Ageing and Dementia Current and Future Concepts

360 Pages·2002·26.66 MB·English

by  Prof. K. A. Jellinger MD (auth.), Prof. Dr. Kurt A. Jellinger, Prof. Dr. Reinhold Schmidt, Dr. Manfred Windisch (eds.)

K. A. lellinger
R. Schmidt
M. Windisch (eds.)
Ageing and Dementia
Current and Future Concepts
SpringerWienNewYork
Prof. Dr. Kurt A. Jellinger
Institut fur Klinische Neurob iolog ie, Kenyongasse 18/7
A- I070 Wien, Austria
Prof. Dr. Reinhold Schmidt
Universitatsklinik fur Neurologie, Auenbruggerplatz 22
A-8036 Graz, Austria
Dr. Manfred Windisch
JWS Research Forschungslabor GmbH, Rankengasse 28
A-8020 Graz, Austria
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Preface
Ageing and dementia are among the most important subjects of basic and
clinical neurosciences as well as of socioeconomics and health care in the
21 st century. Alzheimer disease is the leading cause of dementia in elderly
people but it s aetiology and pathogenesis are still unresolved, and it s rela-
tionship to brain ageing needs further elucidation. Although a variety of risk
factors of dementia in advanced age are known, the impact of some of them
including small vessel disease are still under discussion. Recent advances in
molecular biology and genetics have provided great progress in the under-
standing of some basic problems of brain ageing and dementia, but more
intensive mutual cooperation and exchange between basic scientists and
clinicians are necessary in order to further elucidate the many still open
problems.
With this idea in mind, the International Symposium on "Ageing and
Dementia" was organized by JSW Research in cooperation with the Austri-
an Alzheimer Society, the Department of Neurology, University of Graz
School of Medicine, and the L. Boltzmann Institute of Clinical Neurobiolo-
gy, Vienna, at Graz on September 28-30, 2001. Within a series of biannual
conferences, this workshop offered a carefully selected programme by inter-
nationally renowned invited speakers, although, due to the sequelae of
September 11, it had to be reorganized within a very short time. It is focused
on three key issues: important factors that contribute to the deleterious
effects of brain ageing, problems of detection and conversion of mild cogni-
tive impairment, and possible - preventive and therapeutic - methods of
altering these effects. This volume presents the updated papers dedicated to
vascular risk factors and the impact of white matter le sions, oxidative stress
and other pathogenic factors of dementia, mild cognitive impairment and
preclinical Alzheimer disease, the current role of biological markers in the
early diagnosis of dementia, current and future treatment strategies of
Alzheimer disease including receptor modulation, neurotrophic agents,
inhibition of amyloid mismetabolismldeposition and neurofibrillary degen-
eration. In view of the recently suspended Alzheimer vaccination trials,
these pharmacological targets are of major current interest.
It is hoped that this volume will be helpful and informative to all those
who are interested and working in the field of brain ageing and dementia.
Finally, we would like to acknowledge the sponsors of this conference and
Springer-Verlag Wien NewYork for its excellent publication work.
ViennaiGraz, July 2002 K. A. Jellinger, R. Schmidt, M. Windisch
Contents
Jellinger, K. A.: Vascular-ischemic dementia: an update. 1
van Dijk, E. J., Prins, N. D., Vermeer, S. E., Koudstaal, P. J ., Breteler, M. M. B.:
Frequency of white matter lesions and silent lacunar infarcts . . . . . . . . . . . . . . . 25
Kapeller, P., Schmidt, R., Enzinger, cn., Ropele, S., Fazekas, F.: CT and MRI
rating of white matter changes 41
Schmidt, R., Fazekas, F., Enzinger, C., Ropele, S., Kapeller, P., Schmidt, H.:
Risk factors and progression of small vessel disease-related cerebral abnormali-
ties 47
Schmidt, H., Fazekas, F., Schmidt, R.: Microangiopathy-related cerebral damage
and angiotensinogen gene: from epidemiology to biology . . . . . . . . . . . . . . . . . . 53
Fazekas, F., Ropele, S., Schmidt, R.: Can small-vessel disease-related cere-
bral abnormalities be used as a surrogate marker for vascular dementia
trials? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 61
Perry, G., Nunomura, A., Cash, A. D., Taddeo, M. A., Hirai, K., Aliev, G.,
Avila, J., Wataya, T., Shimohama, S., Atwood, C. S., Smith, M. A.: Reactive
oxygen : its sources and significance in Alzheimer disease 69
Arendt T.: Dysregulation of neuronal differentiation and cell cycle control in Alz-
heimer's disease 77
Kienzl, E., Jellinger, K., Janetzky, B., Steindl, H., Bergmann, J.: A broader hori-
zon of Alzheimer pathogenesis: ALZAS - an early serum biomarker? . . . . . . . . 87
Smith, G.: Is mild cognitive impairment bridging the gap between normal aging
and Alzheimer's disease? 97
Fischer, P., Jungwirth, S., Krampla, W., Weissgram, S., Kirchmeyr, W., Schrei-
ber, W., Huber, K., Rainer, M., Bauer, P., TragI, K. H.: Vienna Transdanube
Aging "VITA": study design, recruitment strategies and level of participa-
tion 105
Almkvist, 0., Axelman, K., Basun, H., Wahlund, L.-O., Lannfelt, L.: Conversi-
on from preclinical to clinical stage of Alzheimer 's disease as shown by decline
of cognitive function in carriers of the Swedish APP-mutation . . . . . . . . . . . . . . 117
Kurz, A., Riemenschneider, M., Drzezga, A., Lautenschlager, N.: The role of
biological markers in the early and differential diagnosis of Alzheimer's
disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Schmitt, F. A., Cragar, D., Ashford, J. W., Reisberg, B., Ferris, S., Mobius, H.-
J., Stoffler, A.: Measuring cognition in advanced Alzheimer's disease for clini-
cal trials : 135
Windisch, M., Hutter-Paler, B., Schreiner, E.: Current drugs and future hopes in
the treatment of Alzheimer's disease 149
Flores-Flores, C., Nissim, A., Shochat, S., Soreq, H.: Development of human
antibody fragments directed towards synaptic acetylcholinesterase using a semi-
synthetic phase display library 165
Giacobini, E.: Long-term stabilizing effect of cholinesterase inhibito rs in the thera-
py of Alzheimer' disease 181
VIII Contents
Fisher, A., Brandeis, R., Haring, R., Bar-Ner, N., KIiger-Spatz, M., Natan, N.,
Sonego, H., Marcovitch, I., Pittel, Z.: Impact of muscarinic agonists for suc-
cessful therapy of Alzheimer's disease 189
Geerts, H., Finkel, L., Carr, R., Spiros, A.: Nicotinic receptor modulation: advan -
tages for successful Alzheimer's disease therapy 203
Winblad, B., Mobius, H. J., Steffler, A.: Glutamate receptors as a target for Alz-
heimer 's disease - are clinical results supporting the hope ? 217
Kesslak, J. P.: Can estrogen playa significant role in the prevent ion of Alzheimer 's
disease? 227
Fahnestock, M., Garzon, D., Holsinger, R. M. D., Michalski, B.: Neurotrophic
factors and Alzheimer's disease: are we focusing on the wrong molecule? ... .. 24 1
Humpel, C., Weis, c.: Nerve growth factor and cholinergic CNS neurons studied
in organotypic brain slices 253
Ruether, E., Alvarez, X. A., Rainer, M., Moessler, H.: Sustained improvement of
cognition and global function in patients with moderately severe Alzheimer 's
disease: a double-blind, placebo-controlled study with the neurotrophic agent
Cerebrolysins 265
Muresanue.Ds.E; Rainer, M. , Moessler, H.: Impro ved global function and activi-
ties of daily living in patients with AD:.a placebo-controlled clinical study with
the neurotrophic agent Cerebrolysins 277
Mucke, H. A. M.: Genomics and dementia - new drug targets ahead? 287
Permanne, B., Adessi, C., Fraga, S., Frossard, M.•J., Saborio, G. P., Soto, C.:
Are ~-sheet breaker peptides dissolving the therapeutic problem of Alzheimer 's
disease? 293
Munch, G., Deuther-Conrad, W., Gasic-Milenkovic, J.: Glycoxidative stress
creates a vicious cycle of neurodegeneration in Alzheimer's disease - a target for
neuroprotective treatment strategies? 303
Iqbal, K., Alonso, A. del C., EI-Akkad, K , Gong, C.-X., Haque, N., Khatoon,
S., Tsujio, I. , Grundke-Iqbal, I.: Pharmacological targets to inhibit Alzheimer
neurofibrillary degeneration 309
Solomon, B., Frenkel, D.: Generation and brain delivery of anti-aggregating anti-
bodies against l3-amyloid plaques using phage display technology 321
Rockenstein, E., Mallory, M., Mante, M., Alford, M., Windisch, M., Moessler,
H., Masliah, E.: Effects of Cerebrolysin" on amyloid-B deposition in a trans-
genic model of Alzheimer's disease 327
Heiser, M., Hutter-Paier, B., Jerkovic, L., Pfragner, R., Windisch, M., Becker-
Andre, M. , Dieplinger, H.: Vitamin E binding protein Afamin protects neuronal
cells in vitro 337
Jellinger, K. A.: Recent developments in the pathology of Parkinson 's
disease 347
Vascular-ischemic dementia: an update
K. A. Jellinger
Institute of Clinical Neurobiology, Vienna, Austria
Summary. Both the clinical criteria and morphologic substrates of dementia
resulting from cerebrovascular disease and its relation to Alzheimer disease
and other age-related brain changes are controversiaL In clinical and autopsy
studies in the Western world the prevalence of vascular-ischemic dementia
(VID) is around 7-10%, while vascular cognitive impairment without demen-
tia is much more frequent and the risk of poststroke dementia is increased in
patients with prestroke cognitive decline. In contrast to previous suggestions
that VID was largely the result of large hemispheral infarcts, according
to recent studies, it is most commonly associated with widespread small
ischemic or vascular lesions (microinfarcts, lacunes) throughout the CNS
with predominant subcortical lesions in the basal ganglia and white matter
or in strategically important brain regions (thalamus, hippocampus). The
lesion pattern of rare "pure" VID, which is related to arteriolosclerotic and
hypertensive microangiopathy, differs from that in mixed type dementia
(Alzheimer disease and cerebrovascular lesions) that more often shows larger
hemispheral infarcts. Another form of VID that is not infrequent in very old
subjects is hippocampal sclerosis, a selective damage to the hippocampus that
is often accompanied by multiple other cerebrovascular lesions. Both, mild
Alzheimer type pathology and small vessel disease-associated subcortical
vascular pathology appear to be common and may interact in causing cogni-
tive decline, but the impact of cerebrovascular lesions on cognitive impair-
ment and dementia needs to be further elucidated.
Introduction
While Alzheimer disease (AD) becomes widely accepted as the most com-
mon cause of dementia in advanced age (Jorm and Jolley, 1998), the role of
cerebrovascular disease (CVD) and ischemic brain lesions in cognitive decline
remains controversial and confusing. Similar to recently refined clinical and
morphologic criteria for AD and other degenerative dementias (see Jellinger,
1999, 2001d), four clinical diagnostic criteria for vascular-ischemic dementia
(VID) supported by the Hachinski Ischemic Score (HIS) in its original
(Hachinski et aL, 1975) or modified form (Small , 1985) and by neuroimaging
data are currently used (Table 1). Several class I and II studies that compared
K. A. Jellinger et al. (eds.), Ageing and Dementia Current and Future Concepts
© Springer-Verlag/Wein 2002
tv
Table 1. Comparison of clinical criteria for vascular-ischemic dementia (VID)
Included
Definition of dementia mechanisms Excluded
of brain injury mechanisms
Memory Cognitive Cerebrovascular of brain Neurologic Structural Causal
Criteria impairment impairment disease AI CI H dysfunction examination neuroimaging relationship
Hachinski NS NS Atherosclerosis Yes No No None ± Focal signs No No
Ischemic
Score (1975)
DSM-IV Yes One other NS Yes NS Yes Delirium ±Focal signs ± Yes, by clinical
(1994) judgement ~
;t>
NINDS- Yes Two others NS Yes NS Yes Delirium Focal signs Yes (probable Yes (probable VaD:
'-<
AIREN aphasia VaD) within 3 mo, abrupt
~
probable psychosis
No (possible onset or stepwise 5'
(Tel
progression) (p
VaD (Roman Alzheimer or VaD) >-t
et al., 1992) other brain No (possible VaD)
disease
ADDTC + Not limited NS Yes Yes No Delirium NS Yes (probable ± (Probable VaD :
(Chui et al., to single or possible temporal relation
1992) narrow VaD) for single lesion)
category
No (possible VaD)
AI acute ischemia ; CI chronic ischemia; H hemorrhage; NS not specified; ± supportive but not necessary for diagnosis; DSM-IV Diagnostic
th
and Statistical Manual of Mental Disorders, 4 Ed.; NINDS-AJREN National Institute of Neurological Disorders and Stroke - Association
Internationale pour la Recherche et l'Enseignement en Neurosciences; A D DTC Alzheimer Disease Diagnostic and Trea tment Centers; VaD vascular
dementia
Vascular-ischemic dementia: an update 3
Table 2. Autopsy series showing prevalence of ViD (compleme nt to Markesbery, 1998)
Year Location Authors No. of cases ViD %
1962 England Corsellis 167 46 27
1970 England Tomlinson et al. 50 9 18
1972 US Birkett 24 14 58
1975 Switzerland Todorov et at. 776 132 22
1977 Sweden Sourander et al. 258 72 28
1985 Finland Molsa et al. 58 11 19
1986 Switzerland Ulrich et al. 54 9 17
1987 Sweden Alafuzoff et al. 55 13 23
1987 Canada Wade et al. 65 6 9
1988 US Joachim et al. 150 3 2
1989 US Boller et al. 54 4 7
1990 Austria Jellinger et al. 675 106 16
1994 Sweden Brun 175 59 34
1995 No rway Ince et al. 69 4 5
1995 US Markesbery 557 13 2
1997 US (CE RA D ) Hulette et al. 1929 6 0.03
1998 Canada Bowler et al. 122 4/5* 3/4*
(*reexamination)
1999 Japan Seno et al. 122 42 35
2001 Japan Akat su et al. 270 60 22
2001 Austria Jellinger (de me ntias/ 810/540 80/7 9.8/1.3
probable AD)
clinical diagnoses and neuropathological findings in referencal cohorts, simi-
lar to population-based studies, reported low sensitivity for these criteria
(average 50%, range 20 to 89%), but high er specificity (average 87%, range 64
to 98%) (Galasko et aI., 1994; Victoroff et aI., 1995; Moroney et aI., 1997; Gold
et aI., 1998). Due to their highly variable specificity and sensitivity (Wetterling
et aI., 1996; Moroney et aI., 1997) , inconsistency in the diagnosis of VID has
been recognized (Bowler et aI., 1997; Erkinjuntti, 1999; Chui et aI., 2000;
Ikeda et aI., 2001). Since the criteria chosen to diagnose VID will influence
estimates of its incidence and prevalence, as well as its recognition and
treatment, new re search criteria, e.g. for subcortical vascular dementia, have
been proposed (Erkinjuntt i et aI., 2000), and the need for prospective
clinico-pathological correlation studies has been emphasized (Chui et aI.,
2000; Knopman et aI., 2001). R ecent clinicopathological validation studies of
four sets of clinical criteria for vascular dementia demonstrated that these are
not interchangeable. The ADDTC criteria for possible IVD were found to be
the most sensitive for the detection of IVD, while the DSM-IV criteria and
the NINDS-AIREN criteria for possible IVD may be more effective in ex-
cluding mixed dementia. Given their inability to detect the vast majority of
cases of IVD, th e ICD-IO criteria and the ADDTC and NINDS-AIREN
criteria for probable IVD should be revised (Gold et aI., 2002; Gertz et aI.,
2002). Furthermore, morphological substrates of dementia resulting from
CVD remain confusing, since it constitutes a multifactorial disorder related to
4 K. A. Jellinger
Table 3. Risk factors for VID
Advancing age Cerebral atrophy
Hypertension Alcohol abuse
Diabetes mellitus Cigarette smoking
Myocardial infarction Low educational attainment
Cardiac disease (especially atrial fibrillation) Asian background
Elevated LDL cholesterol CADASIL
Homocystein Familial cerebral amyloidosis
Prior strokes
a wide variety of pathological lesions (Table 2 and 3), the clinical significance
of which and its relation to concurrent AD and other age-related changes of
the brain, in particular, subcortical white matter lesions (WML), remains
controversial (Vinters et aI., 2000).
Neuropathological criteria have not been established for VID. The
California ADDTC (Chui et aI., 1992) and the NINDS-AIREN criteria
(Roman et aI., 1993) did not suggest specific details for the neuropathological
diagnosis of VID, but indicated that histopathological confirmation of the
brain was necessary to confirm the presence of multiple infarcts. Complicating
the diagnosis of VID are other pathologic entities coexisting with vascular
lesions that could lead to cognitive decline. Many of these can be found by
postmortem examination; thus, autopsy examination of the brain is critical in
the definitive diagnosis of VID. However, it should be emphasized that the
presence of vascular lesions found at autopsy does not prove they cause
cognitive decline, underscoring that thorough clinico-pathological correlation
is essential to establish a definitive diagnosis of VID.
Epidemiology of VID
While VID previously was considered the second commonest type of demen-
tia after AD (Fratiglioni et aI., 1991; Hebert and Brayne, 1995; Erkinjuntti,
1999; Meyer et aI., 2001; Dib, 2001), in the Western world it ranges after
AD (60-75%), dementia with Lewy bodies (DLB) (10-20%), other non-
Alzheimer dementias (about 10%) at place 3 or 4. In most memory clinic-
based series, CVD is considered to be the cause of dementia in no more than
8-10% of affected subjects (Vinters et aI., 2000).
Evaluation of 11 pooled European population-based clinical studies of
persons 65 years and older revealed an age-standardized prevalence of 6.4%
for all causes of dementia, 4.4% for AD, and 1.6% for VaD (Lobo et aI.,
2000). VID accounted for 15.8% of all dementia cases. The prevalence ofVID
ranged from 0.0% to 0.8% at ages 65 to 69 and from 2% to 8.3% in the 90
and older age group in the different countries. In a Canadian clinical study of
603 demented patients, 12.1% had VID and 12.6% had mixed AD/VID
(Rockwood et aI., 2000). In Asian countries, VID may be more common than
AD. Studies from Japan revealed that the prevalence of VID was more than
double that of AD (Veda et aI., 1992; Yoshitake et aI., 1995). White et al.