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Dementia and motor neuron disease Morphometric biochemical and Golgi studies.

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Dementia and Motor Neuron
Disease: Morphometric, Biochemical,
and Golgi Studies
D. S. Horoupian, MD," L. Thal, MD,t R. Katzman, MD,? R. D. Terry, MD," P. Davies, MD,"
A. Hirano, MD," R. DeTeresa, BS," P. A. Fuld, PhD,? C. Petito, MD,$ J. Blass, MD,§ and J. M. Ellis, MD"
In three patients dementia without neurofibrillary tangles or Pick bodies antedated amyotrophy by several years. The
motor neuron disorder in two patients was characterized by terminal bulbar symptoms; in one it was similar to classic
amyotrophic lateral sclerosis. In two patients, quantitative studies of selected regions of the cortex using a computerized image analyzer disclosed, as in patients with senile dementia of Alzheimer type, a marked reduction in the
number of neurons, especially those larger than 90 p2. The findings differed from those in Alzheimer dementia,
however, in that the cells in the substantia innominata were not reduced and the levels of choline acetyltransferase and
somatostatin-like immunoreactivity, determined in one patient, were within normal limits. A variable degree of
sponginess of the upper layers of the cortex was attributed to attrition of pyramidal cell dendrites, observed in the one
patient in whom Golgi study was successful. Because of severe degeneration of the substantia nigra in all three, the
disease in these patients may represent a subset of motor neuron disease or a multisystem atrophy.
Horoupian DS, Thal L, Katzman R, Terry RD, Davies P, Hirano A, DeTeresa R, Fuld PA, Petito C, Blass J,
Ellis JM: Dementia and motor neuron disease: morphometric, biochemical, and Golgi studies.
Ann Neurol 16:305-313, 1984
Dementia in amyotrophic lateral sclerosis (ALS) is well
recognized 122J. It occurs with some frequency in cases
of ALS in the western Pacific, largely because ALS and
parkinsonism-dementia complexes are two progressive
neurological disorders occurring at extraordinarily high
rates in the Chamorro population and certain tribes of
West Guinea 121, 361. It has been reported occasionally in familial ALS, often in its juvenile form, but the
pathological picture in such instances resembles multisystem atrophy more than pure motor neuron degeneration 151. Dementia is rare in sporadic or classic ALS
{8, 231 and is often attributed to concurrent senile dementia of Alzheimer type (SDAT). However, there
are also reports of ALS, sometimes familial, in which
the frequency and severity of the SDAT changes, such
as neurofibrillary tangles and neuritic plaques, were not
commensurate with the degree of intellectual impairment { 141. These patients frequently displayed sponginess and loss of neurons in the upper cortical layers
of the frontal and temporal lobes. Mitsuyama and
Takamiya 1281 suggested that cases of ALS with dementia but without neurofibrillary tangles and parkin-
From the "Department of Neuropathology and Montefiore Medical
Center and tThe Saul R. Korev Deoartment of Neurolom. the Rose
F. Kennedy Center for ResearLh in-Mental RetardationLnd Human
Development, Albert Einstein College of Medicine and the Bronx
Municipal Hospital Center, Bronx, NY; the Departments of
$Pathology and §Neurology, Cornell Medical Center, New York,
NY; and "Berkshire Associates, Pittsfield, MA
sonism may represent a new nosological entity,
whereas Masters and co-workers 1261regarded them as
variants of classic ALS.
This report presents three patients in whom dementia without neurofibrillary tangles antedated by several
years a motor neuron disorder. In two, quantitative
studies were performed on selected sections of the cortex, and in one the levels of certain neurotransmitters
were determined. One patient's brain was studied with
the rapid Golgi technique.
Case Reports
Patient 1
A 52-year-old right-handed man had developed dementia,
personality changes, and fasciculations beginning at age 45.
He had been a chemical engineer and had been in contact
with aluminum and other toxic substances. He had lost his
job and eventually had become unable to retain even menial
jobs because of intellectual deterioration. Judgment and
memory, as well as his ability to abstract and calculate, became impaired. Evaluation two years before death revealed
normal language, diffusely impaired cognition, diffuse fasciculations, mild proximal upper extremity weakness, lower
Received Aug 16, 1983, and in revised form Feb 10, 1984. Accepted
for oubkation Feb 13., 1984.
-
Address
requests
reprint
to Dr Horoupian, Department of Pathology (Neuropathology) K-438, Albert Einstein College of Medicine,
1300 Morris Park Ave, Bronx, NY
305
Fig 1 . (Patient 1 . j The frontal poles are on the right side and
disglay marked atrophy of the frontal gyri and widening of the
sulci. The missing slabs in the left frontal and right parietal
lobes were usedfor biochemical studies.
extremity hyperreflexia, and a mild snout reflex. Laboratory
investigations yielding normal findings included serum and
urine heavy metals, electroencephalogram (EEG), and nerve
conduction velocity studies. Electromyography (EMG) revealed fasciculations, and a computed tomographic (CT) scan
showed diffuse atrophy.
Two months later, swallowing difficulties and a rapid intention tremor developed. Evaluation one year before death
showed a short attention span, limited speech, diminished
word-finding capacity, perseveration, difficulty with left-right
coordination, and decreased comprehension. The patient was
noted to stare, and a palmomental reflex had developed. A
C T scan revealed atrophy and ventricular dilatation. He
underwent right frontal lobe and right deltoid biopsies. The
brain biopsy findings were normal; the muscle biopsy showed
neurogenic atrophy.
He was discharged to a nursing home, where he became
more temperamental and weaker, with pronounced atrophy
and fasciculations of many muscles, including the tongue.
EEG shortly before death at age 52 revealed generalized
slowing. His mother had had parkinsonism and later dementia.
GROSS NEUROPATHOLOGY. The brain was atrophic (Fig 1).
The sulci were widened and the gyri narrowed, particularly in
the frontal and parietal lobes. The ventricles were slightly
dilated, especially in the frontal horns. The cortical gray mantle was of normal thickness. The white matter, basal ganglia,
and thalami were normal. The hippocampi were not atrophic.
The substantia nigra and locus ceruleus were pale. The spinal
cord was normal, but the ventral roots were thinned and
abnormally gray.
MICROSCOPIC NEUROPATHOLOGY. There was moderate
gliosis in the subpial region, with subtle patchy loss of
Fig 2. (Patient 1 .) The secondary and tertiary branches of the
apical dendrites of the pyramidal cells of layer 3 are reduced.
(Rapid Go&; X 160.)
neurons and vacuolization of the neuropil in layer 2. The
tissues were stained with both Bodian’s silver Protargol
and thioflavine S, and none of the sections displayed
neurofibrillary tangles. There were no other abnormal intracellular inclusions except for excess lipofuscin. The proportion of well-impregnated pyramidal cells in Golgi preparation was small and adequately represented only in the frontal
and parietal sections. The apical and basilar dendritic arborizations of several of the pyramidal cells in these areas were
sparse, with depletion of the tertiary branches. The dendrites
were thin and free of varicosities, and many showed a patchy
loss of spines (Fig 2). Fiber loss affected the corticospinal
tracts in the midbrain, basis pontis, and medullary pyramids.
There was severe loss of pigmented neurons in the substantia
nigra and locus ceruleus. Ammon’s horn and substantia innominata were normal. The hypoglossal nucleus showed loss
of neurons, a few spheroids, and gliosis. A Bunina inclusion
body and a Lewy-like body were present in two separate
neurons.
The anterior horns of various segments of spinal cord
were gliotic and depleted of motor neurons. Some surviving neurons were chromatolytic, and one was undergoing
neuronophagia. There were no Bunina bodies or intracytoplasmic arygrophilic spheroids. Both the lateral and anterior
corticospinal tracts displayed mild gliosis, moderate loss of
myelinated fibers, and many neutral lipid-laden macrophages.
One side was more affected than the other (Fig 3). Cross
306 Annals of Neurology Vol 16 No 3 September 1984
Fig 3. (Patient 1 .) Asymmetrical pallor of the corticospinal
tracts. (Heidenhain’s myelin stain; x 4.)
sections of ventral and dorsal spinal roots displayed no abnormalities except for a reduced number of fibers in the former.
Appropriate blocks of the cerebral cortex embedded in
paraffin were sectioned 20 p thick and stained with cresyl
violet. Cell counts using a computer image analyzer (Quantimet 720, Cambridge/Imanco) were performed by the
method previously described by Terry and colleagues [38).
The results appear in Table 1.
Patient 2
A 54-year-old right-handed woman had developed memory
loss and personality changes beginning at age 50. After one
year of illness her examination was notable for findings of
memory loss and dyscalculia. A C T scan showed mild atrophy; an EEG and results of all additional laboratory investigations were normal. Six months later visual hallucinations
developed. Over the next six months there was a slow decline
in the amount and content of speech. Swallowing difficulties
developed, and weight loss ensued. Mental deterioration and
self-care worsened. O n e year later she was able to follow
simple commands but was aphonic. One week prior to death,
examination showed that there was an increased gag reflex,
mild atrophy of the tongue, marked dysphagia, mild decrease
in muscle bulk and power with slightly increased tone, mild
but diffuse hyperreflexia, and a prominent snout reflex.
GROSS NEUROPATHOLOGY. The right half of the cerebrum
was frozen for biochemical assays. The left cerebral hemisphere weighed 500 gm and the half brainstem and cerebellum weighed 90 gm, giving a calculated fixed brain weight of
1,180 gm. The vessels were free of atheroma. The external
configuration was normal except for mild gyral atrophy.
The cortical ribbon was of normal thickness. The lateral
ventricle was minimally enlarged. The basal ganglia and
thalamus were intact. The substantia nigra was depigmented.
The cerebellum and brainstem were normal.
MICROSCOPIC NEUROPATHOLOGY. The cortical ribbon in
the cingulate and superior temporal gyri appeared to be attenuated and hypercellular because of reactive astrocytosis at
the junction of the cortex and white matter. These sections
also displayed spongiform changes in the superficial two or
three layers of the cortex (Fig 4). There were no Pick bodies,
neurofibrillary tangles, or neuritic plaques. Ammon’s horn,
substantia innominata, striatum, and thalamus were normal.
The substantia nigra showed severe degeneration of the nigral cells, especially in the zona compacta (Fig 5 ) . Neuromelanin was present in many reactive astrocytes and occasional
macrophages. No Lewy bodies or tangles were observed. The
locus ceruleus was spared. The corticospinal tracts in the
brainstem were pale in sections stained for myelin, and the
density of axons was reduced in Bodian preparation. The
hypoglossal nucleus was represented by a circular gliotic
patch with prominent reactive astrocytes (Fig 6).The neurons
were markedly depleted, and those present were reduced in
size. Occasional axonal spheroids were present. Only the
very proximal segment of the cervical cord was available for
examination, and this showed mild pallor along the course of
the pyramidal tracts.
The cell counts appear in Table 1.
BIOCHEMICAL FINDINGS. The right cerebral hemisphere
was frozen at postmortem examination and stored at - 70°C.
Samples were assayed for choline acetyltransferase (Ch AT)
activity and somatostatin-like immunoreactivity by methods
previously described Ell, 12). The results obtained are presented in Table 2.
Patient 3
A 5 8-year-old left-handed woman had developed memory
loss and personality change at age 54. Hallucinations and a
fixed delusional system developed; these symptoms failed to
improve with a course of electroconvulsive therapy. After
one year of illness, examination revealed mild dyscalculia,
poor abstraction, mild dysnomia, mild memory loss, bilateral
palmomental reflexes, and a markedly positive snout reflex.
Laboratory evaluation, including an EEG and C T scan,
Horoupian et al: Dementia and Motor Neuron Disease
307
Table I . Cell Counts Using the Computer I m g e Analyzer"
Cell Sizes
Patient 1
Patient 2
SDAT(n
Under 40 p2
40-90 pL2
Over 90 p'.
1,435
762
190
1,539
610
199
1,978
672
213
1,462
850
422
Cell counts (mm2)
Cell area ( 9j
2,072
9.4
1,812
7.5
2,223
8.6
1,667
9.4
Under 40 k2
40-90 pL2
Over 90 k 2
1,998
639
198
2,149
49 1
134
2,004
713
167
917
1,003
469
Cell counts (mm2)
Cell area (57 )
2,072
8.2
1,83 5
5.6
2,311
8.7
1,391
9.1
Under 40 k2
40-90 k2
Over 90 k 2
1,090
707
329
...
...
1,950
654
188
1,313
932
44 5
Cell counts (rnm')
Cell area (%)
1,406
7.8
2,033
7.5
1,670
8.9
=
26)
Normals (n
=
4)
MIDFRONTAL REGION
INFERIOR PARIETAL REGION
SUPERIOR TEMPORAL REGION
...
"Cell counts from the first two patients are compared with the mean results obtamed from a group of patients with SDAT (mean age, 82 years)
and a group of age-matched normal controls (mean age, 5 5 years). Cells under 40
are considered to be glia 1381
SDAT
=
senile dementia of Alzheimer type
Fig 4. (Patient 2.)Astrocytosis and vacuolations of the upper
layers of the frontal cortex. (H&E; X 40.)
308 Annals of Neurology Vol 16 No 3 September 1984
Fig 5 . (Patient 2.) Arrow points t o the degenerating substantia
nigra; the arrowhead shows the pallor of the medial segment of
the baszs pedunculi. I H 6 E ; x 2 0.)
yielded normal findings. Psychometric testing revealed a Verbal I Q of 82, a Performance IQ of 84, and a pattern of test
scores atypical for Alzheimer’s disease (AD).
During the subsequent year delusions and hallucinations
continued. Dyskinetic movements of the face and mouth developed. The patient became hypophonic and bradykinetic.
Repeat psychometric testing one year later showed a decline
in all areas of cognitive functioning, with a pattern still atypical for AD.
Examination eighteen months later revealed weight loss,
hypophonia, swallowing difficulties, severe dysarthria, and
frontal lobe release signs that now included bilateral grasp
reflexes. The patient died in a nursing home after a four-year
course.
The brain weighed 1,230 gm
and showed mild cortical atrophy. The cerebral vessels were
mildly atherosclerotic. There was moderate dilatation of the
lateral ventricles. The substantia nigra and locus ceruleus
were pale. Cerebellum and spinal cord were normal.
GROSS NEUROPATHOLOGY.
MICROSCOPIC NEUROPATHOLOGY. The cortex showed
sponginess of layers 2 and 3, especially in the temporal and
frontal regions. There were no neurofibrillary tangles or
senile plaques. The subcortical nuclei, including the substanria innominata, were normal. The zona compacta showed
moderate neuronal loss, numerous melanin-containing macrophages, and rare Lewy bodies. T h e locus ceruleus was depigmented but without obvious loss of cells. The corticospirial traCtSand frontopontine fibers in the basis pedunculi were
pale. The hypogJ&sal nucleus was atrophic and g,iotic,
its
neurons were shrunken and chromatolytic. Sections of the
spinal cord showed marked neuronal loss, atrophy, rare
neuronophagia, and several axonal spheroids in the anterior
Fig 6. (Patient 2.1 The hyPoglossal n U c h (outlined b dot.() is
Pale andgliotic. A m w Points t o the Cavity o f t b e b r t h 0enh-icle. ( H 6 E ; x 10.) (Inset) The redctiue astrocytosis in the nucleus.
(Phos~hotungstic acid-hematoxylin~
40.)
Horoupian et al: Dementia and Motor Neuron Disease
309
Table 2. Choline Acetyltransferase Activity and
Somatostatin-like Imrnunoreactivity“
Brain Region
Patient 2 Normals
SDAT
CHOLINE ACETYLTRANSFERASE ACTIVITY
Frontal
427
Parietal
465
Occipital
525
Superior temporal 705
Midtemporal
546
Inferior temporal
658
473
Hippocampus
4,374
Caudate
374 ? 59
48 ?
305 47
35 &
216 2 27
31 ?
428 r 67
47?
301 k 35
37 2
306 2 45
33
575 f 77
168 ?
3,140 f 600 1,637 2
*
*
7
8
5
16
14
7
31
300
SOMATOSTATIN-LIKE IMMUNOREACTIVITY
Frontal
Parietal
Occrpital
Superior temporal
Midtemporal
Inferior temporal
3.22
2.57
2.03
2.63
2.83
3.30
2.77 2 0.41
3.27 ? 0.73
1.20 ? 0.30
3.05 ? 0.37
4.34 f 0.44
2.86 ? 0.45
0.73 2 0.15
1.37 ? 0.35
0.43 2 0.09
0.78 0.30
1.07 2 0.22
1.08 t 0.26
*
“Choline acetyltransferase activities in the cortex are expressed in
nanomoles of acetylcholine produced per hour per 100 mg of protein. Values for patient 2 are the means of triplicate determinations;
those for normals and patients with SDAT are means ? SEs for
eleven or twelve cases. Somatostatin-like immunoreactivity in the
cortex is expressed in nanograms per milligram of protein. The
values for patient 2 are the means of duplicate estimations performed
on three separate tissue extract dilutions. Values for normals apd
patients wirh SDAT are means 4 SEs for eleven or twelve cases.
Further details of methodology can be found in refs. [ l l ) and 112).
SDAT = senile dementia of Alzheimer type.
horns. There were no abnormal intracellular inclusions in the
motor neurons. The lateral and anterior corticospinal tracts
were pale and gliotic. The myelinated fibers in the anterior
nerve roots were reduced.
The skeletal muscle displayed scattered small groups of
atrophic, angular fibers.
Discussion
Various forms of psychotic behavior have been described in sporadic ALS { 161, but it is not clear whether
this behavior relates directly to the abnormalities of the
disorder. All three of our patients had prominent behavioral disturbances antedating their motor neuron
disease (MND), and two had hallucinations, as did one
patient of Ziegler (47). Similar behavioral problems
preceding M N D were reported by Boudouresques and
colleagues {6) and by Finlayson and associates [14] in
patients with familial ALS dementia. The association
seems more than coincidence.
Dementia is rare in classic ALS. Brownell and coworkers IS] found only one case of dementia in their
thirty-six patients with ALS, and that patient was about
80 years old. Dementia is more often seen in familial or
unusual variants of ALS (2, 33). In such instances dementia often manifests itself late in the course of the
310 Annals of Neurology Vol 16 No 3
disease, but occasionally it may precede the onset of
MND [47]. Reported patients in whom dementia occurred concurrently with or before motor neuron
symptoms, including our own, are described in Table 3
{I, 3, 6, 14, 20, 27, 28, 35, 40, 43, 45-47]. Excluded
from the list are patients who were assumed to have
Pick‘s disease clinically and those who displayed Pick
bodies or moderate to severe SDAT changes postmortem. In most of the listed patients, dementia occurred
three months to five years before they were suspected
to have MND. Those who had psychometric studies
similar to those of our patients 1 and 3 were said to
have test patterns atypical for AD {17, 32). In AD,
patients generally demonstrate a Verbal-Performance
IQ differential of 15 points or more, with marked lowering of the Performance IQ. Visuospatial relations are
generally severely affected. This Verbal-Performance
IQ differential was not observed in the two patients
who were tested. This finding, coupled with marked
fluctuations in level of responsiveness during the testing procedure, suggested that a process other than AD
was responsible for the dementing illness.
The pathological substrate of the dementia in our
patients and in those reported in the literature consisted mostly of nonspecific neuronal abnormalities and
gliosis, especially of the upper layers of the cortex, with
sponginess of the neuropil. T o our knowledge no
quantitative or Golgi studies were performed in such
brains. In two patients studies of cell counts showed
reduction in neurons, especially in the large cell category (see Table 1); the figures were 190 and 198 m
patient 1 and 199 and 134 in patient 2 for the midfrontal and inferior parietal cortex, respectively. In the normal matched controls the figures were 422 and 469,
respectively. These findings of reduced neurons in the
cortex were somewhat similar to those obtained from
patients with SDAT (213 and 167, respectively) 1381.
Although our study constitutes a small series and it is
prudent to avoid drawing definitive conclusions, this
quantitative analysis suggests that marked loss of
neurons does take place in the frontal lobes in this
condition and that the attrition may be more severe
than in SDAT. It is possible that in this particular disorder the “abiotrophy” (a term coined by Gowers in
1902) of the pyramidal cells commences in the frontal
lobes and later extends into the motor cortex to involve
Betz cells. Cortical atrophy in ALS, especially that of
the frontal lobes, may be diffuse f231, as was recently
confirmed by CT studies in which its incidence was
significantly higher in those with M N D than in
matched controls (30).
Sponginess of the upper layers of the cortex, which
was variable in extent in our three patients, is not
specific to this condition. It has been described in a
number of degenerative disorders, such as AD {l5]
(especially in the familial form), less frequently in
September 1784
Table 3. Characterirtics of Patients Showing Dementia Concurrent(y with or before Motor Neuron SymptomJDuration of Symproms before Drath
Study
t
Sex
Age at
Death (yrl
Dementia
iyr)
Bulbar
Manifestations
Extremity
Involvement IyrJ
Ziegler 1471
Patient 1
Patient 2
Weschler and Davison 1401
Patient 1
Yuasa [451
Harada et al (201
Boudouresques et al [6]
F
M
50
50
M
M
M
M
48
463
54
Bonduelle et al [ 31
Patient 2
F
59
Yuasa (461
F
56
Shirdbe et d [ 3 5 ]
F
13
l++)lyr
F
60
I+J 1 vr
F
F
F
6
( t+ + J L yr
i f )1
'
4
l+++Jhmo
l+++JNC
i+JNC
M
52
F
F
5s
58
Mitsuyama and Takamatsu
Wikstrom et al[43]
Patient 1
Patient 2
A k a et al (11
Present study
Patient 1
Patient 2
Parient 3
[27]
Pathology Findings
Other Than M N Invulvement
Family History
~
~
Stnatal, thalamic and nigral
cell loss and gliosis
T
54
lt++)l'.?
1
I+)
1
Father i '0 y r old)
quadriparetic for 3 yr
Srriatal. thalamic. and nigral
cell IOSS dnd RllOSlS
Striatal and thalamic cell loss
and gliosis
Striaral and thalamic cell loss
and gliosis
-
~
Degeneration o! subsranria nigra
+ + ) 2 yr
4
(+
4
(t++J2yr
MN = motor neuron; F = female; M = male; T = terminally; NC
= severe:
= absent or not mentioned
=
+)T
(+)T
i
Mother had parkinsonism and larer
dementia
Degeneration of substantia nigra
Degeneration of substanria nigra
relation of bulbar symptoms to extremity signs not clear from history;
i =
mild,
~
++
=
moderate;
+++
~
SDAT, Pick's disease, and parkinsonism-dementia
complex of Guam 1371, and in atypical presenile de..
mentia C25J. It has been assumed that the spongy appearance is due largely to attenuation and reduction of
the dendritic arbor of some pyramidal neurons that
expand in the upper layers of the cortex, but to our
knowledge this assumption has not been verified by
Golgi impregnation. Results of our Golgi study, successful only in patient 1, tend to support this view. The
pyramidal cells had thinned-out dendrites with fewer
tertiary branches, partially deprived of their spines. In
classic ALS dendritic changes were also reported singularly affecting Betz cells but not the other pyramidal
cells of layer V of the motor cortex 1171. i t has been
assumed that spine loss and alterations in dendritic
spine geometry affect the integrative process of the
dendritic systems 1311. It is possible, therefore, that
attrition of large neurons and shriveling of the pyramidal cell dendrites provide an anatomical basis for the
mental symptoms, as in SDAT. The findings differed
from those in AD, SDAT 141, 421, and Guamaian
parkinsonism-dementia complex 127J, however, in that
the cells in the substantia innominata were not decreased. Both the ChAT activity and the concentration
of somatostatin-like immunoreactivity in one patient
were within the normal range, further distinguishing
this condition from SDAT Ell, 12). To our knowledge, determination of ChAT was undertaken only
once in a similar case, and the level was found to be
normal {lo].
The first manifestation of motor neuron involvement
in two of our patients and in several of those cited in
Table 3 was bulbar symptoms. Hypophonia, dysphagia,
regurgitation, and atrophy of the tongue were common. Muscular twitchings and pyramidal signs were
elicited largely in the face and proximal upper extremities and less frequently in the trunk and lower
limbs. Gliosis of the hypoglossal nucleus was a constant
finding, and tract degeneration of the corticospinal and
sometimes the frontopontine fibers of varying severity
was demonstrated in the brainstem and spinal cord.
Degeneration of anterior horn cells was most severe in
patient 1 and less striking in the other two.
Patient 3 had signs and symptoms of parkinsonism,
but these were lacking in the other two patients despite
severe degeneration of the substantia nigra. The severity of parkinsonism need not correlate with the extent
of neuronal loss in the substantia nigra, especially when
this condition is associated with MND 1241. In ALS,
particularly in later stages of the disease, the symptoms
of parkinsonism may be masked by weakness and
spasticity [7}. The rare occurrence of extrapyramidal
syndromes with ALS has been previously described [4,
IS}, the best example being that of the family studied
by Van Bogaert and Radermecker 1371. Some of its
members had either parkinsonism or ALS, and in one
Horoupian et al: Dementia and Motor Neuron Disease 311
family member parkinsonism was associated with m y otrophy.
Degeneration of the substantia nigra occurring
with dementia poses a problem in the nosological
classification of such cases of MND. They could be
included among the spectrum of multisystem degeneration, and some have been variously referred to as corticopallidospinal or corticostriatospinal degeneration
113, 441. They also could be considered a subset of
MND. This problem of nomenclature has been debated especially by French authors who regard such
cases as a variant of M N D {2, 3, 4, 6, 91, part of the
reasoning being that despite the occurrence of parkinsonism and dementia with NETS, cases of ALS in
Chamorros were considered a special form of MND.
Castaigne and associates {9] even proposed that some
of these cases be designated as “formes dementielles de
la sclerose amyotrophique laterale.” The findings in our
patients bear some resemblance to those reported by
Boudouresques and co-workers {6],the second case of
Bonduelle and colleagues {3}, and the patients studied
by Castaigne and associates {9]. These researchers all
stressed that these cases were in no way variants of
Creutzfeldt-Jakob disease, as previously suggested, because they lacked the reactive astrocytes and because
the spongy change had a laminar distribution unlike
that of Creutzfeldt-Jakob disease. Salazar and colleagues [34] also concluded from animal transmission
studies that the syndromes of ALS and dementia
should not be considered as amyotrophic CreutzfeldtJakob disease.
Recently Mitsuyama and Takamiya {28] described a
patient with dementia and ALS and suggested that the
condition be considered a new clinicopathological entity; postmortem study was not performed, however,
and “silent” degeneration of the substantia nigra could
not be ruled out. Masters and co-workers {26} regarded these cases as variants of ALS, an opinion endorsed by Hudson {22] after extensive review of the
literature. Irrespective of the nosological classification,
one must be aware of this condition in which dementia
is followed by bulbar manifestations with or without
muscular involvement of the extremities. Whatever
one calls it, and we prefer “dementia of MND,” this
condition should be considered in the differential diagnosis of presenile dementia, especially if the brain
biopsy fails to show N l T s or Pick bodies or spongiform encephalopathy of Creutzfeldt-Jakob d‘isease.
Partially supported by Research Grant AG 02478 from the National
Institutes of Health.
The authors acknowledge the Kresge Foundation for having provided the funds to purchase the image analyzing apparatus, and A.
Geoghan and P. Garcia for the secretarial and technical help, respectively.
312
Annals of Neurology
Vol 16 No 3
References
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of a case with features of presenile dementia and motor neuron
disease. Neuropathology 3:39-48,1982
2. Bonduelle M: Amyotrophic lateral sclerosis. In Vinken PJ,
Bruyn GW (eds): Handbook of Clinical Neurology, Vol 22.
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