Table Of ContentNew Trends
in the Diagnosis and Therapy of
Non-Alzheimer's Dementia
Edited by
K. A. Jellinger and M. Windisch
Journal of Neural Transmission
Supplement 47
SpringerWienN ewYork
Prof. Dr. Kurt A. Jellinger
L. Boltzmann Institute of Clinical Neurobiology, Lainz-Hospital,
Vienna, Austria
Dr. Manfred Windisch
EBEWE-Research Initiative, Graz, Austria
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Foreword
Dementia is an acquired disorder of higher cerebral functions and cognition.
Because of increasing life expectancy dementia poses a major health and socio
economic problem. Alzheimer's disease accounts for 70-90% of mental
decline in the elderly. Degenerative non-Alzheimer's dementi as are responsi
ble for 7-30%. These include a variety of disorders clinically characterised by
progressive cognitive dysfunction often combined with focal neurological def
icits, e.g. Parkinson-plus syndromes, Lewy body dementia, lobar and multisys
tem atrophies, other neurodegenerative disorders, and prion diseases. Often it
is difficult to distinguish these illnesses from Alzheimer's disease and vascu
lar dementia.
In spite of considerable progress in molecular genetics, biochemistry, and
neuropathology, the classification and pathogenesis of non-Alzheimer's
dementias are still debatable. Diagnosis is frequently made only at postmor
tem. Because disease markers are not available for the majority of non
Alzheimer's dementias, consensus criteria for the identification of such diseas
es are warranted. These criteria could serve at a basis for early diagnosis and
distinction from other dementing disorders.
The present volume includes the papers and posters presented at the 4th
International Symposium of the Research Initiative EBEWE, held in October
13 to 15, 1995 in Vienna. This first international workshop on non-Alzheimer
dementias was intended to provide an overview of the current classification,
clinical features, pathomorphology, neuroimaging, and molecular biology of
this important group of central nervous system disorders. The conference's
aims were to ensure correct diagnosis and to give insight into the pathogenesis
of these neurodegenerative diseases becoming increasingly important in neu
robiology, clinical neuropsychiatry and neuropsychology, and, thus, to provide
a basis for future treatment strategies. It is hoped that the data presented will
promote research in the diagnosis, understanding, and treatment of dementing
disorders.
Our thanks are due to Springer-Verlag Wien New York for excellent co
operation and technical performance that enabled a rapid publication of this
volume.
Vienna, April 1996 K. A. J ellinger
M. Windisch
Contents
Jellinger, K. A.: Structural basis of dementia in neurodegenerative disorders 1
Dickson, D. W., Feany, M. B., Yen, S.-H., Mattiace, L. A., Davies, P.: Cytoskele-
tal pathology in non-Alzheimer degenerative dementia: new lesions in Diffuse
Lewy body disease, Pick's disease, and Corticobasal Degeneration . . . . . . . . . . 31
Hauw, J. J., Duyckaerts, C., Seilhean, D., Camilleri, S., Sazdovitch, V., Rancurel,
G.: The neuropathologic diagnostic criteria of frontal lobe dementia revisited. A
study of ten consecutive cases ........................................ 47
Pillon, B., Dubois, B., Agid, Y.: Cognitive deficits in non-Alzheimer's degenerative
diseases ......................................................... 61
Gsell, W., Strein, I., Riederer, P.: The neurochemistry of Alzheimer type, vascular
type and mixed type dementias compared ............................... 73
Gregory, C. A., Hodges, J. R.: Clinical features of frontal lobe dementia in compar-
ison to Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Talbot, P. R.: Frontal lobe dementia and motor neuron disease ................ 125
Kertesz, A., Munoz, D.: Clinical and pathological characteristics of primary pro-
gressive aphasia and frontal dementia .................................. 133
Aichner, F., Wagner, M., Kremser, Ch., Felber, S.: MR-imaging of non-Alzhei-
mer's dementia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Brooks, D. J.: Functional imaging techniques in the diagnosis of non-Alzheimer
dementias ........................................................ 155
Besthorn, C., Sattel, H., Hentschel, F., Daniel, S., Zerfafi, R., Forstl, H.: Quanti-
tative EEG in frontal lobe dementia ................................... 169
Mielke, R., Kessler, J., Szelies, B., Herholz, K., Wienhard, K., Heiss, W.-D.: Vas-
cular dementia: perfusional and metabolic disturbances and effects of therapy .. 183
Fischer, P.: The spectrum of depressive pseudo-dementia .................... 193
Morris, C. M., Massey, H. M., Benjamin, R., Leake, A., Broadbent, C., Griffiths,
M., Lamb, H., Brown, A., Ince, P. G., Tyrer, S., Thompson, P., McKeith, I. G.,
Edwardson, J. A., Perry, R. H., Perry, E. K.: Molecular biology of APO E alle-
les in Alzheimer's and non-Alzheimer's dementias ........................ 205
Brown, P.: Transmissible cerebral amyloidosis ............................. 219
Ironside, J. W.: Human prion diseases ................................... 231
Krieglstein, K., Maysinger, D., Un sicker, K.: The survival response of mesence-
phalic dopaminergic neurons to the neurotrophins BDNF and NT-4 requires prim
ing with serum: comparison with members of the TGF-~ superfamily and charac-
terization ofthe serum-free culture system .............................. 247
Rosier, N., Wichart, I., Bancher, C., Jellinger, K. A.: Tau protein and apolipopro-
tein E in CSF diagnostics of Alzheimer's disease: impact on non-Alzheimer's
dementia? ........................................................ 259
Hutter-Paier, B., Grygar, E., Windisch, M.: Death of cultured telencephalon neu-
rons induced by glutamate is reduced by the peptide derivative Cerebrolysin® ... 267
Boado, R. J.: Molecular regulation of the blood-brain barrier GLUTl glucose trans-
porter by brain-derived peptides ....................................... 275
VIII Contents
Hutter-Paier, B., Fruhwirth, M., Grygar, E., Windisch, M.: Cerebrolysin® protects
neurons from ischemia-induced loss of microtubule - associated protein 2 276
Francis-Turner, L., Valouskova, V., Mokry, J.: The long-term effect of NGF, b-
FGF and Cerebrolysin® on the spatial memory after fimbria-fornix lesion in rats 277
Gschanes, A., Windisch, M.: The influence of Cerebrolysin® and E021 on spatial
navigation of young rats ............................................. 278
Schwab, M., Antonow-Schlorke, I., Durer, U., Bauer, R.: Effects of Cerebrolysin®
on cytoskeletal proteins after focal ischemia in rats ........................ 279
ValouSkova, V., Francis-Turmer, L.: The short -term influence of b-FGF, NGF and
Cerebrolysin® on the memory impaired after fimbria-fornix lesion ........... 280
Wojtowicz, J. M., Xiong, H., Baskys, A.: Brain tissue hydrolysate, Cerebrolysin®,
acts on presynaptic adenosine receptors in the rat hippocampus .. . . . . . . . . . . . 281
Subject Index ....................................................... 283
Listed in Current Contents/Life Sciences
J Neural Transm (1996) [Suppl] 47: 1-29
© Springer-Verlag 1996
Structural basis of dementia in neurodegenerative disorders
K. A. Je llinger
L. Boltzmann Institute of Clinical Neurobiology, Lainz-Hospital, Vienna, Austria
Summary. Progressive dementia syndromes in adults are caused by a num
ber of conditions associated with different structural lesions of the brain. In
most clinical and autopsy series, senile dementia of the Alzheimer type is the
most common cause of mental decline in the elderly accounting for up to 90%,
whereas degenerative non-Alzheimer dementi as range from 7 to 30% (mean
8-10%). They include a variety of disorders featured morphologically by
neuron and synapse loss and gliosis, often associated with cytopathological
changes involving specific cortical and subcortical circuits. These neuronal!
glial inclusions and neuritic alterations show characteristic immunoreactions
and ultrastructure indicating cytoskeletal mismetabolism. They are important
diagnostic sign posts that, in addition to the distribution pattern of degenera
tive changes, indicate specific vulnerability of neuronal populations, but their
pathogenic role and contribution to mental decline are still poorely under
stood. In some degenerative disorders no such cytopathological hallmarks
have been observed; a small number is genetically determined. While in
Alzheimer's disease (AD) mental decline is mainly related to synaptic and
neuritic pathologies, other degenerative disorders show variable substrates of
dementia involving different cortical and/or subcortical circuits which mayor
may not be superimposed by cortical Alzheimer lesions. In most demented
patients with Lewy body disorders (Parkinson's disease, Lewy body
dementia), they show similar distribution as in AD, while in Progressive
Supranuclear Palsy (PSP), mainly prefrontal areas are involved. Lobar atro
phies, increasingly apparent as causes of dementia, show fronto-temporal
cortical neuron loss, spongiosis and gliosis with or without neuronal inclusions
(Pick bodies) and ballooned cells, while dementing motor neuron disease and
multisystem atrophies reveal ubiquitinated neuronal and oligodendroglial
inclusions. There are overlaps or suggested relationships between some
neurodegenerative disorders, e.g. between corticobasal degeneration, PSP
and Pick's atrophy. In many of these disorders with involvement of the basal
ganglia, degeneration of striatofrontal and hippo campo-cortical loops are
important factors of mental decline which may be associated with isocortical
neuronal degeneration and synapse loss or are superimposed by cortical AD
pathology.
2 K. A. Jellinger
Introduction
Dementia, a syndrome of acquired global disturbances of higher cerebral
functions and cognition sufficient to interfere with social and occupational
performance without change of alertness, has become a major health problem
because of worldwide increase in elder population. With the increase of life
expectancy, the prevalence of dementia has risen exponentially from 1 % in
subjects aged 60 to 65 years to 20% up to over 40% of people over 85 years
(Skoog et ai., 1993; Katzman and Kawan, 1994). Dementia can be caused by
many different conditions, particularly by chronic progressive and irreversible
diseases, while the estimated incidence of reversible dementia varies from less
than 1 % to over 10% (Arnold and Kumar, 1993; Weytingh et ai., 1995). The
most widely used clinical classifications, the DSM-III-R and DSM-IV, and
WHO ICD.lO, distinguish several groups of progressive dementia disorders in
adults, i.e. dementia in Alzheimer's disease (AD) (FOO) , vascular dementia
(FOl), dementia in otherwise classified disorders (F02), and unclassified forms
(F04), that correlate with several groups of neuropathologically determined
disorders. In most clinical and autopsy series, degenerative dementia of the
Alzheimer type is the most common cause of mental decline in the elderly; it
accounts for 65 to over 90% (Terry et ai., 1994; Galasko et ai., 1994), whereas
degenerative non-Alzheimer's dementi as range from 7 to 30% and, thus,
represent the second most frequent form, exceeding vascular dementia that
has been suggested to be next to AD (Roman et ai., 1993; Jellinger and
Bancher, 1994; Tatemichi et ai., 1994; Kosunen et ai., 1996); in less than 1 % of
elderly demented subjects no pathological CNS lesions are detected. The post
mortem diagnoses in a personal consecutive 7-year autopsy series of aged
individuals and of those with a clinical diagnosis of probable or possible AD
(using the NINCDS-ADRDA criteria [McKhann et ai., 1984]) are given in
Tables 1 and 2. These data indicate that AD pathology with or without
additional lesions was present in over 80 and 90% of all demented or clinical
AD patients, while vascular dementia accounted for 8.5% of all dementias,
but only for 0.9% of suggested AD cases. Other neurodegenerative disorders
representing 8.2 and 10% of all demented and AD cases, respectively, are
listed in Tables 3 and 4. No abnormal brain lesions beyond age were seen in
0.3 and 0.6% of demented patients, respectively.
Degenerative dementias of non-Alzheimer type are morphologically fea
tured by neuronal degeneration and loss with accompanying astrocytosis
involving specific, often disparate, cortical and subcortical populations
or multiple circuits. They may or may not be associated with intracellular
neuronal and/or glial inclusions/deposits, neuritic alterations or other
cytopathological abnormalities that show characteristic immunoreactions and
ultrastructure indicating cytoskeletal dysmetabolism (Table 5). Although the
molecular basis and pathogenic relevance of these cytoskeletal abnormalities
for most neurodegenerative disorders remain to be elucidated, they are im
portant histological sign posts that are often pointing to the diagnosis (Fig. 1).
Morphological and immunohistochemical overlaps between various types of
Structural basis of dementia in neurodegenerative disorders 3
Table 1. Morphological diagnosis in consecutive autopsy series of demented aged
individuals (1989-1995)
182 males/358 females (age 54-103 years) n percent
"Pure" AD (CERAD pos.; Braak V-VI) 194 35.9
AD "pure plaque type" (CERAD pos.) 10 1.9
"Limbic"/"neurofibrillary type" AD (CERAD neg.) 26 4.8
AD + CVD (lacunar state, infarcts) 80 14.8
AD + cerebral hemorrhage 16 3.0
Lewy body variant of AD 33 6.1
ADIDAT + Parkinson pathology 23 4.3
AD + nigral lesions/incidental Lewy bodies 25 4.6
MIX type dementia (AD + MIElVaD) 22 4.0
AD + other pathology (tumors) 7 1.3
Alzheimer disease - total 436 80.7
Vascular dementia (VaD/MIE, SAE) 46 8.5
Other disorders 55 10.2
Nothing abnormal beyond age 3 0.6
Other pathologies 104 19.3
Total 540 100.0
Table 2. Consecutive autopsy series of patients with clinical diagnosis of probable or
possible Alzheimer's disease (1989-1995) (108 males, 232 females; age 57-103yrs)
Neuropathological diagnosis n percent mean age
"Pure" AD (CERAD+; Braak V-VI) 155 45.6 82.1 :'::: 4.6
"Pure" probable AD (CERAD pos., 11 3.2 87.4 :'::: 2.3
Braak IV-V)
AD "pure plaque type" (CERAD pos.) 8 2.4 78.0 :'::: 8.3
"Limbic" AD (CERAD neg.; Braak IV) 10 2.9 84.0:'::: 2.0
"Neurofibrillary type" AD (CERAD neg.) 4 1.2 84.0:'::: 4.0
AD + CVD (lacunar state, infarcts) 52 15.3 82.6 :'::: 5.5
AD + cerebral hemorrhage 10 2.9 83.4 ± 4.3
Lewy body variant of AD 22 6.5 81.4 :'::: 7.5
DAT + Parkinson pathology 8 2.4 75.4 ± 9.3
AD + nigral lesions (no Lewy bodies) 12 3.6 82.5 ± 6.3
AD + incidental subcort. Lewy bodies 7 2.0 79.4 :'::: 8.3
MIX dementia (AD + MIElVaD) 7 2.0 83.6 ± 5.0
AD + other pathology (tumor) 2 0.6 78.5 ± 4.0
Alzheimer disease - total 308 90.6 81.3 :'::: 5.8
Vascular dementia (MIE, SAE) 3 0.9 84.0 :'::: 1.2
Other disorders 28 8.2 73.7 :'::: 8.3
Nothing abnormal 1 0.3 86.0
Other pathologies 32 9.4 81.2 ± 4.7
Total 340 100.0 81.3 :'::: 5.0
