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Atypical Alzheimer's disease with spastic paresis and ataxia.

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BRIEF COMMUNICATIONS AND CASE REPORTS
Atypical Alzheimer’s
Disease with Spastic
Paresis and Ataxia
Hisashi Aikawa, MD,”? Kinuko Suzuki, MD,t
Yuzo Iwasaki, MD,” and Reiji Iizuka, MDS
~
~~
~~~~
~~
An unusual case of Alzheimer’s disease (AD) is reported.
The patient was a 33-year-old Japanese housewife who
had progressive dementia, severe spasticity, and mild
ataxia for six years. Postmortem examination revealed
severe changes of AD and degeneration of the corticospinal tracts, as well as neuritic plaques and plaquelike
degeneration in the cerebellum. This appears to be the
twelfth reported case of AD with spasticity and ataxia.
Aikawa H , Suzuki K, Iwasaki Y , Iizuka R:
Atypical Alzheimer’s disease with spastic paresis
and ataxia. Ann Neurol 17:297-300, 1985
Alzheimer’s disease (AD), t h e most c o m m o n cause of
dementia, usually affects patients older than 45 years
[9}. Recently, w e examined t h e brain of a patient with
dementia, spasticity, and ataxia which began at age 27
and resulted in death six years later. I n addition to
severe changes of AD in the cerebrum, degeneration
of t h e corticospinal tracts and cerebellar plaques were
observed.
We report the clinicopathological features of this
patient, describe electron microscopic findings in t h e
cerebellar plaques, and review similar cases of AD reported by others.
Case Report
A 30-year-old Japanese housewife was admitted because of
progressive mental deterioration and gait disturbance. The
patient was married and had a healthy child. She had no
siblings and there was no family history of neurological or
mental disorders.
At age 21, she developed difficulty in concentrating on
household matters and at times became irritable. Gradually
she became forgetful and her speech became slurred. At
age 29, progressive right-sided weakness appeared. Subse-
From the ‘Department of Ultrastuctural Research, National Center
for Nervous, Mental and Muscular Disorders, 2620 Ogawa-HigashiMachi, Kodaira, Tokyo 187, Japan; the +Departments of Pathology
(Neuropathology) and Neuroscience, Albert Einstein College of
Medicine, 1300 Morris Park Ave, Bronx, N Y 10461; and the fDepartment of Psychiatry, Juntendo University School of Medicine,
2-1-1 Hongo, Bunkyo-Ku, Tokyo 113, Japan.
Received May 7, 1984, and in revised form Jul 2. Accepted for
publication Jul 8, 1984.
Address reprint requests to Dr Aikawa, Department of Pathology
(Neuropathology),Rose F. Kennedy Center in Mental Retardation
and Human Development, Albert Einstein College of Medicine,
1300 Morris Park Ave, Bronx, NY 10461.
quently, she became more unsteady, stumbied over small
objects, and fell frequently.
Her past medical history was noncontributory. She had
worked as a nurse before marriage. She had no history of
head trauma, severe viral infections, o r alcohol or drug
abuse.
O n admission, neurological examination revealed moderate impairment of recent memory. She was alert but slightly
depressed. No aphasia o r apraxia was noted. She demonstrated cerebellar dysarthria characterized by a slow and
sometimes explosive speech pattern. Cranial nerves were all
intact. There was a spastic right hemiparesis with hyperreflexia and Babinski’s sign. H e r standing posture was broadbased and her gait was spastic and ataxic. Tandem gait was
not possible. Finger-to-nose testing showed dysmetria and
terminal oscillation on the left. No involuntary movements
were observed. Sensory and autonomic functions were normal.
Laboratory test values, including analysis of blood and
urine, were all within normal limits. Cerebrospinal fluid examination showed normal cell counts, protein, and sugar.
Serum levels of vitamin B1 and Bi2were normal. Analyses of
amino acids and lipids in the blood and urine were unremarkable. No antiviral antibodies were found in the blood
and cerebrospinal fluid. No abnormalities were revealed by
electroencephalography and right carotid angiography.
Mental deterioration and gait disturbance progressed
gradually. Spasticity developed on the left side and the cerebellar signs became less obvious. She could utter only a few
words and sometimes would not respond to commands, so
motor and sensory aphasia were suspected. She became
mute and bedridden in the “dementia-in-flexion’’ posture at
age 32. Difficulty in swallowing and paratonic rigidity developed. External ocular movements became slow and sluggish.
The extremities showed marked increase in muscle tone, and
muscle contracture became pronounced, accompanying generalized emaciation and muscle atrophy. An electroencephalogram at age 32 showed low-voltage fast waves with 4 to 6
cycledsec irregular slow waves in the bifrontal region, but
neither generalized seizures nor myoclonic jerks were observed during the entire course of the illness. The patient
died of pneumonia at age 3 3 after six years of illness.
Postmortem Examination
Postmortem examination was carried o u t nine hours
after death and was limited to the brain. Small pieces
were taken from the frontal and temporal cortices and
from the caudate nucleus, thalamus, and cerebellum.
The tissue was fixed in pH-buffered glutaraldehyde,
postfixed in osmium, and embedded i n e p o n for electron microscopic study. T h e brain was then fixed in
10% formalin f o r three weeks. Sections of various
regions were embedded i n paraffin, stained with
hematoxylin-eosin, Nissl, myelin, Bodian, Holzer, and
Congo-red stains, and examined with t h e light microscope.
Neuropathological Findings
The unfixed brain weighed 1,100 gm. There was a
diffuse symmetrical atrophy, predominantly involving
297
Fig 1 . Numerous plaques are observed in Sommer’s sector of the
hipporampu.r.(Bodian stain; x 27 before 3S96 reduction.)
the frontal and temporal lobes. The cerebellum was
slightly reduced in volume. Coronal sections of the
cerebrum revealed atrophic thin frontal temporal cortices and diffusely atrophic white matter. The lateral
ventricles were markedly enlarged. The cerebellar folia
and white matter were slightly atrophic. The pontine
base and both medullary pyramids were markedly reduced in size.
Light miscroscopic examination revealed the typical
histopathological changes of AD in the cerebrum.
Many neurofibrillary tangles and numerous neuritic
plaques with or without central amyloid cores were
particularly prominent in the hippocampus and the
frontal and temporal cortices (Fig 1). The ultrastructural features of the plaques in the cerebrum were
identical to those previously reported [14}. In the
hippocampus and occipital cortex, amyloid plaques
superficially resembling kuru plaques were found in
close proximity to congophilic angiopathy (Fig 2).
Neurofibrillary tangles were also observed in the
caudate nucleus, thalamus, hypothalamus, basal nucleus of Meynert, and oculomotor and vagal nuclei.
They were noted in the substantia nigra and locus
ceruleus, where neuronal loss resulted in accumulation
of extraneuronal melanin pigment and a moderate degree of gliosis. In the cerebral white matter, irregular
swollen axons were often found in Bodian preparations, and a slight but diffuse pallor of the centrum
semiovale was seen with myelin staining. Degeneration
of the corticospinal tracts was observed in the cerebral
peduncles, the pontine base, and the medullary pyramids bilaterally.
In the cerebellum, a few plaques with amyloid cores
were scattered in the molecular layer, granular cell
layer, and even in the white matter. Those in the
molecular layer consisted of amorphous congophilic
298 Annals of Neurology
Vol 17 No 3 March 1985
Fig 2. A radiating amyloid plaque (arrows) in the hzppocampus is contiguous to a blood vessel. (HGE; X 670.)
deposits with finely radiating margins. Some of these
deposits were continuous with the wall of the small
vessels with similar congophilic deposits. Electron microscopic study revealed that the most striking features
were many degenerative neuritic processes adjacent to
thickened basal lamina of blood vessels (Fig 3). Many
amyloid fibrils were seen within these thickened basal
lamina (Fig 3, inset), and they appeared to stream out
into the surrounding parenchyma through gaps in
the glia limitans. There was no relationship between
amyloid fibrils and pericytes. Junctions between endothelial cells were intact. Some of the degenerative
neurites, possibly of granular cell or climbing fibers,
contained many dense bodies and abnormal mitochondria. A few amyloid fibrils could be observed among
these distended or dystrophic neurites.
Cerebellar plaques in the granular cell layer or white
matter had deeply eosinophilic central cores with a less
eosinophilic granular peripheral zone on hematoxylineosin staining. Bodian staining showed irregular swollen
neuritic processes in the peripheral zone. Electron microscopic features of these plaques were similar to
those found in the cerebrum except that no paired
helical filaments were identified in the cerebellar
neuronal perikarya or processes. In contrast to those in
the molecular layer, these plaques were not associated
with blood vessels, and moreover, in this region there
was no evidence of vascular amyloid. Hemidesmosomes in the end-foot of the perivascular astrocyte
were clearly identified in this region.
F i g 3. Electron micrograph of the plaquelike degeneration in the
molecular kzyer of the cerebellum. Note many degenerative
neuronal procesJes around the blood vessel with thickened basal
lamina. ( x S,600.) (Inset) Higher magnificationof the area indicated with an asterisk. Note amyloidfibrils (AM) have an intimate relationship with the basal lamina (BL) of the blood vessel. (E = endothelial cell.) ( x 44,000.)
Discussion
This patient had an early onset of progressive dementia, spasticity, and ataxia without a known family history of a similar disorder. The neuropathological
findings were those of AD. Neurofibrillary tangles and
neuritic plaques have also been reported in the brains
of young adults with Down’s syndrome 131. However,
there was no evidence to indicate that the patient had
Down’s syndrome, since she had worked as a nurse.
Therefore, this patient can be considered to be one of
the youngest affected with sporadic AD.
Unlike those of classic AD, the neurological features were characterized by severe spasticity and moderate ataxia, which appeared shortly after the onset of
dementia. Several patients with AD who had similar
clinical manifestations have been reported previously
(Table). The age at onset of all patients is apparently
younger than that found in classic AD, and pathological lesions seem to be distributed diffusely in the
brain. Our case closely resembles that reported by Barrett [l].
It appears that cerebellar plaques are not uncommon
features in AD; however, the nature of these cerebellar plaques is still controversial. Pro and co-workers
[I41 reported that 7 of their 24 patients with AD had
cerebellar plaques and pointed out that these were
found in familial cases. Cerebellar plaques also have
been reported in nonfamilial cases [I, 2, 7,81. Pro and
associates [ 141 and Ishino and co-workers [8} believed
that the cerebellar plaques in A D were similar to kuru
plaques [ 151.
Kuru plaques are composed of amyloid fibrils radiating peripherally; they are often multicentric [21 and
usually are not associated with degenerative components around amyloid cores 151. The electron microscopic study clearly showed that the cerebellar plaques
in this patient are neuritic and not kuru plaques.
Congophilic angiopathy of the small vessels has
been reported in many cases of A D { 113. Our electron
microscopic study revealed the intimate relationship
Case Report: Aikawa et al: Atypical Alzheimer’s Disease with Cerebellar Plaques
2 9
Alzheimer’s Disease with Spasticity and Ataxia
Age at
Reference
Onset
Family
History
Spasticity
Focal Demyelination in
White Matter
-t+
-
~~~
Barrett [I], 1713
Jervis and Stoltz 191, 1736
Worster-Drought e t a1 E171, 1940
van Bogaert e t a1 [16], 1740
Worster-Drought et alC181, 1944
Liiers [ l o ] , 1947
Friede and Magee [6}, 1962
Matsuoka e t al 1121, 1767
Fukatsu e t a1 [7), 1780
Ishino e t a1 IS], 1983
Ferrer e t al [ 4 ] , 1983
Present report
NE
=
33
38
47
25
44
26
31
28
37
35
37
27
t-
++
++
++
++
+
++
-t
++
++
++
++
NE
+
-
+
+
+
+
-
+
NE
-
Cerebellar
Signs
Cerebellar
Plaques
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
++
++
NE
NE
NE
NE
+
+
+
+
Amyloid
Angiopathy
-
+
++
++
++
++
+
+
not examined.
between amyloid fibrils and the basal lamina of the
vessels in the cerebellum, which was similar to the
relationship reported in the cerebrum of patients with
senile dementia [13]. Amyloid fibrils seemed to remain in the basal lamina as long as the glia limitans was
intact.
In conclusion, we would like to stress two points.
First, it appears that AD with spastic paresis and ataxia
tends to occur in younger persons than does classic
AD. Second, the cerebellar plaques in our patient
were shown to be neuritic plaques and plaquelike degeneration of the vessel, not kuru plaques.
The authors thank Dr Toshiya Watanabe and Dr Hirotaro
Narabayashi Uuntendo University, Tokyo) for referring this patient
and providing us with the clinical information. We are also grateful
to Dr Wayne Moore for his kind suggestions and advice on this
work and Mrs Rosemarie Sass0 for preparation of the manuscript.
References
1. Barrett AM: A case of Alzheimer’s disease with unusual
neurological disturbances. J Nerv Ment Dis 40:361-374, 1913
2. Boellaard JW, Schlore W: Subakute spongiforme Encephalopathie mit multiformer Plaquebildung. Acta Neuropathol
(Berl) 49:205-212, 1980
3. Ellis WG, McCulloch JR, Corley C L Presenile dementia in
Down’s syndrome-ultrastructural identity with Alzheimer’s
disease. Neurology (Minneap) 24:lOl-106, 1974
4. Ferrer I, Aymami A, Rovira A, Grau Veciana JM: Growth of
abnormal neurires in atypical Alzheimer’s disease. Acta Neuropathol (Berl) 5’3167-170, 1983
5. Field EJ, Mathews JD, Raine CS: Electron microscopic observations on the cerebellar cortex in Kuru. J Neurol Sci 8:209-224,
1969
6. Friede RL, Magee KR: Alzheimer’s disease. Presentation of a
300 Annals of Neurology
Vol 17 No 3 March 1785
case with pathologic and enzymatic-histochemical observations.
Neurology (Minneap) 12:213-222, 1962
Fukatsu R, Ikeda T, Ueno T, et al: An unusual case of presenile
dementia with numerous argentophilic plaques and severe amyloid vascular changes. Adv Neurol Sci (Tokyo) 24:271-282,
1980
Ishino H , Higashi S, Chuta M, et al: A case of Alzheimer’s
disease with myoclonus: amyloid plaques and grumose alteration in the cerebellum. Clin Neurol (Tokyo) 23:577-584,
1983
so-called
9. Jervis GA, S o h SE: Alzheimer’s disease-the
juvenile type. Am J Psychiatry 93:39-56, 1936
10. Liiers T: Ueber die familiire juvenile Form der Alzheimerschen
Krankheir mit neurologischen Herderscheinungen. Arch
Psychiatr Nervenkr 179:132-145, 1947
11. Mandybur TI: The incidence of cerebral amyloid angiopathy in
Alzheimer’s disease. Neurology (Minneap) 25:125-126, 1975
12. Matsuoka T, Miyoshi K, Saka K, et al: A case of encephalopathy
with plaque-like bodies, neurofibrillary change, angiopathy and
amyotrophic lateral sclerosis-like lesions. Adv Neurol Sci
(Tokyo) 11:80L-811, 1967
13. Miyakawa T, Shimoji A, Kuramoto R, et al: The relationship
between senile plaques and cerebral blood vessels in Alzheimer’s disease and senile dementia: morphological mechanism of
senile plaque production. Virchows Arch (Cell Pathol) 40: 121129, 1982
14. Pro JD, Smith MCH, Sumi SM: Presenile Alzheimer disease:
amyloid plaques in the cerebellum. Neurology (Minneap) 30:
820-825, 1980
15. Terry RD, Gonatas NK, Weiss M: Ultrastructural studies in
Alzheimer’s presenile dementia. Am J Pathol 44:269-277,
1964
16. van Bogaert L, Maere M, de Smedt E: Sur les formes familiales
precoces de la maladie d’Alzheimer. Monatsschr Psychiatr
Neurol 102:249-301, 1940
17. Worster-Drought C, Greenfield JG, McMenemey WH: A form
of familial presenile dementia with spastic paralysis. Brain
63:237-254, 1940
18. Worster-Drought C, Greenfield JG, McMenemey WH: A form
of familial dementia with spastic paralysis. Brain 67:38-43,
1944
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