FOURTH INTERNATIONAL CONFERENCE ON ALZHEIMER’S DISEASE s137

wss * multicenter,rsndomized.plsceboumtrolied, psrsllel group comparison of 3 regions, the brains treated for a longer period, group B, showed an average of 2.69
doses of S12024 (100, 200, 400 mg o.d.) ova 28 days. Assessment criteria were ug N/g for similar neocortieal regions. Statistical analysis showed no significant
Mini Mental Status (MMS), Clinical Global Impression (CGI) and the Cognitive difference (95% confidence level) within groups A or B, but the difference of the
Drug Reaearcb (CDR) and Score of Memory 5 (Sh45) computerized systems. mean values between groups A and B was significant. Thus, prolonged DFO
Fifty-three in-patients with AD (mean age: 80.0 +I- 1.0 years. mean MMS score: treatment in elderly AD patients causes a reduction in neocortical Al wncentrations.
17.0 +I- 0.5) were included. The 200 mg dose produced an enhancement of all CDR In a clinical trial invoting SO AD patients, all in early stage of the disease with
measures of recognition memory sensitivity. This effect was significant at D14 similar WAIS-R scores, 25 patients were treated with 125 mg DFO twice daily for
@=0.02) for tbe combined recognition measure from digit, word and picture tasks; 3 days followed hy one rest day followed by 2 days of 125 mg DFO followed by
p=O.13 at D28). Tbe SM5 battery also provided support for enhancement of some another day of rest. This weekly cyclewas repeated for 2 years. The control group
word memory tasks at 200 mg. Ibe improvement WBSnear the threshold of received either placebo (lecithin) or no treatment. Over the 2 year treatment period
significancy at the 200 mg dose for the word-recognition task at D28 @=0.07), the there were 5 death in the no treatment/ placeho group, none died in the treatment
combined word-recognition task at D28 @=0.07) and the false face-recognition task group. Further, DFO treated patients, for the initial 18 month deteriorated only half
at D14 (p-0.056). The global tolerability was good 1s demonstrated by the stability as much as the untreated ones and, after 18 month the rate of decline stabilized up
of clinical and biological parameters and the absence of any diffexence on the “lateral to the last behaviour evaluation at 24 month. The data clearly demonstrate that the
effect” item of CGI. DFO-Al-chelation treatment can significantly reduce the rate of decline in liking
In conclusion, SK?024 has shownpreliminaryevidenceof reducing dose-dependently skills of AD patients over a2 year period. Comparison of the data from the brain
some of the deficit in the speed and quality of cognitive prccesses in AD without Al analyses with the treatment trial data shows that on a temporal basis the
reduction in brain Al precedes, or coincides with, an alteration in behaviourial
modifying the clinical deterioration induced by this pathology and with good global
deterioration.
tolerability. The on-going European phase IIb study on 300 AD patients treated
during 3 months will provide further information. It is concluded that DFO can reduce brain Al concentrations in AD and slow
progression of the disease.

564
566
,?FFlCACV AN” SAFETY OF SABELUZOLE IN PATIENTS WIT” PR0BARI.E
ALZHEIMIX’S DISFXGE
EFFECTS OF Two DIFFERENT Il’+INDTROPlC DRUGS IN
EXPERI&NTAL THERAPY OF ALZHEIMER’S DISEASE PATIENTS
J.!-eszek, B.Slesak, B.Kowal-Gierczak,A.D.lnglot
Clinic of Psychiatry, Clinic of Angiology Univeristy
Med.School. Inst.of lnmunology and Experimental
Therapy Polish Academy of Sciences,V\lroclaw, Poland
Sabeluwle is a novel compcuad under development in the treatment of Alzbeimer’s d&a!&.
This abstra~l describes dx phase 2 clinical vial SAB-INT-IO.
Trial design Alzheimer’s Disease (A.D.) and other age-related
In a multi-cenve trial in Canada and tk UK. patients with probable Alrheimer’s disease
(AD) cognitive deficits are associeted with irmunological
ading to theNINCDS-ADRDAcriteriaandhavings sane between12 and23 ontheMini distrubances. The aim of our study was to compare the
Mental State Examinationat enlry. were lnztcd in parallel for 48 weeks in a double-Mind efficiacy of cyclophosphamide (administered in low
design with sabeluzole 5 mg b.i.d. (SABS), sabeluzole 10 mg b.i.d. (SABIO) or placebotablets doses (1.5 mg/kg body weight daily) with TT? (peat
(PLAC). ‘Thecognitive part of thz Alzbeimer’s Disease Assessment Scale (ADAS) served as derived imnunomodulating drug registered in Poland for
a primary parameter to evabJateefficacy.
Results
use in humans) administered in tablets from 5 mg to
The intent-twreat analysis bears on IO8 patients of whom 34 were randomized to SABS. 35
30 mg daily. Sixty four patients with A.D. were trea-
to SABIO aad 39 to the PLAC 8roup. Seventeen patienu (16%) did not complete tbe total
ted either with cyclophosphamide (20 patients) and or
uial period (6 in SABS. 5 in SABIO and 6 in PLAC). Adverse events (AE) were the cause of with TT? (44 patients). The immunotherapy lasted from
premature trial discontinuation in three patients in bMh the SAB5 and SABIO ~rcun and two 15 to 20 months. Fifteen patients with A.D.(approx.
in tbx PLAC group. The median age oi the study group was 70 years. _ 75%) treated with cyclophosphamide and 35 patients
The meanchange from baseline in tbe total ADAS cognitive score after 48 weeks of treatment treated with TTP (approx.fJO%) improved during the time
was 3.4 in SABS. 6.0 in SABIO and 7.5 in PLAC (ANOVA. overallbetween-trcamxnt of observation. The inhibition of the progress of A.D.
I
difference.p= 0.08). The differencein shin betweenSABS and PLAC was -4.1 (95% CI: - was reflected in the neurological and mental state
8.21. -0.02) indicating that delerioration in Ihe SAB5 group was significantly lessthanin
of the patients. The observed therapeutic effects
PLAC (Dunnett test). Moreover, the difference in the ADAS cog-9 scme (cognidve ADAS
without 2 memory ikms) between both groups was -5.04 (95% CI: -9.02, -1.05) after 48 w&s
were found to be associated with fluctuation of sub-
of treatment and -3.81 (95% CI: -7.41, -0.22) at endpoint. None of tie trearment groups population of some lymphocytes (pan-T, I3 and NK cells),
deteriorated over tbe l-year period for the ADAS memory items. and changes in levels of cytokines (IFN-gamma and
indication for a slowed deterioration under treamxat with SABS was also found in a subset TNF-alfa).
analysis for responders (patients without deterioration of dx ADAS scores). !&ie suggest that both imnunotropic drug may be useful
Safety for the symptomatic treatment of A.D.
Sabeluzole was well tolerated and presenled no safely problems as assessedby documentation
of AE. laboratory parameters. vital signs, physical examination and ECG recordings.

Conelusion
Results from this trial suggest that treahnent witb sabeluzole 5 mg b.i.d. CNI slow dx
progression of demenlia in patients witi AD. The magnitude of the effect can be expressed a!.
equivalent to 6 months of disease progression in this l-year trial.
565
REDUCTION OF BRAIN ALuM[NuM BY DESFERRIOXAhfINE AND
RELEVANCE TO ALZHEIMBRS DISEASE. Tbco PA. Kruck, S.S. Krishnan, W.
Smith and D.R.C. McLachlan. Centre for Research in Neurodegenerative Diseases,
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto,
Ontario, Canada. iU4V-2G6.
Alzheimer’s disease (AD) is multifactorial involving genetic and environmental
factors. There are strong indications that aluminum (Al) in the brain plays an active
role in the pathogenesis of AD, thus removal of Al from sites of toxic action is
expected to result in altering the wurse of the disease. We have tested both the
effectiveness of the trivalent metal chelator, desferri-ine (DFO), in removing
Al from brain in advancedAD and, we.have huther evaluated the long term effect
of the DFO-Al-chelation therapy on the course of the disease. Patients with
advanced AD were injected intramuscularly (IM) with 5oomg DFO twice daily for
5 days per week. After death, from causes unrelated to drug administration, brains
were analyzed for Al content and distribution. Six brains became available, 3 with
less than 7 injections and 3 with 47. 76 and 108 injections. The minimally treated
brains, group A, showed an average of 4.09 ug Al/g dry weight for 21 neocortical
567
INTRANASAL DELIVERY OF ‘=I-NGF TO THE BRAIN VIA THE
OLFACTORY ROUTE. W.H. Frey II, J. Liu; R.G. Thome and Y -E. Rahman.’
Alzheimees Treatment and Research Center and Dept. of Neurology, Ramsey
Clinic/St. Paul-Ramsey Med. Ctr.. St. Paul, Minnesota 55101 and Dept. of
Pharmaceutics, Universityof Minnesota, Minneapolis, Minnesota 55455 UsA.
Nerve growth factor (NGF). a potential therapeutic agent capable of
producing pharmacologic effects at nanomolar concentrations, does not cmss
the blood-brain banier. The object of the present study was to assess the
feasibilityof delivering NGF to the brain via the olfactory route,
1251-NGF(DuPont NEN) was further purified to remove traces of free
iodine, salt and proteolyticcontaminants with Centricon 10 ultrafiltration, Male
Sprague-Dawley rats, 200-280 g, were anesthetized with intraperitoneal
urethane (1.1 g/kg). lntranasal (i.n.) administrationof 1251.NGF was compared
with intravenous (i.v.) administration. One femoral vein was cannulated for the
collection of blood samples, while in some rats the other femoral vein was also
cannulated for i.v. administration. For in administration,the rats were placed
on their backs, and r251-NGF was given in single drops to each naris over 30-
40 min. Rats were subsequently perfuse-fixed with physiologicsaline followed
by 1.25% glutaraldehyde and 1% parafonaldehyde in 0.1 M phosphate
buffer, pH 7.4, prior to brain dissection and i25l measurement by gamma
counting.
Followingi.n. administration of NGF, radiolabel appeared rapidly (within 20
min.) in the olfactory bulb and, to a lesser extent, in certain other brain
S138 FOURTH INTERNATIONAL CONFERENCE ON ALZHEIMER’S DISEASE
regions. Radiolabel accumulation was a linear function of the i.n. dose, and of
the radiolabel concentration in the olfactoty epithelium. Radiolabel
accumulation in the olfactory bulb varied between 0.001-2.0 nM depending
the dose administered (10 pmoles - 7 nmoles). Concentration of label in the
olfactory bulb with i.n. administration, but not with i.v. administration, suggests
direct transport of label into the brain along the olfactory route. The rapid
appearance of label in the olfactory bulb is more consistent with entry of label
through intercellular clefts in the olfactory epithelium and extracellular
transport to reach the cerebrospinal fluid and brain, than with uptake by
olfactory neurons and subsequent axonal transport which requires more than
several hours. Demonstration of nanomolar radiolabel in the olfactory bulb of
the brain following i.n administration of 1251-NGFis an encouraging first step.
However, further studies are needed lo determine the neuroanatomic
distribution of r251-NGF and to demonstrate that the NGF delivered remains
intact, active and capable of producing pharmacologic effects.
568
AGGRESSlYE RESIDENTS IN LONG TERhf CARJI PACHITIEP REPORT OP AN
lNTJ3RVENTION STUDY. MB. Ryda, KS. Feldt, K. Bnad, J. Nslm, H. Lse, M.
wunc, 8. we&x. univ&ty of hfd School of NV&S, Milk, MN 55455
USA.
569
THE IMPACT OF THE HOME ENVIRONMENT ON DEMENTIA CAREGIVING
R. V. Olsen, 8. L. Hutchings, E. Ehrenkrantz
There are many variables impacting on the care of a person with
Alzheimer’s disease at home. Variables most frequently focused
on include those relating to the care recipient, such as stage of the
disease, degree of impairment and co-morbidities, and the care
partner, such as their physical and psychological health,
relationship to the care recipient, social and economic support and
tolerance for burden. However, there is a third set of variables
frequently overlooked in the caregiving equation. These variables
relate to the physical environment at the caregiving home.
Architecture & Building Science has completed a Robert Wood
Johnson Foundation funded study of 90+ seasoned caregivers who
provided care at home for a loved one from 2 to 15 years. The
study investigated the impact of the physical setting and caregivers’
strategies for creating a safe and supportive caregiving
environment.
This presentation will summarize findings from the study,
exploring safety concerns, problem behaviors linked to the physical
environment (e.g., hallucinations triggered by window and mirror
reflections, wandering out of improperly secured doors, etc.) and
on home modifications implemented to prevent or decrease these
behaviors and their degree of effectiveness. It will also identify
features of the physical environment which made caregiving easier
or harder and design qualities to look for in searching for a
“model” caregiving environment. Since caregivers clearly saw a
relationship between house form and caregiving, the importance
of the physical context in caregiving will be addressed as it relates to
both institutional and community-based care. Finally, the
relevance of including the home context in larger studies of
caregiver burden and outcomes from treatment protocols and
other interventions, will be emphasized.
(Findings from the study have been published by NJIT Press
(1993) in a book entitled, Homes that Help: Advice from Caregivers
for Creating a Supportive Home.)
NEUROPATHOLOGY I
570
APOLIPOPROTEIN-E IMMUNOREACTIVITY IN AMYLOID DEPOSITS IN
ALZHEIMER’S DISEASE, BUT NOT IN PATHOLOGICAL AGING OR
DIFFUSE LEWY BODY DISEASE (DLBD). D. W. Dickson, A. Ivsnushkin,
S-H. Yen and P. Davies. Department of Pathology (Neuropathology), Albert
Einstein College of Medicine, Bronx, New York 10461, USA.
Apolipoprotein E (ape-E) has recently been recognized as a marker for sporadic
and familial late onset Alzheimer’s disease (AD). In addition, it may be a factor
that modifies risk for AD in subjects with mutations in the amyloid precursor
protein. In order to study the distribution of ape-E in AD and aging brains with
and without P-amyloid (AD) deposits, we used sections of hippocampus from 27
subjects, most of whom had been participants in prospective, longitudinal clinical
studies. Included were subjects with AD (N=9), DLBD/AD (N=S) and DLBD
(N=4), as well as elderly controls with little or no amyloid deposition (N=2) and
elderly controls with extensive amyloid deposition (N=7), which we refer to as
pathological aging (PA). Frozen sections were fixed in acetone and stained with
double labeling immunocytochemical and immunofluorescence methods. In AD
and DLBD/AD, ape-E immunorcactivity was prcscnt in both compact and non-
compact amyloid deposits, amyloid within blood vessels and in extracellular, but
not intracellular, neurotibrillary tangles. Large diffuse amyloid deposits in the
presubiculum and diffuse deposits in the subpial space were immunoreactive for
AP, but consistently negative for ape-E. These apo-E-negative deposits were only
weakly stained with thioflavin S and consistent with pre-amyloid deposits.
Normal elderly patients had no immunoreactive deposits with antibodies to either
AD or apo-E. In PA and DLBD, pre-amyloid and diffuse amyloid deposits were
positive for AP, but not for ape-E. These results indicate that ape-E is not
essential for amyloid deposition in AD, DLBD or PA. Previous studies have
shown that senile plaques in AD have tau-positive dystrophic net&es and
microglial infiltrates, but that plaques in DLBD and PA lack these elements The
present study suggests that ape-E binding also distinguishes senile plaques in AD
from those in PA and DLBD. We hypothesize that AP deposition in diffuse or
non-tibrillar forms is associated with benign senile cerebral amyloidosis that is
not associated with overt clinical manifestations, and that apo-E binding may
participate in conversion of these deposits to a form of amyloid that characterizes
AD and that is associated with neuronal and glial alterations and dementia.
571
LACK
OFREL.ATIONSHlP
BETWEEN
Au-50 STAINING,
B-A4 ACC”H”?.,ATION
AND NEURONAL RCTIVITY IN THE ““NAN HYPoTNALAN”S OF ALZ”En4ER
PATIENTS. D.P.
Swaeb, F.C. remlsheer, J.A.P. van de ties, A. salehi
and R. Ravid, Netherlands Institute for Brain Research,
Heibergdreef 33, 1105 AZ Amsterdam, The Netherlands
The myloid cascade hypethesis predicts that B-A4 sccumulation,
cytoskeletal alterations (i.e. Alz-50 staining), inactivity of
neurons and neuronal death occur in a closely related way. In the