parkinsonian motor deficits were scored using the Unified Parkinson’s Disease Rating Scale (UPDRS). We calculated UPDRS subscores for severity of tremor (items 20 and 21), rigidity (item 22), bradykinesia (items 23–26), and axial motor deficits (items 27, 28, 29, and 30). The present study had been approved by institutional review board of Gangnam Severance Hospital (IRB no. 3-2013-0004). 2.2. Neuropsychological assessment All participants underwent the MMSE for the assessment of global cognitive function. They also underwent a battery of neuropsychological function tests [Seoul Neuropsychological Screening Battery (SNSB)] [10]. The SNSB included forward and backward digit span tests for the assessment of attention and several tests for the measurement of executive function (e.g., motor impersistence, contrast programming, go-no-go test, Luria loop drawing, alternating square and triangle for inhibition of inappropriate response or perseveration, fist-edge-palm test and alternating movements for motor programming and execution, Stroop test for sensitivity to interference, and semantic and phonemic Controlled Oral Word Association Tests for mental flexibility). The SNSB included Rey–Osterrieth Complex Figure Test (RCFT) copying task for the assessment of visuospatial perception. Visuospatial immediate and delayed recall and recognition were
tested using RCFT. Verbal analogs were assessed with the Seoul Verbal Learning Test (SVLT), which included three learning-free recall trials of 12 words, a 20-min delayed recall trial of the 12 target words, and a yes/no recognition test including 12 target and 12 non-target words. The SNSB also included the Korean version of the Boston Naming Test for language function, with the 60 linedrawing pictures adapted for Korean culture. Also, there were several items for the assessment of language-related function (i.e., spontaneous speech, comprehension, repetition, reading, writing, calculation, finger naming, left-right orientation, body part identification, and praxis). MMSE and SNSB scores were compared with scores of 447 age-, sex-, and education level-matched healthy individuals, and those lower than the 16th percentile of the norm were considered abnormal. 2.3. Statistics Group differences in age, disease duration, UPDRS total motor score, and UPDRS subscores were analyzed using Mann–Whitney U-tests. Sex ratios were compared using Chi-square tests. Between-group comparisons of each SNSB items were performed using analysis of covariance (ANCOVA) to examine specific cognitive dysfunction related with recurrent falls. Results were adjusted for duration of disease, UPDRS total motor score, and UPDRS subscores for rigidity, tremor, bradykinesia and axial motor deficits. We did not control age, sex, and education period, because they were already adjusted for norms of neurospychological test. Statistical analyses were performed using SPSS version 20.0. 3. Results 3.1. Characteristics of infrequent and recurrent fall groups (Table 1) There was no significant difference in age between infrequent and recurrent fall group (Mann–Whitney U-test, p = 0.274). Likewise, sex ratios were not significantly different between groups. Both groups had the same median disease duration (3.0 years). Infrequent and recurrent fall group showed no significant differences in UPDRS total motor score or UPDRS subscores for bradykinesia, rigidity, and tremor. Recurrent fall group, however, had a significantly higher UPDRS subscore for axial motor deficits than infrequent fall group (p = 0.049). 3.2. Neuropsychological abnormalities of infrequent and recurrent fall groups (Table 2) Infrequent and recurrent fall group showed no significant difference in global cognitive dysfunction as measured by the MMSE. Also, there was no significant group difference in the frequency of abnormalities in the forward or backward digit span test. Abnormalities in alternating hand movements, alternating square and triangle were more frequent in recurrent fall group than infrequent fall group. Group differences in the abnormal Stroop test was marginal (p = 0.054). However, infrequent and recurrent fall group showed no significant differences in frequency of abnormalities in tests of executive function, including motor impersistence, go-no-go, fist-edge-palm, Luria loop drawing. Also, there were no significant differences in the frequency of abnormalities in the semantic and phonemic Controlled Oral Word Association Tests. Recurrent fall group showed more frequent abnormalities in the RCFT copying task than infrequent fall group, but there were no significant group differences in the frequency of abnormalities in RCFT immediate
Table 1 Comparisons of clinical characteristics between PSP patients with infrequent and recurrent falls.
Age (median; yrs) Sex (male/female) Disease duration (median; yrs) UPDRS score (median) Total Tremor Rigidity Bradykinesia Axial
Infrequent fall group (n = 29)
Recurrent fall group (n = 30)
p
71.0 (45.0–84.0) 19/10 3.0(1.0–5.0)
74.0 (58.0–88.0) 15/15 3.0(1.0–5.0)
0.274a 0.228b 0.981a
29.0 (14.0–64.0) 2.0 (0.0–7.0) 7.0 (1.0–15.0) 10.0 (3.0–28.0) 4.0 (2.0–12.0)
29.0 (14.0–61.0) 2.0 (0.0–7.0) 5.5 (1.0–18.0) 11.0 (5.0–25.0) 6.0 (2.0–14.0)
0.710a 0.478a 0.093a 0.276a 0.049a
Infrequent fall group: fall 1time per year, Recurrent fall group: fall 2 times per year. Abbreviations: PSP, progressive supranuclear palsy; UPDRS, Unified Parkinson’s Disease Rating Scale. Numbers in parentheses = range. a Mann–Whitney test. b Chi-square test,
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Table 2 Comparisons of frequency of abnormalities in different cognitive domains between PSP patients with infrequent and recurrent falls. Infrequent fall group
Recurrent fall group
% abnormal (n)
% abnormal (n)
F
p
37.9 (11)
50.0 (15)
0.330
0.568
13.8 (4) 17.2 (5)
10.0 (3) 30.0 (9)
5.347 2.789
0.065 0.101
0.0 25.0 21.4 17.8 24.1 14.3 14.3
6.7 43.3 34.5 53.3 53.3 51.7 30.0
(2) (13) (10) (16) (16) (15) (9)
1.136 2.002 0.990 5.520 3.916 4.772 1.665
0.292 0.163 0.325 0.023 0.053 0.034 0.203
44.8 (13) 37.9 (11)
70.0 (21) 53.3 (16)
0.836 0.176
0.365 0.677
44.4 (12) 51.9 (14)
72.0 (18) 67.9 (19)
3.676 3.896
0.062 0.054
18.5 (5)
55.6 (15)
4.868
0.032
51.9 (14) 39.3 (11) 28.6 (8)
60.7 (17) 59.3 (16) 37.0 (10)
1.799 1.244 0.029
0.186 0.270 0.867
37.9 (11) 37.9 (11) 17.2 (5)
50.0 (15) 50.0 (15) 36.7 (11)
0.932 2.156 1.831
0.339 0.148 0.182
41.4 (12)
51.9 (14)
2.440
0.125
10.3 (3) 3.4 (1) 17.2 (5) 0 (0) 7.1 (2) 27.6 (8) 13.8 (4) 6.9 (2) 0 (0)
6.7 3.3 24.1 6.7 20.0 40.0 20.0 13.3 10.0
(2) (1) (7) (2) (6) (12) (6) (4) (3)
0.395 0.052 0.000 0.610 0.002 0.653 0.006 0.259 2.467
0.532 0.820 0.983 0.439 0.965 0.219 0.938 0.613 0.122
21.4 (6) 0 (0)
36.7 (11) 3.3 (1)
4.608 0.704
0.037 0.405
Mini Mental State Examination Seoul Neuropsychological Screening Battery Attention Digit span Forward Backward Executive function Motor impersistence Contrast programming Go-no-go test Alternating hand movement Fist-edge-palm Alternating square and triangle Luria loop drawing COWAT Semantic Animal Supermarket Phonemic Total Stroop test Visuospatial RCFT copy Memory Visuospatial (RCFT) Immediate recall Delayed recall Recognition Verbal (SVLT) Immediate recall Delayed recall Recognition Language and related function Naming Spontaneous speech Fluency Comprehension Repetition Reading Writing Calculation Finger naming Rt. Lt. orientation Body part identification Praxis Ideomotor Buccofacial
(0) (7) (6) (5) (7) (4) (4)
Infrequent fall group: fall 1time per year, recurrent fall group: fall 2 times per year. Abbreviations: COWAT, Controlled Oral Word Association Test; PSP, progressive supranuclear palsy; RCFT, Rey–Osterrieth Complex Figure Test; SVLT, Seoul Verbal Learning Test. recall, delayed recall, and recognition. Ideomotor apraxia was more frequently associated with recurrent fall group. Finally, no significant differences between groups were found in the frequency of abnormalities in verbal memory or languagerelated functions.
4. Discussion The present study showed that global cognitive dysfunction and parkinsoinan motor deficits, except for axial motor deficits, did not contribute to frequent falls in patients with PSP [7,11]. Recurrent falls were not associated with abnormalities in several executive (e.g., forward or backward digit span, motor impersistence, go-nogo test for set shifting, fist-edge-palm test for motor programming, Luria loop drawing), visual and verbal memory, and languagerelated functions. However, recurrent falls in PSP patients were associated with some executive and visuospatial dysfunctions (e.g., alternating hand movements, alternating square and triangle, Stroop test, RCFT copying task, and ideomotor apraxia).
Falls in patients with parkinsonian syndrome have been attributed to (1) lack of anticipatory postural adjustment [12], (2) reduced postural security range (i.e., reduced maximum inclination up to the limit of postural stability) [13], (3) impaired adaptive sensory re-weighting (i.e., increased dependence on visual information) [13], (4) inefficient postural responses (i.e., delayed onset of small amplitude and slow compensatory stepping movements) [12] and (5) gait disturbances (i.e., leg dragging, stride-to-stride variability, and gait freezing) [4,14]. Abnormal axial postural orientation, axial Parkinsonian motor deficits, downgaze palsy, and abnormal otolith-mediated reflexes contribute to frequent falls in patients with PSP [6,7,15]. Cognitive function also plays an important role in the maintenance of dynamic balance, particularly when there are unexpected changes in internal sensory inputs or the external environment. Increasing evidence suggests that even subtle cognitive dysfunctions may increase the risk of falls in patients with PD [13]. Falls are associated with abnormalities in specific
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cognitive domains but not with a global decline in cognitive function [16]. In the present study, recurrent falls in patients with PSP were associated with abnormalities in alternating movements. However, there were no significant differences between groups in UPDRS total motor or UPDRS subscores for bradykineisa, rigidity, and tremor. Furthermore, abnormalities in fist-edge-palm tests were not associated with recurrent falls. Therefore, frequent abnormalities of alternating movements in recurrent fallers were not attributed solely to motor disturbances of the arms. Both fist-edge-palm and alternating movement tests assess sequential motor programming and execution ability [8]. However, alternating movements need additional delicate bimanual coordination. We suspect that impairment in alternating movements share a similar neuronal mechanism with stride-to stride variability in bipedal human walking, which is strongly associated with falls in community-dwelling individuals and patients with PD and Alzheimer’s disease [17–19]. In PD and PSP patients, concomitant cognitive or motor task performance interferes with postural control. Shifting attention to the secondary task, which consequently reduces attention to the primary task (i.e., postural control), reveals postural instability related to basal ganglia dysfunction [20]. Based on these findings, previous studies have emphasized the important role of attention in gait control and postural stability [16,20]. In the present study, there was group difference in alternating square and triangle which is related to perseveration. Selective attention and inhibitory control is needed to control alternative movements and prevent perseveration [21]. The Stroop test also has been used to assess the ability to select and execute proper motor behavior in the presence of interference. Such cognitive functions are needed to inhibit automatic responses to irrelevant stimuli and maintain stability [8,22]. A close relationship has been reported between falls and poor performance in the Stroop test among community-dwelling individuals [23]. In addition, in patients with PD, poor performance in the Stroop test correlates with high stride variability that makes vulnerable to falls [22]. The present study also showed marginal associations between recurrent falls and Stroop test abnormalities. The processing of visual information about one’s surroundings plays an important role in the adjustment of ongoing gait parameters and the maintenance of postural stability [24]. Indeed, recent studies of patients with PD demonstrated that disturbances in postural stability correlate with visuospatial dysfunction but not attentional or executive dysfunction [25]. Visuospatial dysfunction is usually mild but frequent in patients with PSP [5]. In the present study, recurrent falls in patients with PSP were associated with abnormalities in visual perceptual and constructional abilities as measured by the RCFT copying task [26]. This finding supports the importance of visuospatial function to postural stability in patients with PSP. However, we cannot exclude an independent contribution of gaze palsy to RCFT copying task abnormalities and more frequent falls in patients with PSP [5– 7,15]. Finally, ideomotor apraxia was more frequently impaired in recurrent fall group. Left Frontoparietal connection lesion has been thought to main area of the ideomotor apraxia. Ideomotor apraxia can be resulted from spatial and temporal errors that are related to visuospatial and executive dysfunction [27]. Deficits in high level representation of body posture associated with ideomotor apraxia may lead to reduced postural response in PSP patients [28]. A functional brain imaging study of patients with PSP demonstrated an association between falls and reduced cholinergic activity in the thalamus [15]. Thalamic cholinergic inputs arise mainly from the pedunculopontine nucleus (PPN), which is a site of severe neuronal loss in PSP [29]. Animals with PPN lesions exhibit
executive and working memory dysfunction [30]. Also, in patients with PD, deep brain stimulation of the PPN may improve working memory and reduce falls [31,32]. Therefore, the loss of ascending cholinergic projections from the PPN to the thalamus might be a common pathological substrate responsible for cognitive dysfunction and frequent falls in patients with PSP. However, limited effects of cholinergic agents on falls among PSP patients suggest that there may be several underlying mechanisms [11]. Further large and well-designed studies for agents strongly effects for executive and visuospatial function are needed for management of falls in patients with PSP. Some limitations of the present study must be acknowledged. In particular, the cross-sectional design does not allow one to determine a causal relationship between cognitive dysfunctions and recurrent falls. Another shortcoming is the dependence on self-reports of the frequency of falls in the last 12 months, which may limit the reliability of the findings. In summary, recurrent falls in patients with PSP were associated with more errors in complex executive function tests and poorer performance in visuospatial function tests [24]. However, it is uncertain whether such executive and visuospatial dysfunctions were a cause of recurrent falls or epiphenomena of pathologies in subcortical areas involved in the maintenance of postural stability. Conflict of interests The authors have no financial conflicts of interest. Funding The corresponding author has been supported by a faculty grant of Yonsei University College of Medicine (grant number 6-2010-0016). Acknowledgements We appreciate to professor Kyungha Seok (Department of Statistics, Inje Uinversity, Busan, Korea) and professor Sang Jin Kim (Department of neurology, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea) for helping statistical analysis. References [1] Nath U, Ben-Shlomo Y, Thomson RG, Lees AJ, Burn DJ. Clinical features and natural history of progressive supranuclear palsy: a clinical cohort study. Neurology 2003;60:910–6. [2] Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 2009;8:270–9. [3] O‘Sullivan SS, Massey LA, Williams DR, Silveira-Moriyama L, Kempster PA, Holton JL, et al. Clinical outcomes of progressive supranuclear palsy and multiple system atrophy. Brain 2008;131:1362–72. [4] Latt MD, Lord SR, Morris JG, Fung VS. Clinical and physiological assessments for elucidating falls risk in Parkinson’s disease. Mov Disord 2009;24:1280–9. [5] Cordato NJ, Halliday GM, Caine D, Morris JG. Comparison of motor, cognitive, and behavioral features in progressive supranuclear palsy and Parkinson’s disease. Mov Disord 2006;21:632–8. [6] Williams DR, Watt HC, Lees AJ. Predictors of falls and fractures in bradykinetic rigid syndromes: a retrospective study. J Neurol Neurosurg Psychiatry 2006;77:468–73. [7] Lindemann U, Nicolai S, Beische D, Becker C, Srulijes K, Dietzel E, et al. Clinical and dual-tasking aspects in frequent and infrequent fallers with progressive supranuclear palsy. Mov Disord 2010;25:1040–6. [8] Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a frontal assessment battery at bedside. Neurology 2000;55:1621–6. [9] Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele– Richardson–Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996;47:1–9. [10] Kang Y, Na DL. Seoul neuropsychological screening battery (SNSB). Incheon, South Korea: Human Brain Research & Consulting Co.; 2003. [11] Sidiropoulos C, Lewitt PA. Localizing imbalance in progressive supranuclear palsy: is the thalamus the ‘‘fall guy’’. Neurology 2011;77:92–3.
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