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Neuropathological Correlates of Dysarthria in Progressive Supranuclear Palsy
Karen J. Kluin, MS, CCC, BC-NCD;
Sid Gilman, MD;
Norman L. Foster, MD;
Anders A. F. Sima, MD, PhD;
Constance J. D'Amato, BS;
Leslie A. Bruch, MD;
Laurie Bluemlein, RN, MS;
Roderick Little, PhD;
Jewel Johanns, PhD
Arch Neurol. 2001;58:265-269.
ABSTRACT
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Background The dysarthria of progressive supranuclear palsy consists of prominent
hypokinetic and spastic components with less prominent ataxic components.
Objective To correlate the types of dysarthria with neuropathological changes
in patients with progressive supranuclear palsy.
Design and Methods In 14 patients with progressive supranuclear palsy, we correlated the
perceptual speech findings with the neuropathological findings. A dysarthria
assessment was performed a mean ± SD of 31 ± 15 months (range,
10-53 months) before death. The deviant speech dimensions were rated on a
scale of 0 (normal) to 3 (severe). The neuropathological examination consisted
of semiquantitative analysis of neuronal loss and gliosis by investigators
(A.A.F.S., and L.A.B.) blinded to the clinical findings. Correlation and linear
regression analysis were used to correlate the severity of the hypokinetic,
spastic, and ataxic components with the degree of neuronal loss and gliosis
in predetermined anatomical sites.
Results All patients had hypokinetic and spastic dysarthria, and 9 also had
ataxic components. The severity of the hypokinetic components was significantly
correlated with the degree of neuronal loss and gliosis in the substantia
nigra pars compacta (r = 0.61, P = .02) and pars reticulata (r = 0.64, P = .01) but not in the subthalamic nucleus (r = 0.51, P = .07) or the striatum or globus
pallidus (/r/<0.34, P>.20).
The severity of the spastic and ataxic components was not significantly correlated
with the neuropathological changes in the frontal cortex (r = 0.20, P = .50) and cerebellum (/r/<0.28, P>.33), respectively.
Conclusion The hypokinetic dysarthria of progressive supranuclear palsy may result
from degenerative changes in the substantia nigra pars compacta and pars reticulata
and not from changes in the striatum or globus pallidus.
INTRODUCTION
DYSARTHRIA is a cardinal feature of progressive supranuclear palsy (PSP).1 Dysarthria consists of a combination of hypokinetic,
spastic, and ataxic components, usually with prominent hypokinetic and spastic
and less prominent ataxic features.2 Neuropathological
changes in patients with PSP involve neuronal loss and gliosis with neurofibrillary
tangles, argyrophilic and  -positive threadlike structures, and -positive
astrocytic tanglelike inclusions in many subcortical regions, including the
substantia nigra (SN), striatum, globus pallidus, subthalamic nuclei, periaqueductal
gray, pontine nuclei, inferior olives, cerebellar dentate nuclei, and certain
cranial nerve nuclei.1, 3, 4, 5, 6, 7
The anatomical locations of the neuropathological changes responsible for
the dysarthria in patients with PSP have not been determined. In other neurological
disorders, the major types of dysarthria have been linked to specific anatomical
connections in the nervous system. Bilateral involvement of the corticobulbar
pathways is associated with spastic dysarthria, disorders of the cerebellum
and its connections with ataxic dysarthria,8, 9
and diseases of the extrapyramidal pathways with hypokinetic dysarthria.8
We examined the speech disorders of 14 patients with PSP who later underwent
autopsy. We correlated the severity of the specific components of the dysarthria
with the neuropathological changes in structures that have been associated
with dysarthria in other neurological diseases. Preliminary findings have
been reported.10
PATIENTS AND METHODS
Patients with PSP have been studied in research protocols at the University
of Michigan, Ann Arbor, since 1984, and many have been followed up with longitudinal
clinical assessments using the protocols of the Michigan Alzheimer's Disease
Research Center since 1989. The evaluations included neurological examinations,
speech pathology assessments, structural and functional imaging studies, and
subsequent neuropathological examinations at autopsy. We identified all patients
with PSP examined postmortem who had been evaluated by a speech pathologist
(K.J.K.) between 1984 and 1994.
Evaluation of dysarthria included assessment of oral motor and oral
agility skills and perceptual speech analysis. Oral motor examination consisted
of assessment of muscular strength; coordination; accuracy; range of excursion;
and symmetry of head and neck, face, mandibular, tongue, palatopharyngeal,
and respiratory muscles at rest and during reflex and voluntary movements.
Oral agility was assessed by oral diadochokinetic rates and the oral agility
skills subtest of the Boston Diagnostic Aphasia Examination.11
Perceptual speech analysis included identification and rating of the severity
of the deviant speech dimensions during the examination and from videotaped
or audiotaped samples of spontaneous speech, description of the Cookie Theft picture from the Boston Diagnostic Aphasia Examination,11 and oral reading of the "Grandfather Passage."8 We used the definitions of deviant speech dimensions
of Darley et al8 and the University of Michigan
classification of hypokinetic, ataxic, and spastic dysarthrias2, 10, 12
(Table 1). Each deviant speech
dimension identified was assigned a severity score extending from 0 (normal)
to 3 (severe). Weighting factors were applied to emphasize the deviant speech
dimensions most characteristic of each type of dysarthria.2, 10, 12
A total score was obtained reflecting the degree of hypokinesia, spasticity,
and ataxia in speech. The possible scores ranged from 0 to 48 for each dysarthria
type, with higher scores indicating more severe impairment. To ensure consistency,
all speech pathology examinations were performed by a single speech pathologist
(K.J.K.). Methods of measuring the severity of speech disorders have been
described in previous publications.2, 9, 10, 12
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Table 1. Deviant Speech Dimensions for Hypokinetic, Spastic, and Ataxic
Dysarthrias: University of Michigan Classification*
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The neuropathological diagnosis of PSP was based on the findings specified
in the National Institute of Neurological Disorders and Stroke criteria,3 including neuronal loss, gliosis, and neurofibrillary
tangles; the latter were detected with a modified Bielschowsky silver stain
in subcortical nuclei.3, 4, 13
Coexistent Alzheimer disease was determined using the Reagan criteria.3, 14 Neuronal loss and gliosis were graded
semiquantitatively in 46 brain sections stained with cresyl violet–Luxol
fast blue–eosin and phosphotungstic acid–hematoxylin using the
following scale: absent is 0; mild, 1; moderate, 2; and severe, 3. Intermediate
changes were given half values. The pathological changes were scored by consensus
of 2 neuropathologists (A.A.F.S., and L.A.B.), unaware of the clinical findings,
who viewed the sections concurrently in a multiheaded microscope. We formulated
hypotheses concerning the anatomical sites in the nervous system where neuropathological
changes might be correlated with the components of dysarthria. Since the distribution
of the data deviated from normality, we used Spearman rank correlation coefficients
to analyze the relation between hypokinetic, spastic, and ataxic dysarthria
types and neuropathological abnormalities in these predetermined anatomical
sites. The scores for neuronal loss and gliosis in each anatomical area were
added to produce a composite neuropathological score. We created a composite
neuropathological score to limit problems with multiple comparisons, given
the modest sample size and the number of analyses conducted. Based on the
association of hypokinetic dysarthria with several nuclei of the basal ganglia,
we correlated the hypokinetic dysarthria rating with the composite neuropathological
scores in the SN pars compacta (SNc), SN pars reticulata (SNr), subthalamic
nucleus, caudate nucleus, putamen, lateral globus pallidus, medial globus
pallidus, and periaqueductal gray. Based on the association of spastic dysarthria
with corticobulbar projections, we correlated the spastic dysarthria rating
with the composite neuropathological scores in the frontal cortex. Based on
the association of ataxic dysarthria with the cerebellum and related structures,
we correlated the ataxic dysarthria rating and the composite neuropathological
scores in the cerebellar cortex, dentate nuclei, inferior olives, and red
nuclei.
RESULTS
NEUROLOGICAL EXAMINATION
The 14 patients consisted of 7 men and 7 women (mean ± SD age
at death, 69.0 ± 5.8 years; range, 59-80 years). The clinical diagnosis
at the last clinic visit was PSP in all patients. One patient initially was
diagnosed as having Alzheimer disease because of progressive dementia, but
later developed rigidity and supranuclear gaze palsy. Several others were
diagnosed as having Parkinson disease (PD) elsewhere, but had clear signs
of PSP by the time of our initial examination. Twelve patients had received
levodopa during their illness. No benefit was noted in 11, and 1 had a "poor"
response. Motor speech was assessed at the time of the initial examination.
At this time, all 14 patients had cognitive impairments, limb rigidity, supranuclear
gaze palsy, and frequent falls. Although we regularly see our patients at
6-month intervals, some subjects were unable to return for examination as
they became more impaired or were institutionalized. Consequently, the last
clinical neurological examination ratings were performed on average a mean
± SD of 8 ± 8 months before death. The mean ± SD duration
of neurological symptoms before death was 7 ± 2 years (range, 3-10
years). Most of the patients had moderate to severe parkinsonism and gaze
limitations at their last examination. Bradykinesia and axial rigidity were
the most severe motor signs, and 7 patients were unable to stand. Limitation
of vertical gaze was greater than limitation of horizontal gaze in all patients.
At their last clinical examination, nearly all patients had completely lost
voluntary vertical eye movements. Gait ataxia was a common complaint early
in the disease, but frequently became less apparent as the patients became
increasingly immobile. One patient had resting distal tremor, and 2 others
had extensor plantar responses.
SPEECH PATHOLOGY EVALUATION
In most patients, the speech pathology evaluation was performed only
at the time of the patient's initial examination, a mean ± SD of 31
± 15 months (range, 10-53 months) before death. All patients had mixed
dysarthria with hypokinetic and spastic components, and 9 also had ataxic
components (Table 2). Hypokinetic
dysarthria scores ranged from 4 to 39 (mean, 15), spastic dysarthria scores
from 6 to 34 (mean, 18), and ataxic dysarthria scores from 0 to 20 (mean,
5). All patients had masked faces. Thirteen patients had impaired lingual
rapid alternating movements ranging in severity from mild to severe, with
a mean rating of moderate. Ten patients had a brisk jaw jerk, and 9 had a
hyperactive gag reflex. The nonverbal agility skills scores ranged from 0
to 11 of a total of 12 (mean, 4.5). The verbal agility skills scores ranged
from 0 to 14 of a total of 15 (mean, 9).
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Table 2. Speech Pathology Evaluation
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NEUROPATHOLOGICAL FINDINGS
Whole brain weight ranged from 951 to 1390 g (mean, 1197 g). Gross inspection
demonstrated no abnormal cerebral atrophy. Pallor of the SN was seen in all
patients. Extensive subcortical neuropathological changes were found in a
distribution characteristic of PSP, with neurofibrillary tangles and extensive
neuronal loss and gliosis.3, 13
Neurofibrillary tangles were found in all patients in the subthalamic nucleus,
SNc, third nuclear complex, periaqueductal gray, and pontine nuclei. In 13
patients, neurofibrillary tangles were found in the lateral globus pallidus,
locus ceruleus, and inferior olivary nucleus. Tangles were also found in the
putamen of 6 patients, in the claustrum of 5, and in the caudate nucleus of
3. Neuronal loss and gliosis accompanied these changes, and were most severe
in the SNc, periaqueductal gray, subthalamic nucleus, and medial globus pallidus.
Neuronal loss, gliosis, and neurofibrillary tangles were apparent in the regions
chosen for correlational analysis (Table
3). Two patients had neuropathological changes of Alzheimer disease
and PSP, and the other 12 had only pure PSP.
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Table 3. Neuropathological Findings*
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CORRELATION OF SPEECH DISORDER WITH NEUROPATHOLOGICAL CHANGES
The severity of the hypokinetic component of dysarthria was significantly
correlated with the neuropathological score in the SNc and SNr. A sizeable
correlation was also found with the degree of neuronal loss and gliosis in
the subthalamic nucleus, but this did not reach statistical significance (Table 4 and Figure 1). Correlations with other predetermined anatomical sites
in the striatum and globus pallidus were smaller and statistically insignificant
(/r/<0.34, P>.20). We
adjusted for the duration from the speech pathology evaluation to death by
multiple regression with dysarthria as outcome, and the adjusted correlations
were similar.
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Table 4. Correlations of Hypokinetic Dysarthia With Neuropathological
Changes
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Severity of hypokinetic dysarthria and neuropathological score in
predetermined regions. A significant relation was found between the severity
of hypokinetic dysarthria and the neuropathological score in the substantia
nigra pars compacta (A) and the substantia nigra pars reticulata (B). There
was a relation that did not reach statistical significance between the severity
of hypokinetic dysarthria and the neuropathological score in the subthalamic
nucleus (C) but no correlation for the striatum (caudate nucleus and putamen)
(D). The number 1 signifies data from 1 patient; 2, data from 2 patients at
overlapping sites.
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To assess whether the relation between neuropathological changes in
the SN and hypokinetic dysarthria might be attributable to symptoms of dysarthria
in general, we correlated the sum of 2 nonhypokinetic types of dysarthria,
spastic and ataxic, with the severity of the neuropathological changes. We
found no significant correlations in any of the regions (P>.12 for all); estimated correlations with the SN were in fact slightly
negative (SNc: r = -0.43, P>.12; SNr: r = -0.15, P>.60). Furthermore, the correlations between hypokinetic dysarthria
and neuropathological scores in the SN persisted when the sum of spastic and
ataxic dysarthria was controlled by linear regression. Specifically, the P values for these partial correlations were .05 for the
SNc and .03 for the SNr.
Spastic dysarthria components were not closely correlated with neuropathological
changes in the frontal cortex (r = 0.20, P = .50), and ataxic dysarthria components did not correlate significantly
with the neuropathological changes in the dentate nucleus, inferior olives,
or red nuclei (/r/<0.28, P>.33).
All patients except 1 had neuropathological scores of 0 in the cerebellar
cortex, preventing correlations of the severity of ataxic dysarthria with
pathological features in this site. The dysarthria scores of the 2 patients
with Alzheimer disease and PSP were within the same range as those of the
patients with pure PSP.
COMMENT
This study revealed significant correlations between the intensity of
the neuropathological changes in the SNc and SNr and the severity of the hypokinetic
components of dysarthria in patients with PSP. We found no significant correlations
with neuropathological changes in the striatum, globus pallidus, or periaqueductal
gray. We selected the SN for correlation in relation to the hypokinetic components
of dysarthria because of the similarity of the hypokinetic dysarthria in patients
with PSP to that in patients with PD and the known intense neuropathological
changes in this site in those with both PD and PSP. Darley et al8
proposed that hypokinetic dysarthria reflected extrapyramidal dysfunction
based on examination of patients with PD. In patients with both PSP and PD,
there is severe neurodegeneration within the SNc and decreased inhibitory
input to the SNr from the globus pallidus, but only in those with PSP is there
substantial loss of SNr neurons.15 In patients
with PSP, the striatum and the globus pallidus are also involved, but in those
with PD these regions are spared. The severity of neuropathological changes
was considerably less in the striatum than in the SN, which may be a reason
for the nonsignificant correlations for this structure. The medial globus
pallidus, subthalamic nucleus, and periaqueductal gray had severe neuronal
loss and gliosis, but the neuropathological changes in these structures were
not significantly correlated with the severity of hypokinetic dysarthria.
Hence the findings in the present study suggest that the most important structures
in the pathophysiology of hypokinetic dysarthria in patients with PSP may
be the SNc and the SNr. The SNr is the output station of the basal ganglia
and projects to anterior/ventral lateral, mediodorsal, and midline thalamic
nuclei, superior colliculus, and pedunculopontine nucleus in the brainstem.16 The role of the SNr in patients with dysarthria may
be related to the projections into the brainstem.
We found no significant correlations between the spastic and ataxic
components of dysarthria and the severity of neuropathological abnormalities
in sites known to be affected in those with PSP and associated with these
types of dysarthria. We also correlated with neuropathological scores the
sum of the 2 nonhypokinetic types of dysarthria, spastic and ataxic. We found
no correlations in any of the regions studied, indicating that symptoms of
dysarthria in general do not account for the correlation between hypokinetic
dysarthria and neuropathological changes in the SN. While these results should
be interpreted with caution given the limited sample size, they are consistent
with a link with the SN that is specific to the hypokinetic dysarthria components.
Dysarthria has been reported as the second most common clinical manifestation
of PSP.17 The SN, globus pallidus, and subthalamic
nucleus are the areas with the most severe neuropathological abnormalities
in patients with PSP, raising the possibility that the pathological process
starts there.18
The patients described in this study appear to represent an appropriate
sample of patients with PSP. All met clinical and neuropathological criteria
for PSP.1, 3, 4, 5, 13
All had mixed dysarthria with hypokinetic and spastic components, and more
than half had ataxic components. The spectrum of clinical findings in these
patients was similar to those in previous reports.4, 17
In keeping with an earlier report,19 our series
included an equivalent proportion of men and women; however, a recent report20 stated that PSP affects men more frequently than
women. As in our sample, in PSP, resting tremor is unusual, dysarthria and
gaze limitation are consistently present late in the illness, and vertical
eye movements are more severely affected than horizontal eye movements.4, 17, 20, 21
In this study, the time from diagnosis and speech pathology evaluation
to death was long, and many of our patients became anarthric during that time.
The neuropathological changes doubtless advanced in the SN and the other structures
affected from the time of diagnosis and dysarthria assessment to the time
of death. Despite these concerns, the correlations of hypokinetic dysarthria
with neuropathological changes in the SNc and SNr were significant, perhaps
reflecting the importance of these sites in the pathogenesis of hypokinetic
dysarthria.
AUTHOR INFORMATION
Accepted for publication August 1, 2000.
This study was supported in part by grant P50AG08671 from the National
Institute on Aging, National Institutes of Health, Bethesda, Md (Michigan
Alzheimer's Disease Research Center).
From the Departments of Speech-Language Pathology (Ms Kluin), Neurology
(Mss Kluin and Bluemlein and Drs Gilman and Foster), Pathology (Dr Sima and
Ms D'Amato), and Biostatistics (Drs Little and Johanns), University of Michigan
Health System, Ann Arbor; the Department of Pathology, Wayne State University,
Detroit, Mich (Dr Sima); and the Department of Pathology and Microbiology,
University of Nebraska, Omaha (Dr Bruch).
Corresponding author and reprints: Karen J. Kluin, MS, CCC, BC-NCD,
Department of Speech-Language Pathology, University of Michigan Health System,
1D203 University Hospital, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0043.
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