Journal ofNeurology, Neurosurgery, and Psychiatry 1991;54:932-934

SHORT REPORT

Dementia of frontal lobe type and motor neuron

disease. A Golgi study of the frontal cortex

I Ferrer, C Roig, A Espino, G Peiro, X Matias Guiu

AbstractNeuropathological findings in a 38 yearold patient with dementia of frontal lobetype and motor neuron disease includedpyramidal tracts, myelin pallor andneuron loss, gliosis and chromatolysis inthe hypoglossal nucleus, together withfrontal atrophy, neuron loss, gliosis andspongiosis in the upper cortical layersof the frontal (and temporal) lobes.Most remaining pyramidal and non-pyramidal neurons (multipolar, bi-tufted and bipolar cells) in the upperlayers (layers II and III) of the frontalcortex (area B) had reduced dendriticarbors, proximal dendritic varicositiesand amputation of dendrites as revealedin optimally stained rapid Golgi sec-tions. Pyramidal cells in these layers alsoshowed depletion of dendritic spines.Neurons in the inner layers werepreserved. Loss of receptive surfaces inneurons of the upper cortical layers inthe frontal cortex are indicative ofneuronal disconnection, and are "hid-den" contributory morphological sub-strates for the development of dementia.

UnidadNeuropatologia, DeptAnatomia Patologica,Hospital Principes deEspafia, Universidadde Barcelona,BarcelonaI Ferrer*A EspinoHospital de la SantaCreu i Sant Pau,Barcelona, SpainServicio de NeurologiaC Roig

Servicio de AnatomiaPatologica*G PeiroX Matias GuiuCorrespondence to:Dr Ferrer, UnidadNeuropatologia, DeptoAnatomia Patol6gica,Hospital Principes deEspana, 08907 Hospitalet deLlobregat, SpainReceived 3 September 1990and in revised form6 December 1990.Accepted 20 December 1990

Motor neuron disease associated with demen-tia with or without Parkinsonism is commonon the island of Guam and other areas in thewestern Pacific region.' Patients have largenumbers of neurofibrillary tangles in thehippocampus, cerebral cortex and severalnuclei of the brainstem, together with typicallesions of amyotrophic lateral sclerosis (ALS).Motor neuron involvement in patients withdementia can occur in Alzheimer's disease(AD), Pick's disease, Creutzfeldt-Jakobdisease (CJD), Shy-Drager syndrome,olivoponto-cerebellar atrophy and otherdegenerative diseases.2 There is a third groupof patients with classic ALS associated withdementia which includes sporadic and familialcases and patients with ALS and dementiaand Parkinsonism.23 Clinically these patientssuffer from dementia with predominant frontalsigns. Histologically all of them have loss ofnerve cells and status spongiosus in the uppercortical layers of the frontal and temporallobes, whereas involvement of the substantianigra, caudate/putamen, thalamus, othernuclei of the brainstem and sensitive spinalcord fascicles may be found in some cases. We

report on the structure of neurons, revealedwith the Golgi method, in the frontal cortex ofa patient with dementia and motor neurondisease.

Case reportThe patient was a 38 year old woman who hadhad slowly progressing deterioration of mentalfunctions in the previous year. There was nofamily history of neurological disease. She hadbeen working as a teacher and had given birthto eight healthy children. She first noticedfrequent spelling errors and mistakes in cal-culating, together with slowness in thinking,repetitive acts and memory loss. Theneurological examination revealed, in addition,a positive jaw jerk and snout reflex, as well asgrasping. Plantar responses were flexor.Analytical tests in blood, urine and CSF,thyroid hormone and treponemal tests werenormal or negative. CT scans showed slightfrontal atrophy; EEC was normal. At this time,EMG examination did not reveal abnor-malities.

In the following months the patientdeveloped severe dysphagia and amyotrophy ofthe interoseous muscles of the hands. Fas-ciculations of the tongue also appeared. Thesecond EMG study, carried out one year later,revealed signs of proximal and distal denerva-tion in all four limbs. Motor and sensoryconduction velocities were normal. Someweeks later, she complained of marked atrophyofthe tongue and severe difficulty in swallowingdrinks and *foods. Her mental status haddramatically worsened. Both the knee andankle reflexes were present but there was noBabinski sign. The patient died of bilateralbronchopneumonia four months after theappearance of motor signs, less than two and ahalf years from the beginning of theneurological disease.

NEUROPATHOLOGICAL EXAMINATIONThe fresh weight ofthe brain was 1250 g. It wasremoved less than six hours after death andimmediately fixed in 5% buffered formalin forabout four weeks. Small samples of the leftfrontal lobe cerebral cortex (area 8) wereobtained on the second day of fixation, washedseveral times in phosphate buffer and potassiumbichromate, and stained according to the rapidGolgi method. The spinal cord was not avail-able. Atrophy of the frontal lobes was seen on

932 on D

ecember 1, 2021 by guest. P

rotected by copyright.http://jnnp.bm

j.com/

J Neurol N

eurosurg Psychiatry: first published as 10.1136/jnnp.54.10.932 on 1 O

ctober 1991. Dow

nloaded from

Dementia offrontal lobe type and motor neuron disease. A Golgi study of the frontal cortex

va,

10.Figure I Mainneuropathologicalfindingsin dementia offrontal lobetype associated with motorneuron disease. A)Demyelination of thepyramidal tracts. B)Massive neuron loss andsevere gliosis in thehypoglossal nucleus;surviving neurons havemarked chromatolyticchanges (arrows). C)Neuron loss, spongiosis andgliosis in layers II and IIIof thefrontal cortex.A: Kluver Barrera x 3;B: Nissl stain x 160; C:H&E x 160.

IS

SO. ;k

S,*;

*"l

(B

p.

_ r

s

$' 0

laa

A

e {C-;,(211a

*

# e

, Y '. a s

t*vV

0

gt.'.

Mol

t

t *O

* NC4Va.

S

'.0

0

J

';.e

I

I&

SI . f

I

a 4..I

4 t * iIwel

*u'I *

A 4 a*1 *4

4 r 4 ww

4 V-

IS .4' ,

0 & *

4'

44C* *6*.s

::At*t

It4

It

1

;4 e0.:... lbt .

A6~

Iit

PS

11

1 4- . t

S Iz* *

- *1 74,tL

* 4 :-' 9

Q**o

1

It

S

Figure 2 Golgiimpregnated neurons in thefrontal cortex. A and B)Medium-sized and smallpyramidal neurons in layerII showing severereduction of the dendriticarbor and lack of dendriticspines (arrows). C)Proximal varicosity in abasilar dendrite of amedium-sized pyramidalneuron of layer III. D)Multipolar cell of layerIII with reduced dendritesand displaying a proximaldendritic varicosity(arrow). E) Bipolarneuron of layer II withmutilated dendrites(arrow); ax: axon. F)Large pyramidal neuron oflayer V with normalbasilar dendrites coveredwith dendritic spines.Rapid Golgi method. Allbut C x 400; C x 1000.

r) Ir

... i)..

* ~rfA)9

vr ,,,t~~~W

0000.......

'.. * f~~~~~ superficial examination. Stained sections

revealed demyelination of the pyramidal tractsat the level of the bulbar pyramids (fig 1A).Marked neuron loss, gliosis and chromatolyticchanges in the remaining neurons were presentin the hypoglossal nucleus (fig 1B). The locuscoeruleus and substantia nigra did not showabnormalities nor were lesions found in thestriate complex, thalamus and hypothalamus.The hippocampus, subiculum and amygdaloidcomplex were unremarkable. Neurofibrillarytangles, senile plaques, granulovacuolar degen-eration, Hirano bodies, vacuolated neurons andPick bodies were conspicuously absent.Neuron loss, status spongiosus (coarse vacuol-isation of the neuropil) and gliosis in layers IIand III occurred in the cerebral cortex of thefrontal lobes, and to a lesser extent of thetemporal lobes as well (fig 1C). Spongiformchanges (fine vacuolisation of the neuropil), ascommonly seen in spongiform encephalo-pathies were not observed. The cerebral whitematter of the frontal lobes had diffuse myelinpallor and slight gliosis.

Sections ofthe frontal cortex stained with theGolgi method revealed large numbers ofoptimally impregnated pyramidal and non-pyramidal neurons at the different corticallayers. The most striking abnormalities werelocalised in neurons ofthe upper cortical layers.Small and medium-sized pyramidal neuronsexhibited reduced dendritic arbors and markedreduction in the number of dendritic spines(DS) (fig 2A and B). Proximal varicosities ofthebasilar dendrites were also frequently seen inthese cells (fig 2G). Non-pyramidal neurons,mainly multipolar and small bipolar and bi-

933

r

'1I4 a

00

a a

4'r^ v

11%4

.6 ,a-i

1.1

I

I`-Iz"k:

.Ul

.1.

P09k .4,....": ..:- .:

P'll.

on Decem

ber 1, 2021 by guest. Protected by copyright.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.54.10.932 on 1 October 1991. D

ownloaded from

Ferrer, Roig, Espino, Peiro, Matias Guiu

tufted types, had similar dendritic lesions; theextent of their dendritic domains was reduced-and some dendrites looked amputated. Prox-imal varicosities and deformations were alsoencountered in these cells (fig 2D and E). Mostseverely damaged neurons had shrunkenperykaria and a few ruined dendrites. In con-trast, neurons in the inner cortical layers hadpreserved dendritic arbors and dendrites ofpyramidal cells in layers V and VI were largelycovered by DS with a normal appearance (fig2F).

DiscussionClinical and neuropathological manifestationsin this patient are similar to those observed inother cases of dementia associated with motorneuron disease.27 Similar clinical and histo-logical findings are found in patients afflicted bya type of dementia which has been named withdifferent descriptive terms such as dementia offrontal lobe type,8 frontal lobe degeneration ofnon-Alzheimer type9 and dementia lackingdistinctive histological features.'0 Involvementof the hypoglossal nucleus, substantia nigra,caudate/putamen and medial thalamus occur insome of these cases, thus suggesting that thereis an overlap between the spectrum ofdementiaof frontal lobe type plus amyotrophy (with orwithout Parkinsonism) and ALS plus dementia(with or without Parkinsonism).

Golgi impregnations of the frontal cortex inour case show striking morphological abnor-malities in pyramidal and non-pyramidalneurons of the upper cortical layers. Similarmorphological anomalies have been found inbiopsy samples, stained with the Golgi method,from patients with different types of dementiaincluding AD, Pick's disease and CJD." 52Shrunken neurons with proximal dendriticswellings, tortuous and mutilated dendritesand lacking DS are therefore not artifacts ofdelayed fixation but vivid images of degenerat-ing cells.

It is known that pyramidal neurons of layers

II and III are the main source and the mainrecipient of callosal and ipsilateral cortico-cortical projections in the primate brain.'3 Forthis reason, degeneration of the neuronalreceptive surfaces, as seen in our case, is anindicator of the progressive loss of cortico-cortical (callosal and ipsilateral) and localconnections. In addition to neuron loss, dis-connection of surviving cells in the frontalcortex may play an important role in patientswith frontal lobe dementia.

We thank Mr L Barnett for linguistic advice. This work wassupported in part by a grant FISss 90E1263.

1 Garruto MR, Yase Y. Neurodegenerative disorders of thewestern Pacific: the search for mechanisms and patho-genesis. Trends in Neurosciences 1986;9:368-74.

2 Hudson AJ. Amyotrophic lateral sclerosis and its associationwith dementia, parkinsonism and other neurological dis-orders: a review. Brain 1981;104:217-47.

3 Neary D, Snowden JS, Mann DMA, Northern B, GouldingPJ, Macdermott N. Frontal lobe dementia and motorneuron disease. J Neurol Neurosurg Psychiatry 1990;53:23-32.

4 Brownell B, Oppenheimer DR, Trevor Hughes J. Thecentral nervous system in motor neuron disease. J NeurolNeurosurg Psychiatry 1970;33:338-57.

5 Horoupian DS, Thal L, Katzman R, Terry RD, et al.Dementia and motor neuron disease: morphometric, bio-chemical and Golgi studies. Ann Neurol 1984;16:305-13.6 Morita K, Kaita H, Okeda T, Namba M. Presenile dementiacombined with amyotrophy: a review of34 Japanese cases.Arch Gerontol Geriatry 1987;6:263-77.

7 Gilbert JJ, Kish SJ, Chang LJ, Hornykiewicz 0. Dementia,parkinsonism and motor neuron disease: Neurochemicaland neuropathological correlates. Ann Neurol 1988;24:688-91.

8 Neary D, Snowden JS, Northern B, Goulding P. Dementiaof frontal lobe type. J Neurol Neurosurg Psychiatry1988;51:353-61.

9 Brun A. Frontal lobe degeneration ofnon-Alzheimer type. I.Neuropathology. Arch Gerontol Geriatry 1987;6:193-208.

10 Knopman DS, Mastri AR, Frey WH, Sung JH, Rustan T.Dementia lacking distinctive histologic features: a com-mon non-Alzheimer degenerative dementia. Neurology1990;40:251-6.

11 Catala I, Ferrer I, Galofre E, Fabregues I. Decreasednumbers ofdendritic spines on cortical pyramidal neuronsin dementia. A quantitative Golgi study on biopsy sam-ples. Human Neurobiology 1988;6:255-9.

12 Ferrer I, Guionnet N, Cruz-Sanchez F, Tunion T. Neuronalalterations in patients with dementia: a Golgi study onbiopsy samples. Neurosci Let 1990;114:1 1-16.

13 Jones EG. Laminar distribution of cortical efferent cells. In:Peters A, Jones EG, eds. Cerebral cortex vol 1, Cellularcomponents of the cerebral cortex. New York, London:Plenum Press, 1984:521-53.

934

on Decem

ber 1, 2021 by guest. Protected by copyright.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.54.10.932 on 1 October 1991. D

ownloaded from