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Original Contribution |

Cognitive Impairments in Machado-Joseph Disease FREE

Yoshinari Kawai, MD; Akinori Takeda, MD; Yuji Abe, MD; Yukihiko Washimi, MD; Fumiaki Tanaka, MD; Gen Sobue, MD
[+] Author Affiliations

Author Affiliations: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya (Drs Kawai, Takeda, Tanaka, and Sobue); and Department of Neurology, Chubu National Hospital, Aichi (Drs Abe and Washimi), Japan.


Arch Neurol. 2004;61(11):1757-1760. doi:10.1001/archneur.61.11.1757.
Text Size: A A A
Published online

Background  Cognitive function of Machado-Joseph disease (MJD) patients has not been clarified.

Objectives  To determine the characteristics of cognitive dysfunction in MJD patients and to assess the relationship of dysfunction to age at onset, age at examination, disease duration, education, ataxia, depression, anxiety, and CAG repeat length.

Design  Case-control study.

Setting  Research-oriented hospitals.

Participants  Sixteen genetically confirmed MJD patients able to complete neuropsychological tests and 20 control subjects matched to patients by age and education.

Main Outcome Measures  Neuropsychological tests, including general cognition, verbal and visual memory, working memory, visuospatial and constructional ability, language, executive function, depression, and anxiety.

Results  Machado-Joseph disease patients scored significantly lower than controls in verbal and visual memory, in visuospatial and constructional tasks, and in phonemic and semantic fluency tasks. None of these impairments correlated with CAG repeat length, age at onset, age at examination, disease duration, or education. Verbal fluency (words named in a category) correlated with the International Cooperative Ataxia Rating Scale score.

Conclusion  Machado-Joseph disease patients have verbal and visual memory deficits, visuospatial and constructional dysfunction, and verbal fluency deficits, all unrelated to CAG repeat length.

Machado-Joseph disease (MJD), first reported in North American families of Portuguese-Azorean ancestry,1 is now foundthroughout the world and is the most prevalent autosomal dominant cerebellar ataxia in North America, Europe, and much of Asia. Machado-Joseph disease is caused by an expansion of CAG trinucleotide repeats in a gene located at chromosome 14q32.1.2 The wide range of clinical manifestations includes cerebellar ataxia, pyramidal signs, progressive external ophthalmoplegia, exophthalmos, dystonia, and peripheral neuropathy. Machado-Joseph disease is a slowly progressive neurodegenerative disease, and patients typically will become confined to a wheelchair and later be bedridden.

Few reports have described cognitive impairment in MJD, and these were anecdotal or based on a small number of patients. For the most part, these previous studies lacked adequate control subjects. Therefore, no consensus concerning features of cognitive dysfunction in MJD has been established. One study3 noted slow processing of visual information in demanding tasks and deficient shifting of visual attention in 6 MJD patients. Another study4 described executive dysfunction and depressive symptoms in 6 MJD individuals. In still another study,5 only verbal memory deficits were found in MJD, while dysexecutive syndrome and verbal memory deficits were found in spinocerebellar ataxia 1 and 2.

In the present study, we evaluated a wide range of cognitive functions in a large number of Japanese MJD patients. We used well-matched control subjects to determine the characteristic features of cognitive impairments in MJD.

Sixteen genetically confirmed MJD patients and 20 control subjects were the subjects for the study. The characteristics of these subjects are shown in Table 1. All were native Japanese speakers. Severity of ataxia was rated on the International Cooperative Ataxia Rating Scale.6 Genomic DNA was extracted from patient leukocytes. MJ-N (5′-TCGTGAAACAATGTATTTTCCTTATG-3′) and MJ-RN (5′-GATGTGAACTCTGTCCTGAT-3′) were used as primer pairs for polymerase chain reaction analysis. Genomic DNA (200 ng) was subjected to polymerase chain reaction. Reaction volume was 20 μL, and amplification and CAG repeat size analysis were carried out as previously described.2,7 Paid volunteers were recruited as control subjects. They were selected from a larger control subject pool to ensure that their ages and education were comparable to those of the MJD patients. Control subjects had no history of any neurologic or psychiatric disease that affected cognition. Written informed consent was received in advance from MJD patients and control subjects. The study was approved by the ethics committee of the Department of Neurology, Nagoya University Hospital.

Table Graphic Jump LocationTable 1.  Clinical Characteristics of Machado-Joseph Disease (MJD) Patients and Controls*

Each patient underwent a standard cognitive status assessment. All of a patient’s neuropsychological tests were given on the same day. The Mini-Mental State Examination was used as a screen.8 Estimates of the IQ were derived from the information, digit span, and picture completion subtests of the Wechsler Adult Intelligence Scale–Revised, as described elsewhere.9 To evaluate working memory, the digit span subtest of the Wechsler Adult Intelligence Scale–Revised was used.10 Visual memory was examined using visual reproduction subtests 1 and 2, and visual paired associates subtests 1 and 2 of the Wechsler Memory Scale–Revised.11 Verbal memory was examined using logical memory subtests 1 and 2 of the Wechsler Memory Scale–Revised. Sequential commands and object naming subtests from the Western Aphasia Battery were selected as measures of language functions.12 To evaluate verbal fluency, subjects were asked to name as many items as possible within 1 minute from a semantic category (animals) and from a phonemic category (Japanese nouns starting with the Japanese Kana character Ka). To assess executive function, the simplified version of the Wisconsin Card Sorting Test13 was used. Constructional ability was tested using the block design subtest of the Wechsler Adult Intelligence Scale–Revised10; in addition to the original scoring (timed), one scoring was done without speed credits (untimed) to take into account the motor deficits of patients with MJD. In this scoring, the number of completed problems was compiled in the absence of a time limit.14 All subjects completed a self-reporting instrument concerning anxiety and depression (Hospital Anxiety and Depression Scale).15

Statistical comparisons were made using the Mann-Whitney test. Differences were considered significant at P<.05.

Neuropsychological Tests

Seven patients could ambulate without assistance. Three others used a cane or an item of furniture to assist in walking. Six patients were wheelchair bound. Machado-Joseph disease patients did not differ significantly from controls with regard to Mini-Mental State Examination score or IQ (Table 2). No significant difference in the working memory (digit span) or language functions such as sequential commands and object naming was evident between MJD patients and controls. No significant difference in any score was noted on the Wisconsin Card Sorting Test. Machado-Joseph disease patients had difficulty with logical memory subtests 1 and 2, visual reproduction subtest 2, and visual paired associates subtests 1 and 2 of the Wechsler Memory Scale–Revised. Visuospatial and constructional function, as tested using block design with and without a time limit, was impaired in MJD patients. Machado-Joseph disease subjects had significant problems in naming nouns from phonemic and semantic categories. Machado-Joseph disease patients were more depressed and anxious than controls.

Table Graphic Jump LocationTable 2.  Results of Neuropsychological Testsin Machado-Joseph Disease (MJD) Patients and Controls*
Correlative study

Next, we statistically analyzed the relationships between the cognitive dysfunction results and neurologic findings of age at onset, age at examination, disease duration, education, ataxia (International Cooperative Ataxia Rating Scale), depression, anxiety, and CAG repeat length using the Spearman rank correlation coefficient (Table 3). Scores that differed between MJD patients and controls (logical memory subtests 1 and 2, visual reproduction subtest 2, visual paired associates subtests 1 and 2, block design, phonemic fluency, and category fluency) showed no significant relation to CAG repeat length, age at onset, age at examination, disease duration, education, or depression. Among cognitive function tests, only logical memory subtest 2 and phonemic fluency were significantly related to anxiety, and only category fluency was significantly related to International Cooperative Ataxia Rating Scale scores.

Digit span and Wisconsin Card Sorting Test scores were significantly related to age at onset, age at examination, disease duration, and education. However, no significant differences in digit span and Wisconsin Card Sorting Test scores were evident between MJD patients and controls.

In this study, we describe verbal and visual memory deficits, impairment of verbal fluency, and visuospatial and constructional dysfunction in MJD patients. Previous studies35 have shown deficits of verbal memory, visual information processing, visual attention shifting, and executive function, including verbal fluency. Visual memory deficits and impairment of visuospatial and constructional function in MJD are new findings of this study. Because tasks of visual reproduction 2 and visual paired associates were impaired in MJD patients, we can assume that visual memory impairment is present in MJD patients. Furthermore, the task of visual paired associates does not need constructional abilities; therefore, the visual memory deficits observed in MJD are not the consequence of constructional dysfunction.

Left temporal lobe damage has been reported to cause verbal memory deficits,16 with right temporal lobe damage resulting in visual memory deficits.17 Combined verbal and visual memory deficits in MJD in this study suggest possible bilateral temporal lobe dysfunction. Impairment of verbal fluency is considered to reflect frontal lobe damage,18 and the visuospatial and constructional dysfunction shown in the block design test is thought to result from damage to the parietal lobe. Based on these observations, we believe that widespread multiple regions of the cerebral cortex show dysfunction in MJD patients. This view is supported by functional imaging results, in which defects of blood flow spread throughout the cerebrum in MJD.19

Widespread neuropathologic involvement in MJD patients20 has been thought to spare the cerebral cortex. However, an immunohistochemical study21 using a specific antibody against expanded polyglutamine (polyQ) demonstrated nuclear accumulation of mutant MJD protein in neurons of the cerebral cortex, although the degree of protein accumulation and cortical disruption varied between cases. Therefore, one possible reason for the wide-ranging cognitive dysfunction in MJD patients may be a similarly wide-ranging involvement of cortical neurons.22

Another possible explanation for cognitive impairment in MJD is disruption of cerebellar modulation of neural circuits. The cerebellum is reported to have connections with prefrontal,23 posterior parietal,24 and superior temporal25 cortex via the pons. Indeed, cerebellar disorders generally are known to impair verbal fluency, visuospatial function, and memory.26 Moreover, functional imaging studies provided evidence of activation of the cerebellum during a memory task27 and verbal fluency task.28 In MJD, the cerebellum and related structures, including cerebellar peduncles and dentate nucleus, are closely involved. Cognitive impairment in MJD could result from involvement of cerebellar cortical circuits, although most cognitive impairments were poorly correlated with severity of ataxia in this study. In addition to cerebellar connections, disruption of the basal ganglia–thalamocortical circuitry in MJD patients, including the substantia nigra and subthalamic nucleus, may take part in cognitive impairment. The basis for cognitive dysfunction in MJD may be multifactorial; further functional imaging studies, including functional magnetic resonance imaging, are needed to resolve this issue.

In MJD patients, age at onset and certain neurologic signs, such as ophthalmoplegia, pyramidal signs, dysphagia, and dystonia, have been shown to be related to CAG repeat length.7,29 In the present study, although all MJD patients showed deficits of verbal memory, visual memory, verbal fluency, or visuospatial and constructional ability, scores of these neuropsychological tests were not related to CAG repeat length, age at onset, or disease duration. These results suggest that CAG repeat expansion beyond the normal range may lead to cognitive impairments, with severity unrelated to length of expansion. On the other hand, MJD patients in this study showed varying combinations and severity of cognitive impairments; such heterogeneity among MJD patients may have obscured any relationship between cognitive deficits and CAG repeat length. Determining which stage of MJD shows onset of cognitive dysfunctions and whether these deteriorate together with motor dysfunction awaits further investigation. Longitudinal study, including neuropsychological examinations of “asymptomatic” gene carriers, may yield answers to these questions.

Correspondence: Gen Sobue, MD, Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho Showa-ku, Nagoya 466-8550, Japan (sobueg@med.nagoya-u.ac.jp).

Accepted for Publication: March 17, 2004.

Author Contributions:Study concept and design (Sobue); acquisition of data (Kawai and Abe); analysis and interpretation of data (Takeda, Washimi, and Tanaka); drafting of the manuscript (Kawai); critical revision of the manuscript for important intellectual content (Takeda, Abe, Washimi, Tanaka, and Sobue); statistical analysis (Tanaka); obtained funding (Kawai); administrative, technical, and material support (Takeda); study supervision (Sobue).

Funding/Support: This study was supported in part by grants from the Ministry of Health, Labour and Welfare, Tokyo, Japan.

Acknowledgment: We thank Kuniyuki Kawai, MD, Satoshi Okuda, MD, Takako Yamada, MD, Katsushige Iwai, MD, and Ikuko Aiba, MD, for referring MJD patients to our department.

Rosenberg  RNNyhan  WLBay  CShore  P Autosomal dominant striatonigral degeneration: a clinical, pathologic, and biochemical study of a new genetic disorder. Neurology 1976;26703- 714
PubMed Link to Article
Kawaguchi  YOkamoto  TTaniwaki  M  et al.  CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 1994;8221- 228
PubMed Link to Article
Maruff  PTyler  PBurt  TCurrie  BBurns  CCurrie  J Cognitive deficits in Machado-Joseph disease. Ann Neurol 1996;40421- 427
PubMed Link to Article
Zawacki  TMGrace  JFriedman  JHSudarsky  L Executive and emotional dysfunction in Machado-Joseph disease. Mov Disord 2002;171004- 1010
PubMed Link to Article
Bürk  KGlobas  CBösch  S  et al.  Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3. J Neurol 2003;250207- 211
PubMed Link to Article
Trouillas  PTakayanagi  THallett  M  et al.  International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. J Neurol Sci 1997;145205- 211
PubMed Link to Article
Maruyama  HNakamura  SMatsuyama  Z  et al.  Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease. Hum Mol Genet 1995;4807- 812
PubMed Link to Article
Folstein  MFFolstein  SEMcHugh  PR Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMed Link to Article
Kaufman  ASIshikura  TKaufman-Packer  JL Amazingly short forms of the WAIS-R. J Psychoedu Assess 1991;94- 15
Link to Article
Wechsler  D Manual for the Wechsler Adult Intelligence Scale–Revised.  San Antonio, Tex: Psychological Corporation; 1981
Wechsler  D Wechsler Memory Scale–Revised.  San Antonio, Tex: Psychological Corporation; 1981
Kertesz  A The Western Aphasia Battery.  New York, NY: Grune & Stratton Inc; 1982
Nelson  HE A modified card sorting test sensitive to frontal lobe defects. Cortex 1976;12313- 324
PubMed Link to Article
Fehrenbach  RAWallesch  CWClaus  D Neuropsychological findings in Friedrich’s ataxia. Arch Neurol 1984;41306- 308
PubMed Link to Article
Zigmond  ASSnaith  RP The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983;67361- 370
PubMed Link to Article
Milner  B Psychological defects produced by temporal lobe excision.  In: Solomon  HC, Cobb  S, Penfield  W, eds.The Brain and Human Behavior. Vol 36. Baltimore, Md: Williams & Wilkins; 1958:244-257
Kimura  D Right temporal lobe damage: perception of unfamiliar stimuli after damage. Arch Neurol 1963;8264- 271
PubMed Link to Article
Benton  A Differential behavior effects in frontal lobe disease. Neuropsychologia 1968;653- 60
Link to Article
Etchebehere  ECSCCendes  FLopes-Cendes  I  et al.  Brain single-photon emission computed tomography and magnetic resonance imaging in Machado-Joseph disease. Arch Neurol 2001;581257- 1263
PubMed Link to Article
Spinella  GMSheridan  PH Research initiatives on Machado-Joseph disease: National Institute of Neurological Disorders and Stroke Workshop summary. Neurology 1992;422048- 2051
PubMed Link to Article
Yamada  MHayashi  STsuji  STakahashi  H Involvement of the cerebral cortex and autosomal ganglia in Machado-Joseph disease. Acta Neuropathol (Berl) 2001;101140- 144
PubMed
Ishikawa  AYamada  MMakino  K  et al.  Dementia and delirium in 4 patients with Machado-Joseph disease. Arch Neurol 2002;591804- 1808
PubMed Link to Article
Schmahmann  JDPandya  DN Prefrontal cortex projections to the basilar pons in rhesus monkey: implications for the cerebellar contribution to higher function. Neurosci Lett 1995;199175- 178
PubMed Link to Article
Brodal  P The corticopontine projection in the rhesus monkey: origin and principles of organization. Brain 1978;101251- 283
PubMed Link to Article
Schmahmann  JDPandya  DN Projections to the basis pontis from the superior temporal sulcus and superior temporal region in the rhesus monkey. J Comp Neurol 1991;308224- 248
PubMed Link to Article
Schmahmann  JDSherman  JC The cerebellar cognitive affective syndrome. Brain 1998;121561- 579
PubMed Link to Article
Grasby  PMFrith  CDFriston  KJBench  CFrackowiak  RSJDolan  RJ Functional mapping of brain areas implicated in auditory-verbal memory function. Brain 1993;1161- 20
PubMed Link to Article
Schlösser  RHutchinson  MJoseffer  S  et al.  Functional magnetic resonance imaging of human brain activity in a verbal fluency task. J Neurol Neurosurg Psychiatry 1998;64492- 498
PubMed Link to Article
Jardim  LBPereira  MLSilveira  IFerro  ASequeiros  JGiugliani  R Neurologic findings in Machado-Joseph disease: relation with disease duration, subtypes, and (CAG)nArch Neurol 2001;58899- 904
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Clinical Characteristics of Machado-Joseph Disease (MJD) Patients and Controls*
Table Graphic Jump LocationTable 2.  Results of Neuropsychological Testsin Machado-Joseph Disease (MJD) Patients and Controls*

References

Rosenberg  RNNyhan  WLBay  CShore  P Autosomal dominant striatonigral degeneration: a clinical, pathologic, and biochemical study of a new genetic disorder. Neurology 1976;26703- 714
PubMed Link to Article
Kawaguchi  YOkamoto  TTaniwaki  M  et al.  CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 1994;8221- 228
PubMed Link to Article
Maruff  PTyler  PBurt  TCurrie  BBurns  CCurrie  J Cognitive deficits in Machado-Joseph disease. Ann Neurol 1996;40421- 427
PubMed Link to Article
Zawacki  TMGrace  JFriedman  JHSudarsky  L Executive and emotional dysfunction in Machado-Joseph disease. Mov Disord 2002;171004- 1010
PubMed Link to Article
Bürk  KGlobas  CBösch  S  et al.  Cognitive deficits in spinocerebellar ataxia type 1, 2, and 3. J Neurol 2003;250207- 211
PubMed Link to Article
Trouillas  PTakayanagi  THallett  M  et al.  International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. J Neurol Sci 1997;145205- 211
PubMed Link to Article
Maruyama  HNakamura  SMatsuyama  Z  et al.  Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease. Hum Mol Genet 1995;4807- 812
PubMed Link to Article
Folstein  MFFolstein  SEMcHugh  PR Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMed Link to Article
Kaufman  ASIshikura  TKaufman-Packer  JL Amazingly short forms of the WAIS-R. J Psychoedu Assess 1991;94- 15
Link to Article
Wechsler  D Manual for the Wechsler Adult Intelligence Scale–Revised.  San Antonio, Tex: Psychological Corporation; 1981
Wechsler  D Wechsler Memory Scale–Revised.  San Antonio, Tex: Psychological Corporation; 1981
Kertesz  A The Western Aphasia Battery.  New York, NY: Grune & Stratton Inc; 1982
Nelson  HE A modified card sorting test sensitive to frontal lobe defects. Cortex 1976;12313- 324
PubMed Link to Article
Fehrenbach  RAWallesch  CWClaus  D Neuropsychological findings in Friedrich’s ataxia. Arch Neurol 1984;41306- 308
PubMed Link to Article
Zigmond  ASSnaith  RP The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 1983;67361- 370
PubMed Link to Article
Milner  B Psychological defects produced by temporal lobe excision.  In: Solomon  HC, Cobb  S, Penfield  W, eds.The Brain and Human Behavior. Vol 36. Baltimore, Md: Williams & Wilkins; 1958:244-257
Kimura  D Right temporal lobe damage: perception of unfamiliar stimuli after damage. Arch Neurol 1963;8264- 271
PubMed Link to Article
Benton  A Differential behavior effects in frontal lobe disease. Neuropsychologia 1968;653- 60
Link to Article
Etchebehere  ECSCCendes  FLopes-Cendes  I  et al.  Brain single-photon emission computed tomography and magnetic resonance imaging in Machado-Joseph disease. Arch Neurol 2001;581257- 1263
PubMed Link to Article
Spinella  GMSheridan  PH Research initiatives on Machado-Joseph disease: National Institute of Neurological Disorders and Stroke Workshop summary. Neurology 1992;422048- 2051
PubMed Link to Article
Yamada  MHayashi  STsuji  STakahashi  H Involvement of the cerebral cortex and autosomal ganglia in Machado-Joseph disease. Acta Neuropathol (Berl) 2001;101140- 144
PubMed
Ishikawa  AYamada  MMakino  K  et al.  Dementia and delirium in 4 patients with Machado-Joseph disease. Arch Neurol 2002;591804- 1808
PubMed Link to Article
Schmahmann  JDPandya  DN Prefrontal cortex projections to the basilar pons in rhesus monkey: implications for the cerebellar contribution to higher function. Neurosci Lett 1995;199175- 178
PubMed Link to Article
Brodal  P The corticopontine projection in the rhesus monkey: origin and principles of organization. Brain 1978;101251- 283
PubMed Link to Article
Schmahmann  JDPandya  DN Projections to the basis pontis from the superior temporal sulcus and superior temporal region in the rhesus monkey. J Comp Neurol 1991;308224- 248
PubMed Link to Article
Schmahmann  JDSherman  JC The cerebellar cognitive affective syndrome. Brain 1998;121561- 579
PubMed Link to Article
Grasby  PMFrith  CDFriston  KJBench  CFrackowiak  RSJDolan  RJ Functional mapping of brain areas implicated in auditory-verbal memory function. Brain 1993;1161- 20
PubMed Link to Article
Schlösser  RHutchinson  MJoseffer  S  et al.  Functional magnetic resonance imaging of human brain activity in a verbal fluency task. J Neurol Neurosurg Psychiatry 1998;64492- 498
PubMed Link to Article
Jardim  LBPereira  MLSilveira  IFerro  ASequeiros  JGiugliani  R Neurologic findings in Machado-Joseph disease: relation with disease duration, subtypes, and (CAG)nArch Neurol 2001;58899- 904
PubMed Link to Article

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