Asymmetrical temporal lobe atrophy with massive neuronal inclusions in multiple system atrophy

Journal of the Neurological Sciences 179 (2000) 50–58www.elsevier.com/ locate / jns

Asymmetrical temporal lobe atrophy with massive neuronal inclusionsin multiple system atrophy

a,b , b b c*Katsuhiko Shibuya , Hideki Nagatomo , Kiyoshi Iwabuchi , Masayuki Inoue ,c cSaburo Yagishita , Yoji Itoh

aDepartment of Neurology and Psychiatry, Numazu Central Hospital, Nakasecho 24-1, Numazu, Shizuoka, 410-8575 JapanbDepartment of Neurology and Psychiatry, Kanagawa Rehabilitation Center, Nanasawa 516 Atugi, Kanagawa 243-0121, Japan

cDepartment of Pathology, Kanagawa Rehabilitation Center, Nanasawa 516 Atugi, Kanagawa 243-0121, Japan

Received 11 December 1998; received in revised form 6 June 2000; accepted 3 July 2000

Abstract

This report concerns a rare association of asymmetrical temporal lobe atrophy with multiple system atrophy (MSA). A 53-year-oldJapanese woman developed cerebellar ataxia and parkinsonism and was diagnosed as olivopontocerebellar atrophy (OPCA). This patientshowed forgetfulness and subsequent disorientation even in the early stage of the disease. She fell into a decorticate state at the age of 64,and died a year later. The autopsy showed MSA with asymmetrical atrophy of temporal lobes, intraneuronal globular inclusions mostlyconfined to the hippocampus, amygdaloid nucleus, and most abundant in the granule cells in the dentate fascia. These inclusions wereintensely argyrophilic and expressed marked immunoreactivity to ubiquitin, but not to neurofilament (NF), tau and paired helical filaments(PHF). Ultrastructurally, they were composed of scattered short filamentous structures of 15 to 30 nm in diameter, ribosome-like granules,mitochondria and lipofuscin. The lack of immunoreactivity against tau, NF and PHF suggests that the inclusions are distinct from Pickbodies. To our knowledge, MSA in association with asymmetrical temporal lobe atrophy with the present neuronal inclusions has not beenreported. This case is distinct from MSA combined with atypical Pick’s disease in the distribution and immunohistochemical properties ofneuronal inclusions, and may present a new variant of MSA since the neuronal inclusions are similar, in many respects, to those ofneuronal inclusions reported in MSA. Globular inclusions are also discussed in variants of Pick’s disease, amyotrophic lateral sclerosisand Alzheimer’s disease. 2000 Published by Elsevier Science B.V.

Keywords: Multiple system atrophy; Globular argyrophilic neuronal bodies; Pick body; Immunohistochemistry; Ultrastructure

1. Introduction of a patient with MSA who displays asymmetrical tempo-ral lobe atrophy with neuronal intracytoplasmic inclusions

Multiple system atrophy (MSA) includes olivopon- having some features of Pick bodies.tocerebellar atrophy (OPCA), striatonigral degeneration(SND) and Shy–Drager syndrome [1]. Theclinicopathological unity of these syndromes is supported 2. Case reportby the presence of characteristic argyrophilic cytoplasmicinclusions in the oligodendroglia and neurons [2–9]. A 53-year-old woman, the proprietress of ‘ryokan’Rarely, this disease may be associated with Alzheimer’s (Japanese inn) developed an unsteady gait, dysarthria, anddisease [10], progressive supranuclear palsy [11], or impairment of memory. The dysmnesia gradually becameatypical Pick’s disease [12]. This study documents the case worse. She often forgot the telephone number of booking

visitors and was unable to continue her work as propriet-ress. At age 55 years, she was diagnosed as having OPCA*Corresponding author. Tel.: 181-559-314-100; fax: 181-559-319-

221. by one of the authors (K.I.). The patient developed

0022-510X/00/$ – see front matter 2000 Published by Elsevier Science B.V.PII : S0022-510X( 00 )00364-6

K. Shibuya et al. / Journal of the Neurological Sciences 179 (2000) 50 –58 51

depressive state and neurogenic bladder that gradually sections of the cerebrum and cerebellum were embedded inprogressed. She was admitted to Kanagawa Rehabilitation paraffin wax. The routine stains employed were hemato-

¨Center on June 5, 1984. On admission she looked expres- xylin-eosin, Kluver–Barrera for myelin, Holzer for glialsionless and slightly disoriented, and showed ataxia of the fiber, Bodian and Bielschowsky silver impregnation, andarms, legs and trunk, cogwheel rigidity of both extremities, Gallyas silver development.and incontinence of urine. Wechsler Adult Intelligence For electron microscopy, a small fragment of Ammon’sScale scores were a verbal IQ of 99, performance IQ of 83 horn was taken from the formalin-fixed brain (postmortemand total IQ of 93. A cranial computed tomography (CT) delay of 6 h). The specimens were fixed in 2.5% glutaral-scan showed marked atrophy of the cerebellum and pons dehyde solution, and post-fixed in 1% osmium tetroxide.(Fig. 1). She became bedridden at 60 years old. Three After serial dehydration in graded alcohol, the samplesyears later, she became indifferent to daily events and her were embedded in epon mixture. Thin sections weresickness. At the age of 64, she fell into a decorticated double-stained with uranyl acetate and lead citrate, andposture. She had a laughing appearance with a stiffened observed by a JEOL 2000FX electron microscope.face when she met her daughter. She appeared euphoric. In addition, immunohistochemistry was performed usingCT scans disclosed right temporal atrophy (Fig. 2). She a panel of antibodies against human tau (1:200), phos-also sometimes suffered from a urinary tract infection and phorylated neurofilaments (NF) (200 kD) (1:120), pairedphlegmon of the skin. The clinical course went gradually helical filaments (PHF) (1:50) and ubiquitin (1:10), and andownhill and the patient died at age 65, 12 years after the avidin–biotin–peroxidase kit. Two cases of Pick’s diseaseonset of symptoms. The clinical diagnosis was mostly with Pick bodies were handled in the same manner andcompatible with MSA. served as controls.

3. Subject and methods 4. Neuropathologic findings

The brain was fixed in 20% formalin solution for a week The brain weight was 920 g. Marked atrophy of theand the representative sections including large hemispheric cerebellum and pons was present (Fig. 3a). On coronal

sections, the putamen was atrophic and showed browndiscoloration. The substantia nigra was totally depig-mented. In addition, the right anterior temporal lobe andhippocampus appeared considerably atrophic, and in con-trast, the left one was spared, being asymmetrical (Fig. 3b).

Microscopically, the cerebellar hemispheres showedconsiderable loss of Purkinje cells and thinning of thegranular layer with accentuation of the line of Bergmannglia. The white matter was severely demyelinated andgliotic (Fig. 3c and d). Marked neuronal loss with gliosiswere seen in the olivary and pontine nuclei. There wassecondary loss of the olivocerebellar and pontocerebellarfibers afferent to the cerebellum. The putamen and sub-stantia nigra showed severe neuronal loss with extensiveastrocytic proliferation (Fig. 3e).

Slight pallor of the myelin with severe gliosis was seenin the anterior temporal lobe, hippocampal formation, andentorhinal area, and was much more severe on the rightside. The other areas in the temporal lobes were slightlyaffected in a similar manner. The granule cells in thedentate fascia were decreased in number and accompaniedby gliosis, the remainders of which showed globular andpale amphophilic inclusions in their cytoplasm with dis-placement of the nucleus (Fig. 4a). The inclusions wereintensely argyrophilic and rounded on silver impregnationsuch as Bodian and Bielschowsky and Gallyas method(Fig. 4b). Some inclusions were shown to be doughnut-shaped by diffuse staining of the perikarya, with unstainednuclei.Fig. 1. A cranial computed tomography (CT) scan showing marked

atrophy of the cerebellum and pons (September 19, 1985). There was a great loss of neurons and astrocytic gliosis

52 K. Shibuya et al. / Journal of the Neurological Sciences 179 (2000) 50 –58

Fig. 2. CT scans disclosing right temporal atrophy (a) and mild cerebral atrophy (b) (August 6, 1993).

in the pyramidal cell layer of Ammon’s horn and dria were displaced to the periphery of the cytoplasm (Fig.prosubiculum. The subiculum and presubiculum were 6a). They consisted of scattered fibrillary structures, somespared. The remaining neurons often showed globular mitochondria and abundant osmiophilic granules. Theargyrophilic inclusions similar, but much larger, to those in fibrillary structures were randomly distributed and in-the granule cells (Fig. 4c). Many similar inclusions were frequently arranged in bundles. The fibrils were 15 to 30also seen in the amygdala, entorhinal and insular cortices, nm in diameter to which many osmiophilic structures wereand a few in the middle and superior temporal and parietal attached along the entire length (Fig. 6b).cortices. The distribution of the neuronal loss is illustrated These neuronal inclusions were similar in ultrastructurein Fig. 5. The inclusions were also seen in the left cerebral to oligodendroglial argyrophilic inclusions, but they werehemisphere but were much fewer than in the right. easily differentiated by their shape and location, morePrimitive plaques were scattered in the cerebral cortex.

Table 1Neither Lewy bodies, Pick cells (swollen neurons) norProperties of inclusions of this case

typical Alzheimer’s neurofibrillary tangles were presentStainingsanywhere.Hematoxylin-eosin EosinophilicImmunohistochemically, the inclusions were immuno-

¨Kluver–Barrera Slightly bluereactive to ubiquitin (Fig. 4d), but not to tau, NF or PHF Bodian Argyrophilic(Table 1). In contrast, Pick bodies in two Pick’s disease Bielschowsky Argyrophilic

Gallyas–Braal Argyrophilicexpressed intense immunoreactions to tau and PHF. Thehistochemical properties of the inclusions are listed in

ImmunohistochemistryTable 2.Tau Negative

Ultrastructurally, the inclusions were recognized as PHF Negativeglobular structures that were fairly well demarcated from Neurofilament 200 kD Negative

Ubiquitin Positivethe other cytoplasmic structures, but had no limitingb-Amyroid Negativemembranes.Synaptophisin NegativeLipofuscin, granular endoplasmic reticula and mitochon-


Fig. 3. The brain showing marked atrophy of the cerebellum and pons (a). Coronal section of the right hemisphere. The anterior temporal lobe and¨ ¨hippocampus appeared atrophic (b, Kluver–Barrera). The cerebellar white matter is severely demyelinated and gliotic (c, Holzer; d, Kluver–Barrera). The

substantia nigra showing severe neuronal loss with extensive astrocytic proliferation (e, HE, original magnification 3200).

easily in the granule cells of the dentate fascia. Oligoden- gliosis in the olivopontocerebellar system involving thedroglial inclusions were widely distributed throughout the cerebellar cortex, and in the striatonigral system. Incentral nervous system as previously described [2–5]. addition, oligodendroglial argyrophilic inclusions [2–

4,8,9,13] were widely distributed throughout the brain. So,this case was easily diagnosed as MSA [1,14].

5. Discussion Interestingly, the patient developed dysmnesia and sub-sequent disorientation even in the early stage of the

In the present case, there was severe neuronal loss and disease. The cerebrum showed asymmetrical atrophy of the


Fig. 4. There are many globular inclusions in the granule cells in the dentate fascia on HE preparation (a). The inclusions are argyrophilic by Gallyas (b)and are immunoreactive to ubiquitin (d). The remaining neurons of Ammon’s horn often showed globular inclusions similar, but much larger, to those inthe granule cells (c, HE). Original magnification: a, b, d 3400, c 3200.


Fig. 5. Schema showing the distribution of the inclusions in the cerebral cortex (right hemisphere). Black, numerous; dark gray, many; light gray, a few.

anterior temporal lobe including Ammon’s horn, being and entorhinal cortex where many neurons disappearedmore severe on the right side. Numerous argyrophilic with reparative gliosis. The other cortical areas such asinclusions were seen in the neuronal cytoplasm, and were insular and inferior temporal cortices were also, but to amainly confined to the hippocampus, amygdaloid nucleus, lesser extent, involved.


Fig. 6. (a) Ultrastructurally, a neuronal inclusion shows globular filamentous structures, fairly well-demarcated from the other cytoplasmic organellae andno limiting membranes. Lipofuscin, granular endoplasmic reticula and mitochondria are displaced toward the periphery of the cytoplasm (granule cell ofdentate fascia, 32000). (b) Higher magnification of Fig. 6a. The fibrillary structures are randomly distributed and infrequently arranged in bundles,measuring 15 to 30 nm.

The inclusions were intensely argyrophilic on Bodian, with classical [15,16] and atypical Pick bodies [12], andBielschowsky and Gallyas stains, and immunoreactive Pick-body-like inclusions in some other diseases [17–19].only to ubiquitin, not to tau, phosphorylated NF or PHF. Pick bodies were immunoreactive to tau and PHF. SomeThe histochemical and topographical properties of the Pick bodies, but not all, were immunoreactive to ubiquitinpresent inclusions are summarized in Table 2, compared [16]. Love et al. [20] reported that most of the Pick bodies

Table 2aNeuronal cytoplasmic inclusions, immunohistochemistry, ultrastructure and distribution

Case Lobar Immunohistochemistry Ultrastructure Distribution

atrophy Bodian Biel Gal PHF Tau NF Ub Diameter Granules DG HP EC Am Insula Cortex BG BS

Typical Pick [16] 1 1 11 11 11 21 21 15 nm 2 11 11 1 11 1 1 1 1

Generalized variant [15] 1 21 21 15 nm 1 2 2 2 2 2 2 1 1

MSA1Pick [12] F 11 Alz50(2) 2 21 1 11 nm 1 1 1 2 1 1 P 1 1

Alzheimer [18] 1 ANT(1) 1 15–18 nm 1 1

ALS1Pick [19] F,T 1 12–16 nm 1 1 1 F 1

ALS1Pick [17] 1 9–15 nm 1 F 1

Pick variant [25] F,T 1 1 2 2 1 2 12 nm 1 1 1 1 1 1 2 2

Our case T 1 1 1 2 2 2 1 15–30 nm 1 1 1 1 1 1 F,P,T 1 1

Our two Pick cases F,T 1 1 1 1 1 2 21 15 nm 2 1 1 1 1 1 F,T 1 1

a Biel, Bielschowsky; Gal, Gallyas; NF, neurofilament 200 kD; Ub, ubiquitin; DG, dentate granular cell layer; HP, hippocampal pyramidal cell layer; EC,entorhinal cortex; Am, amygdala; BG, basal ganglia; BS, brain stem nucleus; F, frontal cortex; P, parietal cortex; T, temporal cortex.


[2] Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in thewere positive to ubiquitin. Thus, the present neuronalCNS of patients with multiple system atrophy (striatonigral degene-inclusions were superficially similar to but apparentlyration, olivopontocerebellar atrophy and Shy–Drager syndrome). Jdistinct from Pick bodies.Neurol Sci 1989;94:79–100.

Neuronal cytoplasmic inclusions (NCIs) in MSA were [3] Nakazato Y, Yamazaki H, Hirato J, Ishida Y, Yamaguchi H.positive for ubiquitin and occasionally positive for neuro- Oligodendroglial microtubular tangles in olivopontocerebellar atro-

phy. J Neuropathol Exp Neurol 1990;49:521–30.filament, while negative for tau and PHF [21]. Therefore,[4] Arai N, Nishimura M, Oda M, Morimatsu Y, Oue R. Immuno-the present inclusions are very similar, in their stainability,

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[5] Abe H, Yagishita S, Amano N, Iwabuchi K, Hasegawa H, Kowa Kconfined to the pontine neurons in their cases. The et al. Argyrophilic glial intracytoplasmic inclusions in multipleinclusions in a case of MSA reported by Horoupian and system atrophy: immunocytochemical and ultrastructural study. Acta

Neuropathol 1992;84:273–7.Dickson [12] were also different in distribution form.[6] Kobayashi K, Miyazu K, Katsukawa K, Fukutani Y, Mukai M,Ultrastructurally, the present inclusions were composed

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tached along the entire length of the fibrils. In contrast, the 1992;18:237–49.inclusions of classical Pick disease [15,16] consisted of [7] Mochizuku A, Mizusawa H, Ohkoshi N, Yoshizawa K, Komatsuzaki

Y, Inoue K et al. Argentophilic intracytoplasmic inclusions instraight filaments [22,23], paired twisted profiles [16] ormultiple system atrophy. J Neurol 1992;239:311–6.periodically constricted filaments or NF with a geometrical

[8] Papp MI, Lantos PL. The distribution of oligodendroglial inclusionspattern [22,24]. Thus, the inclusions of the present case arein multiple system atrophy and its relevance to clinical symp-

distinct from that of classical Pick disease. Munoz-Garcia tomatology. Brain 1994;117:235–43.et al. [15] described generalized variants of Pick’s disease [9] Nakazato Y, Suzuki S. Oligodendroglial microtubular tangles inin which the bodies consisted of straight fibrils coated with multiple system atrophy. Neuropathology 1996;16:145–50.

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Asymmetrical temporal lobe atrophy with massive neuronal inclusions in multiple system atrophy

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