Reduction of the Substantia Nigra Width and Motor Decline in Aging and Parkinson's Disease Jes\l=u'\sPujol, MD; Carme Junqu\l=e'\,PhD; Pere Vendrell, PhD; Josep \s=b\ We studied the functional significance of the involutional and degenerative changes in the substantia nigra as seen on magnetic resonance imaging. The width of the pars compacta correlated with motor performance in both healthy elderly subjects and idiopathic Parkinson's disease groups. Patients exhibited significant reduction of the width of the pars compacta and the level of this reduction correlated strongly with the clinical status evaluated by the Unified Parkinson's Disease Rating Scale. These results suggest that pars compacta shrinkage may account for a substantial part of the structural substratum of motor decline in the elderly. Moreover, an analysis of the relationship of the midbrain damage with specific symptoms in Parkinson's disease could contribute to a better understanding of the pathogenesis of this degenerative process. (Arch Neurol. 1992;49:1119-1122)
A
progressive
loss of
in the substantia
nigra pars compacta occurs with advancing age, together with a marked functional decline in the nigrostriatal dopaminergic system. Normal senescence is accompanied neurons
obvious decrease in spontaneous movement and skills. Structural changes in the substantia nigra probably account to a considerable extent for motor impairment in the elderly.1 In idiopathic Parkinson's dis¬ ease, a pathologic process that results mainly from degen¬ eration of the pigmented neurons of the substantia nigra, pars compacta shows a decrease in fresh volume of 25% (superimposed on age-related attrition2). Patients with Parkinson's disease exhibit extrapyramidal symptoms that produce progressive incapacity, surpassing the motor dis¬ turbances occurring in normal aging. Such symptoms are clearly related to the dopamine deficiency secondary to the degeneration of dopaminergic neurons. At present, magnetic resonance imaging (MRI) allows the measurement of the major nuclei of the midbrain. Shrinkage of the substantia nigra pars compacta is ob¬ served in normal aging3 and a more marked narrowing of
by
an
motor
Accepted
for
publication April 27,
1992.
Department of Neurology, Sta Creu i St Pau Hospital, Autonomous University of Barcelona (Spain) (Drs Pujol, Vendrell, and Grau); Department of Psychiatry and Clinical Psychobiology, University of Barcelona (Dr Junqu\l=e'\);and Centre M\l=e`\dicde Resson\l=a`\nciaMagn\l=e`\tica From the
de Barcelona (Dr Capdevila). Reprint requests to the Department of Neurology, Sta Creu i St Pau Hospital, Av St AM Claret 167, E-08025 Barcelona, Spain (Dr Pujol).
M.
Grau, MD; Antoni Capdevila, MD
in Parkinson's disease.4"6 The opportu¬ the shrinkage of the main locus of dopa¬ nity quantify mine allows the study of the relationship, not yet estab¬ lished "in vivo," between structural changes in the substantia nigra and motor efficiency, and thus to contrib¬ ute to the knowledge of the origin of both motor decline in old people and symptoms in Parkinson's disease. To study this relationship we performed correlations between MRI measurements of the pars compacta and motor performance in normal healthy subjects and in pa¬ tients with Parkinson's disease. We selected the Purdue Pegboard, a classic test of motor performance, to quantify motor deterioration in both study groups and the Unified Parkinson's Disease Rating Scale (UPDRS) as representa¬ tive of motor impairment of patients.
this
region
occurs
to
SUBJECTS AND METHODS
Healthy Aged Subjects
We stressed the selection of a group of optimally healthy sub¬ jects to avoid as far as possible individuals with subclinical dis¬ ease (ie, essential tremor, senile dyskinesia) or subtle brain changes associated with vascular risk factors such as leukoaraiosis. Selected subjects met the following criteria: (1) age, 65 years or older, (2) no history of neurologic or psychiatric disease, (3) absence of cerebrovascular risk factors (hypertension or diabetes), and (4) normal neurologic examination results. The sample con¬ sisted of 21 subjects (13 men and eight women), with a mean age of 69.7±3.2 years (range, 65 to 75 years).
Parkinson's Disease
Twenty-one patients with idiopathic Parkinson's disease with similar demographic characteristics of normal elderly subjects were selected from a cohort of parkinsonian patients who regu¬ larly attend the neurology clinic at our hospital. We selected the sample according to the following criteria: (1) good response to treatment, (2) absence of vsscular risk factors (hypertension or diabetes), (3) absence of treatment with anticholinergic drugs, and (4) absence of dementia according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria.7 The groups were composed of 21 subjects (15 men and six women) with a mean of age 70.3 ±4.2 years (range, 65 to 79 years). The mean Hoehn-Yahr stage was 2.5±0.8. Duration of disease ranged from 2 to 14 years (mean, 5.7±3.5). All subjects had been treated chronically with carbidopa-levodopa. Mean daily dose of levodopa was 532.1 ±310.5 mg. MRI Analysis All MRI
scans were
net at a field
strength
performed using a superconducting mag¬ of 1.5 (Signa System, General Electric,
Milwaukee, Wis). A field of view of 24
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/16/2015
cm, a matrix size
of
a slice thickness of 5 mm were used. The images obtained at an axial plane with defined anatomic references from the sagittal plane. We analyzed a single slice in which the differentiation between pars reticulata and pars compacta was most striking. It was accurately referred in each study to a line passing through the superior colliculus and the orbital surface of the frontal lobe. We used the third echo (75-millisecond echo time) from a multiecho spin echo pulse sequence with a 2000millisecond repetition time and four echoes with a 25-millisecond interecho time. Images were processed in our laboratory console using a com¬ puter image analysis system (IMCO system developed by Kon¬ tron Bildanalyse, Eching, Germany) and a specific software pack¬ age (MIP-CNS). The data were displayed using a gray scale ranging from 0 to 255 on a 256X256 matrix. Determination of the width of the pars compacta signal was made using the variation of the method of Duguid et al4 as described by Braffman et al.' Intensity values of a straight line perpendicular to the pars com¬ pacta through the center of the red nucleus were measured on the selected image. We drew two additional parallel straight lines 1 mm to either side. At the half-height maximum intensity value between the hypointense red nucleus and relatively hyperintense pars compacta we placed one cursor. At the corresponding halfheight maximum intensity value between the pars compacta and relatively hypointense pars reticulata we placed a second cursor. The distance in pixels between the two was taken as the width of the pars compacta and then was converted to millimeters. We averaged three values for each pars compacta and the values for each hemimidbrain were also averaged.
256X256, and were
3.5
4.0
Pars Compacta
Width,
3.0
Fig
4.5
5.0
mm
1.—Correlations between the width of the substantia
nigra pars
performance (Purdue Pegboard test) in normal subjects (open circles) and parkinsonian patients (solid circles). compacta and
motor
Motor Evaluation
performance in normal subjects and in Parkinson's dis¬ ease was assessed by the Purdue Pegboard, a classic test of motor skills generally used in the objective evaluation of motor impair¬ ment in Parkinson's disease.8 The measurement computed was the number of pins inserted in 30 seconds for the right and left hands. The clinical status of patients was evaluated by the UPDRS.9 To obtain precise motor measurement we assessed superior/inferior limbs and right/left parts of the body sepa¬ rately. The cardinal symptoms of Parkinson's disease10 were also recorded separately. Thus, we computed the severity of resting tremor, rigidity, and akinesia adding respective scores to each limb and face. Postural difficulties were computed adding scores from the following items of the UPDRS: postural stability, posture, gait, falling, and freezing. Scores for these four cardinal symptoms can range from 0 to 20. Motor
Statistical
Analysis
Pearson's product-moment correlation was used to determine the relationship between clinical parameters and width of the substantia nigra pars compacta. The unpaired f test was used for comparison between groups.
3.0
RESULTS
Performance of healthy elderly subjects on the Purdue Pegboard test showed a strong correlation with the pars compacta width (r=.62; P=.001). This correlation, although significant, was weaker in the Parkinson's disease group (r=.40; P=.037). Figure 1 depicts these correlations. The two study groups differed in the size of the substantia nigra pars compacta. Patients showed a signif¬ icant decrease in the width of this region. The mean breadth of the pars compacta in normal elderly subjects was 3.89 mm (SD, 0.35) and 3.57 mm (SD, 0.55) in patients. Comparing groups, we obtained significant differences: f(40)=2.23; P=.03. In patients, the width of the substantia nigra pars com¬ pacta showed strong correlation with global clinical status evaluated by the UPDRS. In Fig 2, MRI measurements are
3.5 Pars
4.0
Compacta Width,
4.5 mm
2.—Plot of substantia nigra pars compacta width against Unified Parkinson's Disease Rating Scale (UPDRS) global scores of patients with Parkinson's disease.
Fig
plotted against the global score of patients (Parts I through IV of the UPDRS). This global score was strongly associ¬ ated with performance on the Purdue Pegboard test (r= —.83; P=.0000). Analyzing the parts of the scale sepa¬ rately we found significant correlations for part II (activ¬ ities of daily living) and part III (motor examination). Part I (mentation, behavior, and mood) and part IV (complica¬ tions of therapy) were unrelated with the present measure of substantia nigra. The stage of the disease (part V) and the Schwab and England scale of daily living activities
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/16/2015
Correlations of Clinical Features With Pars Compacta Width in Patients With Parkinson's Disease Global
score
Part I II III IV V VI
Range
Mean
SD
r
10-99
46.1
23.4
-.52
.009
0-8 6-45 0-54 0-8 2-5 40-90
3.8 17.9 21.5 2.9 2.5 80.0
2.0 8.9 15.2 2.6 0.7 14.1
.03 -.57 -.44 -.09 -.28 .36
.446 .003 .023 .349 .112 .056
Resting tremor Rigidity
0-10
3.8
2.9
-.54
.006
0-8
2.1
3.0
-.17
.232
Akinesia
0-16
5.3
4.7
-.32
.081
Postural difficulties
1-15
4.9
3.3
-.38
.045
(part VI) did not reach statistical significance (Table). Du¬ ration of the disease was poorly related to degeneration of the pars compacta (r=— .21, P=.18). Individual analyses of the cardinal symptoms of Par¬ kinson's disease (resting tremor, rigidity, akinesia, pos¬ tural difficulties), showed that resting tremor was the symptom most related to changes in the substantia nigra
(Table).
COMMENT We studied the functional significance of the involutional changes of the substantia nigra as seen on MRI studies. We found strong negative correlations between pars compacta width and motor impairment both in nor¬ mal elderly subjects and in patients. In the Parkinson's disease group, which exhibited significant size reduction of the pars compacta, the degree of degeneration was also related to clinical features. Although normal senescence tends to a parkinsonlike condition, our selected healthy subjects did not manifest
overt parkinsonian symptoms and, consequentially, motor
clinical scales were not applicable. Performance on the Purdue Pegboard test, a test strongly related to parkinso¬ nian symptoms, was a priori a suitable measurement of motor skills for the purpose of our investigation. The cor¬ relation obtained in normal elderly subjects between degeneration of the substantia nigra and deterioration in motor performance assessed by the Purdue Pegboard test is attractive, because somehow it denotes the functional significance of the changes in the midbrain appreciated in MRI studies. The shrinkage of the pars compacta reflects failure in specific skills. Here, it is important to emphasize the utility of the Purdue Pegboard test as a sensitive func¬ tional measurement of the dopaminergic system status. It can be stated with certainty that the nigrostriatal pathway undergoes attrition over the course of aging. The decrease in nigral neurons is estimated to be about 10% per decade in the elderly.11 According to the results of McGeer et al,1,12 normal individuals showed a cell count of about 450000 in the substantia nigra pars compacta, which declined in an approximately linear fashion to reach a level of about 275 000 by the age of 60 years. Neurochemically, in normal aged people the most severe loss in enzymes concerned with neurotransmitter synthesis is found in the activity of striatal tyrosine hydroxylase, the ratecontrolling enzyme in the synthesis of dopamine. By the age of 65 years the dopamine content in the neostriatum is
reduced to half that found at birth.13 The relationship be¬ dopaminergic cell loss and the decrease in neuro¬ chemical activity in aging has been clearly established. However, an in vivo correlation between age-related degeneration in the substantia nigra and motor perfor¬ mance has not been previously reported. Changes in the substantia nigra in patients with Parkin¬ son's disease are more conspicuous than in healthy aged individuals. In the study by McGeer et al,12 patients with Parkinson's disease all had cell counts below 140000 and other authors reported loss of pigmented neurons ranging from 50% to 85%.2 Although cell loss in Parkinson's disease appears to be dramatic, the fresh volume in the pars com¬ pacta is reduced by only 25% in autopsy material. This discrepancy between neuronal depletion and overall shrinkage in the pars compacta partially explains the lack of accuracy in differentiating Parkinson's disease from controls using MRI measurements. Another contributory factor could be the limited resolution of current MRI. We found significant reduction in the substantia nigra pars compacta in Parkinson's disease relative to control sub¬ jects. However, there was some overlap in the measure¬ ments between the two groups, which limits the diagnos¬ tic utility of such measurements. Our results agree with those previously reported in the literature.4"6 Nevertheless, further studies with improved imaging techniques (highresolution MRI) might demonstrate the sensitivity and specificity of this approach.14 The relationship between the size of the substantia nigra pars compacta and the clinical status of patients has been poorly studied in previous works. Duguid et al,4 in a sam¬ ple of six patients found no relation of the pars compacta with the stage or the duration of the disease. Braffman et al5 analyzed the width of the pars compacta in 16 patients but did not report clinical data, and Huber et al6 found significant correlation of the MRI measurements with the stage and the duration of the disease, but they did not study the correlation with clinical scales and motor per¬ formance. Although a gradual decline in the extrapyramidal func¬ tion appears with aging, biochemical investigations sug¬ gest that a depletion in striatal dopamine of the order of 70% to 80% is necessary for the symptom threshold to be crossed. In fact, dopaminergic cell depletion precedes the appearance of overt clinical manifestations of parkinsonism by many years.1015 Paradoxically, the correlation between the MRI measurements and the Purdue Pegboard tween
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/16/2015
test was stronger in normal aging subjects than in subjects with Parkinson's disease, even when patients performed worse in this test. It is plausible that at the level at which the amount of neuronal loss becomes symptomatic in pa¬ tients with Parkinson's disease, the existing linear correla¬ tion is partially distorted. At this level, a further minor de¬ crease in size could produce excessive motor impairment and, as a result, the Purdue Pegboard test could be less sensitive. Nevertheless, in this situation the rate of symp¬ toms assessed by the UPDRS was significantly related to the in vivo visible size reduction of the pars compacta. This suggests that, after the symptom threshold has been crossed, loss of dopaminergic neurons is optimally re¬ flected by the clinical status. We found resting tremor to be the symptom most related to changes in the pars compacta. The origin of this symp¬ tom in Parkinson's disease is obscure to date. Parkinsonian tremor has generally been postulated to result from the oscillatory activity of thalamocortical loops, relatively in¬ dependent of basal ganglia circuitry,16 or has been believed to require additional damage to the cerebellofugal sys¬ tem.15 Current research on the methyl-phenyl-tetrahydropyridine neurotoxin provides powerful support for the argument that tremor is produced by lesion of the sub¬ stantia nigra.15 The correlation found in our study between resting tremor severity and width of the pars compacta re¬ inforces this hypothesis on the dopaminergic origin of this kind of tremor. This study was supported in part by a grant of the Ministerio de Sanidad (Spanish Government, grant FTSSs 90/0767) and the Consel¬ leria de Sanitat de la Generalität de Catalunya (autonomous govern¬ ment of Catalonia). We thank Robin Rycroft, PhD, for the English-language revision of the manuscript.
References 1. McGeer PL, McGeer E, Suzuki JS.
Aging and extrapyramidal function. Arch Neurol. 1977;34:33-35. 2. Jellinger K. Overview of morphological changes in Parkinson's disease. In: Yahr MD, Bergmann KJ, eds. Advances in Neurology. New York, NY: Raven Press; 1986;45:1-18. 3. Doraiswamy PM, Shah SA, Husain MM, et al. Magnetic resonance evaluation of the midbrain in Parkinson's disease. Arch Neurol. 1991 ;48:360. 4. Duguid JR, DeLa Paz R, DeGroot J. Magnetic resonance imaging of the midbrain in Parkinson's disease. Ann Neurol. 1986;20:744-747. 5. Braffman BH, Grossman RI, Golbert HI, et al. MR Imaging of Parkinson's disease with spin-echo and gradient-echo sequences. AJR Am J Roentgenol.
1989;152:159-165. 6. Huber SJ, Chakeres DW, Paulson GW, Khanna R. Magnetic resonance imaging in Parkinson's disease. Arch Neurol. 1990;47:735-737. 7. American Psychiatric Association, Committee on Nomenclature and Statistics. Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Washington, DC: American Psychiatric Association; 1987.
8. Lezak MD. Neuropsychological Assessment. New York, NY: Oxford Press Inc; 1983. 9. Fahn S, Elton RL, and Members of the UPDRS Development Committee. Unified Parkinson's Disease Rating Scale. In: Fahn S, Marsden CD, Goldstein M, Calne DB, eds. Recent Developments in Parkinson's Disease. New York, NY: Macmillan Publishing Co Inc; 1987:153-163. 10. Barbeau A. Parkinson's disease: clinical features and etiopathology. In:
University
Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of Clinical Neurology. Extrapyramidal Disorders. Amsterdam, the Netherlands: Elsevier Science
Publishers; 1986;5.
11. Calne DB, Peppard RF. Aging of the nigrostriatal pathway in humans. Can J Neurol Sci. 1987;14:424-427. 12. McGeer PL, Itagaki S, Akiyama H, McGeer EG. Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol.
1988;24:574-576. 13. Cot\l=e'\LJ, Kremzner LT. Biochemical changes in normal aging in human brain. In: Mayeux R, Rosen WG, eds. The Dementias. New York, NY: Raven Press; 1983:19-30. 14. Perlmutter JS. Neuroimaging in Parkinson's disease. In: Koller WC, Paulson G, eds. Therapy of Parkinson's Disease. New York, NY: Marcel Dekker Inc; 1990. 15. Tetrud JW, Langston JW. Tremor in MPTP-induced parkinsonism. Neurology. 1992;42:407-410. 16. Bergman H, Wichmann T, Delong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science. 1990;249:1436\x=req-\ 1438.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/16/2015
A
progressive
loss of
in the substantia
nigra pars compacta occurs with advancing age, together with a marked functional decline in the nigrostriatal dopaminergic system. Normal senescence is accompanied neurons
obvious decrease in spontaneous movement and skills. Structural changes in the substantia nigra probably account to a considerable extent for motor impairment in the elderly.1 In idiopathic Parkinson's dis¬ ease, a pathologic process that results mainly from degen¬ eration of the pigmented neurons of the substantia nigra, pars compacta shows a decrease in fresh volume of 25% (superimposed on age-related attrition2). Patients with Parkinson's disease exhibit extrapyramidal symptoms that produce progressive incapacity, surpassing the motor dis¬ turbances occurring in normal aging. Such symptoms are clearly related to the dopamine deficiency secondary to the degeneration of dopaminergic neurons. At present, magnetic resonance imaging (MRI) allows the measurement of the major nuclei of the midbrain. Shrinkage of the substantia nigra pars compacta is ob¬ served in normal aging3 and a more marked narrowing of
by
an
motor
Accepted
for
publication April 27,
1992.
Department of Neurology, Sta Creu i St Pau Hospital, Autonomous University of Barcelona (Spain) (Drs Pujol, Vendrell, and Grau); Department of Psychiatry and Clinical Psychobiology, University of Barcelona (Dr Junqu\l=e'\);and Centre M\l=e`\dicde Resson\l=a`\nciaMagn\l=e`\tica From the
de Barcelona (Dr Capdevila). Reprint requests to the Department of Neurology, Sta Creu i St Pau Hospital, Av St AM Claret 167, E-08025 Barcelona, Spain (Dr Pujol).
M.
Grau, MD; Antoni Capdevila, MD
in Parkinson's disease.4"6 The opportu¬ the shrinkage of the main locus of dopa¬ nity quantify mine allows the study of the relationship, not yet estab¬ lished "in vivo," between structural changes in the substantia nigra and motor efficiency, and thus to contrib¬ ute to the knowledge of the origin of both motor decline in old people and symptoms in Parkinson's disease. To study this relationship we performed correlations between MRI measurements of the pars compacta and motor performance in normal healthy subjects and in pa¬ tients with Parkinson's disease. We selected the Purdue Pegboard, a classic test of motor performance, to quantify motor deterioration in both study groups and the Unified Parkinson's Disease Rating Scale (UPDRS) as representa¬ tive of motor impairment of patients.
this
region
occurs
to
SUBJECTS AND METHODS
Healthy Aged Subjects
We stressed the selection of a group of optimally healthy sub¬ jects to avoid as far as possible individuals with subclinical dis¬ ease (ie, essential tremor, senile dyskinesia) or subtle brain changes associated with vascular risk factors such as leukoaraiosis. Selected subjects met the following criteria: (1) age, 65 years or older, (2) no history of neurologic or psychiatric disease, (3) absence of cerebrovascular risk factors (hypertension or diabetes), and (4) normal neurologic examination results. The sample con¬ sisted of 21 subjects (13 men and eight women), with a mean age of 69.7±3.2 years (range, 65 to 75 years).
Parkinson's Disease
Twenty-one patients with idiopathic Parkinson's disease with similar demographic characteristics of normal elderly subjects were selected from a cohort of parkinsonian patients who regu¬ larly attend the neurology clinic at our hospital. We selected the sample according to the following criteria: (1) good response to treatment, (2) absence of vsscular risk factors (hypertension or diabetes), (3) absence of treatment with anticholinergic drugs, and (4) absence of dementia according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria.7 The groups were composed of 21 subjects (15 men and six women) with a mean of age 70.3 ±4.2 years (range, 65 to 79 years). The mean Hoehn-Yahr stage was 2.5±0.8. Duration of disease ranged from 2 to 14 years (mean, 5.7±3.5). All subjects had been treated chronically with carbidopa-levodopa. Mean daily dose of levodopa was 532.1 ±310.5 mg. MRI Analysis All MRI
scans were
net at a field
strength
performed using a superconducting mag¬ of 1.5 (Signa System, General Electric,
Milwaukee, Wis). A field of view of 24
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/16/2015
cm, a matrix size
of
a slice thickness of 5 mm were used. The images obtained at an axial plane with defined anatomic references from the sagittal plane. We analyzed a single slice in which the differentiation between pars reticulata and pars compacta was most striking. It was accurately referred in each study to a line passing through the superior colliculus and the orbital surface of the frontal lobe. We used the third echo (75-millisecond echo time) from a multiecho spin echo pulse sequence with a 2000millisecond repetition time and four echoes with a 25-millisecond interecho time. Images were processed in our laboratory console using a com¬ puter image analysis system (IMCO system developed by Kon¬ tron Bildanalyse, Eching, Germany) and a specific software pack¬ age (MIP-CNS). The data were displayed using a gray scale ranging from 0 to 255 on a 256X256 matrix. Determination of the width of the pars compacta signal was made using the variation of the method of Duguid et al4 as described by Braffman et al.' Intensity values of a straight line perpendicular to the pars com¬ pacta through the center of the red nucleus were measured on the selected image. We drew two additional parallel straight lines 1 mm to either side. At the half-height maximum intensity value between the hypointense red nucleus and relatively hyperintense pars compacta we placed one cursor. At the corresponding halfheight maximum intensity value between the pars compacta and relatively hypointense pars reticulata we placed a second cursor. The distance in pixels between the two was taken as the width of the pars compacta and then was converted to millimeters. We averaged three values for each pars compacta and the values for each hemimidbrain were also averaged.
256X256, and were
3.5
4.0
Pars Compacta
Width,
3.0
Fig
4.5
5.0
mm
1.—Correlations between the width of the substantia
nigra pars
performance (Purdue Pegboard test) in normal subjects (open circles) and parkinsonian patients (solid circles). compacta and
motor
Motor Evaluation
performance in normal subjects and in Parkinson's dis¬ ease was assessed by the Purdue Pegboard, a classic test of motor skills generally used in the objective evaluation of motor impair¬ ment in Parkinson's disease.8 The measurement computed was the number of pins inserted in 30 seconds for the right and left hands. The clinical status of patients was evaluated by the UPDRS.9 To obtain precise motor measurement we assessed superior/inferior limbs and right/left parts of the body sepa¬ rately. The cardinal symptoms of Parkinson's disease10 were also recorded separately. Thus, we computed the severity of resting tremor, rigidity, and akinesia adding respective scores to each limb and face. Postural difficulties were computed adding scores from the following items of the UPDRS: postural stability, posture, gait, falling, and freezing. Scores for these four cardinal symptoms can range from 0 to 20. Motor
Statistical
Analysis
Pearson's product-moment correlation was used to determine the relationship between clinical parameters and width of the substantia nigra pars compacta. The unpaired f test was used for comparison between groups.
3.0
RESULTS
Performance of healthy elderly subjects on the Purdue Pegboard test showed a strong correlation with the pars compacta width (r=.62; P=.001). This correlation, although significant, was weaker in the Parkinson's disease group (r=.40; P=.037). Figure 1 depicts these correlations. The two study groups differed in the size of the substantia nigra pars compacta. Patients showed a signif¬ icant decrease in the width of this region. The mean breadth of the pars compacta in normal elderly subjects was 3.89 mm (SD, 0.35) and 3.57 mm (SD, 0.55) in patients. Comparing groups, we obtained significant differences: f(40)=2.23; P=.03. In patients, the width of the substantia nigra pars com¬ pacta showed strong correlation with global clinical status evaluated by the UPDRS. In Fig 2, MRI measurements are
3.5 Pars
4.0
Compacta Width,
4.5 mm
2.—Plot of substantia nigra pars compacta width against Unified Parkinson's Disease Rating Scale (UPDRS) global scores of patients with Parkinson's disease.
Fig
plotted against the global score of patients (Parts I through IV of the UPDRS). This global score was strongly associ¬ ated with performance on the Purdue Pegboard test (r= —.83; P=.0000). Analyzing the parts of the scale sepa¬ rately we found significant correlations for part II (activ¬ ities of daily living) and part III (motor examination). Part I (mentation, behavior, and mood) and part IV (complica¬ tions of therapy) were unrelated with the present measure of substantia nigra. The stage of the disease (part V) and the Schwab and England scale of daily living activities
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/16/2015
Correlations of Clinical Features With Pars Compacta Width in Patients With Parkinson's Disease Global
score
Part I II III IV V VI
Range
Mean
SD
r
10-99
46.1
23.4
-.52
.009
0-8 6-45 0-54 0-8 2-5 40-90
3.8 17.9 21.5 2.9 2.5 80.0
2.0 8.9 15.2 2.6 0.7 14.1
.03 -.57 -.44 -.09 -.28 .36
.446 .003 .023 .349 .112 .056
Resting tremor Rigidity
0-10
3.8
2.9
-.54
.006
0-8
2.1
3.0
-.17
.232
Akinesia
0-16
5.3
4.7
-.32
.081
Postural difficulties
1-15
4.9
3.3
-.38
.045
(part VI) did not reach statistical significance (Table). Du¬ ration of the disease was poorly related to degeneration of the pars compacta (r=— .21, P=.18). Individual analyses of the cardinal symptoms of Par¬ kinson's disease (resting tremor, rigidity, akinesia, pos¬ tural difficulties), showed that resting tremor was the symptom most related to changes in the substantia nigra
(Table).
COMMENT We studied the functional significance of the involutional changes of the substantia nigra as seen on MRI studies. We found strong negative correlations between pars compacta width and motor impairment both in nor¬ mal elderly subjects and in patients. In the Parkinson's disease group, which exhibited significant size reduction of the pars compacta, the degree of degeneration was also related to clinical features. Although normal senescence tends to a parkinsonlike condition, our selected healthy subjects did not manifest
overt parkinsonian symptoms and, consequentially, motor
clinical scales were not applicable. Performance on the Purdue Pegboard test, a test strongly related to parkinso¬ nian symptoms, was a priori a suitable measurement of motor skills for the purpose of our investigation. The cor¬ relation obtained in normal elderly subjects between degeneration of the substantia nigra and deterioration in motor performance assessed by the Purdue Pegboard test is attractive, because somehow it denotes the functional significance of the changes in the midbrain appreciated in MRI studies. The shrinkage of the pars compacta reflects failure in specific skills. Here, it is important to emphasize the utility of the Purdue Pegboard test as a sensitive func¬ tional measurement of the dopaminergic system status. It can be stated with certainty that the nigrostriatal pathway undergoes attrition over the course of aging. The decrease in nigral neurons is estimated to be about 10% per decade in the elderly.11 According to the results of McGeer et al,1,12 normal individuals showed a cell count of about 450000 in the substantia nigra pars compacta, which declined in an approximately linear fashion to reach a level of about 275 000 by the age of 60 years. Neurochemically, in normal aged people the most severe loss in enzymes concerned with neurotransmitter synthesis is found in the activity of striatal tyrosine hydroxylase, the ratecontrolling enzyme in the synthesis of dopamine. By the age of 65 years the dopamine content in the neostriatum is
reduced to half that found at birth.13 The relationship be¬ dopaminergic cell loss and the decrease in neuro¬ chemical activity in aging has been clearly established. However, an in vivo correlation between age-related degeneration in the substantia nigra and motor perfor¬ mance has not been previously reported. Changes in the substantia nigra in patients with Parkin¬ son's disease are more conspicuous than in healthy aged individuals. In the study by McGeer et al,12 patients with Parkinson's disease all had cell counts below 140000 and other authors reported loss of pigmented neurons ranging from 50% to 85%.2 Although cell loss in Parkinson's disease appears to be dramatic, the fresh volume in the pars com¬ pacta is reduced by only 25% in autopsy material. This discrepancy between neuronal depletion and overall shrinkage in the pars compacta partially explains the lack of accuracy in differentiating Parkinson's disease from controls using MRI measurements. Another contributory factor could be the limited resolution of current MRI. We found significant reduction in the substantia nigra pars compacta in Parkinson's disease relative to control sub¬ jects. However, there was some overlap in the measure¬ ments between the two groups, which limits the diagnos¬ tic utility of such measurements. Our results agree with those previously reported in the literature.4"6 Nevertheless, further studies with improved imaging techniques (highresolution MRI) might demonstrate the sensitivity and specificity of this approach.14 The relationship between the size of the substantia nigra pars compacta and the clinical status of patients has been poorly studied in previous works. Duguid et al,4 in a sam¬ ple of six patients found no relation of the pars compacta with the stage or the duration of the disease. Braffman et al5 analyzed the width of the pars compacta in 16 patients but did not report clinical data, and Huber et al6 found significant correlation of the MRI measurements with the stage and the duration of the disease, but they did not study the correlation with clinical scales and motor per¬ formance. Although a gradual decline in the extrapyramidal func¬ tion appears with aging, biochemical investigations sug¬ gest that a depletion in striatal dopamine of the order of 70% to 80% is necessary for the symptom threshold to be crossed. In fact, dopaminergic cell depletion precedes the appearance of overt clinical manifestations of parkinsonism by many years.1015 Paradoxically, the correlation between the MRI measurements and the Purdue Pegboard tween
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test was stronger in normal aging subjects than in subjects with Parkinson's disease, even when patients performed worse in this test. It is plausible that at the level at which the amount of neuronal loss becomes symptomatic in pa¬ tients with Parkinson's disease, the existing linear correla¬ tion is partially distorted. At this level, a further minor de¬ crease in size could produce excessive motor impairment and, as a result, the Purdue Pegboard test could be less sensitive. Nevertheless, in this situation the rate of symp¬ toms assessed by the UPDRS was significantly related to the in vivo visible size reduction of the pars compacta. This suggests that, after the symptom threshold has been crossed, loss of dopaminergic neurons is optimally re¬ flected by the clinical status. We found resting tremor to be the symptom most related to changes in the pars compacta. The origin of this symp¬ tom in Parkinson's disease is obscure to date. Parkinsonian tremor has generally been postulated to result from the oscillatory activity of thalamocortical loops, relatively in¬ dependent of basal ganglia circuitry,16 or has been believed to require additional damage to the cerebellofugal sys¬ tem.15 Current research on the methyl-phenyl-tetrahydropyridine neurotoxin provides powerful support for the argument that tremor is produced by lesion of the sub¬ stantia nigra.15 The correlation found in our study between resting tremor severity and width of the pars compacta re¬ inforces this hypothesis on the dopaminergic origin of this kind of tremor. This study was supported in part by a grant of the Ministerio de Sanidad (Spanish Government, grant FTSSs 90/0767) and the Consel¬ leria de Sanitat de la Generalität de Catalunya (autonomous govern¬ ment of Catalonia). We thank Robin Rycroft, PhD, for the English-language revision of the manuscript.
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