a-Glycerophosphocholine in the Mental

Recovery of Cerebral Ischemic Attacks

An Italian Multicenter Clinical Trial
GIUSEPPE BARBAGALLO SANGIORGI,
MARIO BARBAGALLO, MARCELLO GIORDANO,
MARIA MELI, AND RITA PANZARASA
Institute of Internal Medicine and Geriatrics
Universityof Palermo
Via Del Vespro 141
90127 Palemo, Italy

INTRODUCTION

Patients affected by acute ischemic cerebral event (TIA, p-TIA, stroke) may
develop a syndrome characterized by sensitive-motor and, often, cognitive deficit,
depending on the type of occlusion and individual response.1,2
Cerebrovascular disease is commonly considered to be the second cause of
dementia, and stroke in particular accounts for 20-25%.3 The term “dementia”
implies a change in the mental state, from one level of mental functioning to a lower
one over time. The explanation of the elevated risk of dementia following stroke is
not yet fully understood: injury of different and multiple brain regions, each specific
for certain cognitive functions, might lead to dementia simply on an additive basis, or
a multiplicative mechanism may apply with the cumulative effect of several lesions.
Many drugs, have been clinically tested in order to assess their role in the functional
recovery of these patients.
Among these, a-glycerophosphocholine (a-GPC), a new molecule belonging to a
class of choline donors, has shown a very promising profile on the basis of pharmaco-
kinetics and pharmacological studies: in animals it has shown to exert an integrated
neuronal function4 and to facilitate learning and memory in a dose-related w a ~ . ~ . ~
Once a-GPC crosses the blood-brain barrier, it directly increases the synthesis and
the release of acethylcholine, and serves as a precursor for membrane phospholipids,
improving the functionality of neuronal membrane^."^ In healthy human volunteers,
it has been possible to prevent the memory deficit produced by scopolamine.I0 And
both in open and controlled clinical studiesI1-l4on a substantial number of patients,’S
it has shown a good therapeutic effect on the outcome of dementia regardless of its
etiology.
The aim of the present study was to assess a-GPC efficacy and tolerability in the
treatment of neuropsychic symptoms following acute stroke.

MATERIAL AND METHODS

Experimental Design

The present study was an open multicenter uncontrolled trial involving 176
centers of internal medicine, geriatrics, and neurology spread all over Italy.
253
254 ANNALS NEW YORK ACADEMY OF SCIENCES

TABLE I. Clinical Assessment and Evaluation Time

First Part Second Part
Baseline 1st Month 3rd Month 6th Month
Demography and run-in assessment X
SYS/DIAS BP and HR X X X X
Mathew Scale X X
MMSE X X X
GDS X X X
Crichton Rat. Scale X X X
Blood Analyses X X X
a-GPC therapy 1000 mg/day im 3 x 400 mg/day orally

The study was carried out in two phases that lasted 6 months altogether: during
the first part (which lasted from day 1 to day 28, generally in hospital), the patients
were treated parenterally with a-GPC at the dosage of 1000 mg/day, and in the
second part (which lasted from day 29 to the end of the 6th month), the patients were
treated orally with a-GPC at a dosage of 1200 mg/day, at a regimen of 400 mg three
times a day.
The clinical assessments were made at the admission visit (baseline), at the end
of the first part, and after 3 and 6 months from the beginning.
TABLE1 reports the list of the clinical assessments and the checking times.
First part (baseline, 28th day): the clinical assessments consisted of patient’s
medical history (only at baseline), physical and neurological examination, arterial
blood pressure and heart rate control, Mathew Scale and blood analyses.
Second part (28th day or secondary baseline, 3rd month, 6th month): the clinical
assessments consisted of physical and neurological examination, Minimental State
Test, Crichton Rating Scale, Global Deterioration Scale, arterial blood pressure and
heart rate control, blood analyses (only at the 6th month).

Experimental Sample

The study population consisted of 2058 patients 45-85 years of age, with
diagnosis of cerebral ischemic attacks (stroke or TIA), within the previous 10 days.
The exclusion criteria were patients with a baseline Mathew score <35, or
presenting consciousness deficit such that no cooperation was possible in performing
the assessment tools requested by the protocol, or those receiving pharmacological
therapy with psychotropic or nootropic drugs, or with short life expectancy, or with
previous psychiatric and neurologic diseases, or with severe renal, liver, or heart
diseases and neoplasms. Furthermore those patients with hemorragic infarction,
head injury, or intracerebral or subarachnoid hemorrage, as well as alcohol and/or
drug addictions, were not considered eligible for the study.

Concomitant Treatments

Conventional treatment for stroke was accepted; concomitant treatments with

other brain-related drugs were excluded. Possible concomitant treatments for other
diseases had to be kept as stable as possible during the six months of the study. The
BARBAGALLO SANCIORGI el al.: CEREBRAL ISCHEMIC AITACKS 255

short half-life anxiolitics were accepted only at doses already stabilized for 30 days,
and they had to be recorded on the patients' case report forms.

Treatment Discontinuation and Adverse Effects

Investigators could discontinue the treatment at any time, and were asked to
report this information on the patient's form, especially if the discontinuation was
due to an adverse effect reported by the patient or detected by the investigator that
could be related to the drug in study.

Statistical Analysis

Data were expressed as mean 2 standard deviation (SD). The statistical analyses
were performed by Medical Statistics Service (Castellanza, VA, Italy); for the
analysis of continuous variables parametric tests were used, and nonparametric tests
were used to assess the efficacy of the drug (Friedman test, x 2 approximation).

RESULTS

Demographic Characteristics

A total of 2058 patients with diagnosis of ischemic attacks were recruited.

Inclusion and exclusion criteria were not fulfilled by 14 patients, who were not
considered in the statistical analysis for efficacy. The 14 patients were excluded on
the grounds of age limits (2 patients), different diagnosis (2 patients), inappropriate
dosage of the drug in study (1 patient), and for low scoring at the Mathew Scale (9
patients). Features of the 2044 remaining patients are reported in TABLE 2.

TABLE 2. Demographic Characteristics

Patients enrolled 2058
Patients evaluated 2044 u
Gender:
Males 1132 55.5%
Females 908 44.5%
Missing 4
Mean age 70.3 e8.65
Patients aged 45-65 485 23.7%
Patients aged > 65 1559 76.3%
Years of schooling:
1-5 429 21.0%
5-8 965 47.2%
>8 397 19.4%
Missing 253 12.4%
Family history of cerebrovascular events 761 37.2%
Diagnosis: ischemic stroke 1152 56.4%
TIA 892 43.6%
"4 drop out.
256 ANNALS NEW YORK ACADEMY OF SCIENCES

Males and females were equally represented, accounting for 55.5 and 44.5%
respectively. The mean age was 70.3 years (485 patients, 23.7%, aged 45-65; 1559
patients, 76.3%, aged 66-85 years); nearly 50% of patients had 5-8 years schooling,
and around 20% each had elementary or high school diplomas; 1152 patients
(56.4%) suffered from an ischemic stroke, and 892 (43.9%) from transient ischemic
attack (TIA).
Most of the patients enrolled had concomitant diseases, as shown in TABLE 3. In
fact, 1781 patients (87.1%) had concurrent diseases, mainly related to the cardiovas-
cular apparatus (72.4%) and metabolic disturbances (31.5%).
In parallel, concurrent therapies were recorded for 78.3% cases, and, likewise,
drugs for the cardiovascular therapy were the majority (82.5%).

Eflcacy
First Part of the Study (Days 1-28)

In order to assess the efficacy of a-GPC administered intramuscularly (im)

during the 28 days of the first part of the study, which took place mainly in hospital,
the Mathew Scale assessment was used; this scale scores 0 (clinical death) to 100

TABLE 3. Concomitant Diseases and Drugs

Patients with concomitant diseases 1721 87.1%
Patients without concomitant diseases 263 12.9%
Concomitant Disease:
Cardiovascular 1290 72.4%
MetaboWdiabetes 561 31.5%
Concomitant drugs:
Cardiac therapy 1470 82.5%
Antithrombotics 588 37.5%
Drugs for diabetes 308 19.5%

(patient with perfect consciousness).16 A minimum score = 35 was chosen for

enrollment, in order to have patients with a sufficient level of consciousness to
cooperate in performing the psychometric tests.
FIGURE 1 and TABLE4 show the trends and the mean values of the scoring to this
scale at baseline and on the 28th day of treatment. The mean Mathew scale value
increases from 58.7 to 74.6 corresponding to 15.9 points (p < 0.001).
In agreement with Gelmers,”Js the patients were furthermore divided into two
classes: “more deteriorated” (score 35-65) and “less deteriorated” (score > 65). A
high percentage of patients improved their conditions at the end of the first phase of
the trial, moving to the “less deteriorated” class. These changes were statistically
significant (p < 0.001).

Second Part of the Study (Days 29-180)

In order to assess the efficacy of a-GPC during the second part of the study, in
which 400 mg tid were administered orally to patients mainly discharged from
hospital, the Crichton Rating Scale (CRS) and the Mini Mental State Test (MMST)
BARBAGALLO SANGIORGI el al.: CEREBRAL ISCHEMIC A'ITACKS 257

NUMBER OF PATIENTS IN TWO CLASSES

OF MATHEW SCORE

FIGURE 1. Top: Mean values of Mathew Scale in time. Bottom: Number and percentage in
time of patients in the two classes of Mathew Scale score according to Gelmers.

TABLE 4. Mathew Scale (&100) (First Part of the Study)

Basal 28th Day
(m 2 SD) (58.7 f 12.7) (74.6 2 10.3)
p < 0.001
Number of patients with
score 35-65 1348 (66%) 370 (18.5%)
score >65 696 (34%) 1635 (81.5%)
258 ANNALS NEW YORK ACADEMY OF SCIENCES

were administered to the patients on the day in which the therapy route of
administration was changed (28th day) and on the 3rd and 6th month. The Crichton
Geriatric Rating Scale19 score 1-10 is considered “normal,” the score 11-20 “mild
deterioration,” 21-30 “moderate deterioration,” and > 30 “severe deterioration.”
TABLE5 and FIGURE 2 show the trend of the mean score value for the patients
treated: they achieved a significant decrease (improvement) of 4.3 points, from 20.2
to 15.9, between the 28th day and the final visit. The lower part of FIGURE 2 shows
the number of patients with the score corresponding to “mild deterioration”: their
number grows with time, increasing from 72.7% at the 3rd month to the 83.7% at the
final visit (6th month).
Cognitive functions were assessed by the Mini Mental State Test in which score
0-23 is commonly considered as “abnormal deterioration” and score >23 as
“normal.”20The mean score values increased in time, showing an improvement of 2.2
points at the 3rd month (p < 0.001) and above the score of normality, and a further
1.1 points at the 6th month, up to 24.3. The trend of the mean values is reported in
TABLE 6 and in FIGURE3.
Moreover, the lower part of FIGURE 3 shows the percentage of patients who
recovered from an abnormal to a normal score: it increases in time, moving from 40%
at the 28th day to 55.8% at the 3rd month and to 65% at the 6th month.

TABLE 5. Crichton Geriatric Rating Scale (Second Part of the Study)

28th Day 3rd Month 6th Month
(m r SD) (20.2 f 7.2) (17.8 f 6.05) (15.9 f 5.35)
p < 0.001 p < 0.001
Number of patients with deterioration
Mild ( < 20) 1205 (59.8%) 1405 (72.7%) 1588 (83.7%)
Moderate (21-30) 613 (30.4%) 450 (23.3%) 271 (14.3%)
Severe ( > 30) 197 (9.8%) 77 (4%) 38 (2%)

The degree of global deterioration was assessed with the Global Deterioration
Score (GDS),**in which the value 0 means normality and 7 means severe deteriora-
tion. TABLE7 and FIGURE 4 report the trend of the mean values of GDS. The mean
values decreased from 2.72 at the beginning of the second phase to 2.16 at the end of
the trial; the difference between the mean scores was statistically significant
(p < 0.01).
At the end of both parts of the study, investigators were requested to report their
subjective opinions about the overall clinical efficacy and tolerability of a-GPC.
FIGURE 5 shows the different percentages of the investigators’ opinion at the end of
each one of the two parts of the study.
A “very good”/“good” efficacy was reported by 68.9% (first part) and 77.6%
(second part) of the investigators; a “moderate” efficacy was reported by 24.8% (first
part) and 17.5% (second part) of investigators, and a “poor”/“none” efficacy was
reported by 6.3% (first part) and 4.9% (second part) of the investigators.

Tolerability

Of the 2044 patients considered for the study, 140 (6.8%) withdrew from the
treatment: 101 during the first part and 38 during the second part. The reasons for
BARBAGALLO SANGIORGI el al.: CEREBRAL ISCHEMIC ATTACKS 259

SCORE
28

22

16

10
1 3 6
MONTH

PERCENT OF PATIENTS IN 3 CLASSES

OF CRICHTON RATING SCALE

FIGURE 2. Top: Mean values of Crichton Geriatric Rating Scale in time. Bottom: Number and
percentage in time of patients in the deterioration classes of Crichton Geriatric Rating Scale.

TABLE 6. Minirnental State Test (Second Part of the Study)

28th Day 3rd Month 6th Month
(m f SD) (21.0 5 6.1) (23.2 2 5.41 (24.3 ? 5.11
p <0.001 p < 0.001
Number of patients with score
0-23 1204 (60%) 851 (44.2%) 665 (35%)
> 23 803 (40%) 1074 (55.8%) 1234 (65%)
260 ANNALS NEW YORK ACADEMY OF SCIENCES

SCORE
29

27
p<O.OOl
P'O.001
26
23.2* I

23

21

19

17
1 3 6
MONTH

PERCENT OF PATIENTS IN TWO CLASSES

OF MMSE SCORE

FIGURE 3. Top: Mean values of Mini Mental State Test in time. Bottom: Number and
percentage in time of patients in the two deterioration classes of the Mini Mental State Test.

TABLE7. Global Deterioration Scale (Second Part of the Study)

28th Day 6th Month
m -C SD 2.72 f 1.3 2.16 f 1.1
p < 0.01
BARBAGALLO SANGlORGl ef al.: CEREBRAL ISCHEMIC ATTACKS 261

NUMBER OF PATIENTS IN TWO CLASSES

OFQDSSCORE

FIGURE 4. Top: Mean values of Global Deterioration Scale in time. Bottom: Number and
percentage in time of patients in the classes of Global Deterioration Scale.

withdrawal are reported in TABLE8; 41 patients died; the investigator related all the
deaths to a worsening of the underlying pathology; none to the drug treatment.
Systemic tolerability was also controlled by monitoring arterial blood pressure,
heart rate and blood analyses (full blood count and renal, liver functionality).
The patients were also observed for adverse events which were recorded at each
control visit. TABLE9 shows the mean values of blood pressure and heart rate: no
changes occurred during all the treatment period.
262 ANNALS NEW YORK ACADEMY OF SCIENCES

No abnormal values were observed in the blood analyses as well as in the other
monitoring records during the trial.

Unwanted Events

In total, 51 unwanted effects were reported by 44 out of the 2058 enrolled

patients (2.14%). TABLE10 lists all the unwanted effects complained of by the
patients enrolled into the trial. Of the 2058 treated patients, 14 (0.68%) had to
withdraw from the therapy with a-GPC for concomitant events: 10 in part I and 4 in
part 11. The reason for withdrawal were: 4 heartburn (3 in part I and 1 in part II), 2
nausea/vomit (in part I), 2 excitation/insomnia (in part I), 2 diarrhea (1 in part I, 1 in
part 11), 1 dizziness, 1 skin rash (in part 11), 1 confusion, 1 repeated drop attacks (in
part I). All the other events complained of did not result in a therapy withdrawal, and
were of light or mild severity.

Yo
80

60

4746.2

40
1
31.5

!
20 45

0
VERY GOODGOODPART MODERATE POOR NONE

~ 1st PART 02nd PART

FIGURE 5. Overall clinical impression of efficacy reported by the investigators at the end of
each of the two parts of the study.
BARBAGALLO SANGIORGI el al.: CEREBRAL ISCHEMIC AlTACKS 263

TABLE 8. Discontinuation of the Trial

Reason First Part Second Part Total
Drop out 52 21 73 (3.55%)
Exitus 30 11 41 (1.99%)
Unwanted events 10 4 14 (0.68%)
Improved 5 2 7 (0.34%)
Inefficacy 4 1 5 (0.24%)
101 39 140 (6.8%)

The most frequent reported side effects were: heartburn (14), excitation-
insomnia (9), nausea (8) and headache (4).

CONCLUSIONS

The present results collected from a large patient population diagnosed for acute
ischemic cerebral attacks confirm the efficacy of a-GPC on the mental recovery after
stroke.
At the end of the first part of the study, after 1 month of parenteral therapy with
a-GPC, the results were very good both in tolerability and in efficacy: Mathew Scale
reached a mean score equivalent to a less deteriorated neurological condition ( > 65)
and the tolerability was good: 34 events (1.66%) and 10 withdrawals (0.49%).
The improvement was maintained in time during the following 5 months of oral
therapy, and a further improvement in cognitive functions (by the Minimental State
Test), in behavioral functions (by the Crichton Geriatric Rating Scale), and in
medical conditions related to cognitive decline (by the GDS) was statistically
evaluable.
Tolerability was very good also in the second part: 17 events (0.33%) and 4
withdrawals (0.2%).
These data confirm in a large patient population the efficacy and the therapeutic
role of a-GPC on the cognitive enhancement of patients with an acute cerebrovascu-
lar attacks (stroke and/or TIA): the very low incidence of adverse events confirms
that a-GPC can be safely administered also for a long period after the occurrence of
stroke.

Arterial Blood Pressure and Heart Rate (Mean,

TABLE 9.
Standard Deviation, Range)
First Part Second Part
Basal 28th Day 3rd Month 6th Month
Systolic (mean f SD) 159 2 23 149 f 17 149.5 f 15 149 2 14.6
Range 100-240 100-200 100-200 100-205
Diastolic (mean f SD) 9 0 2 12 85 2 9 85 f 8 85 f 8
Range 50-140 50-170 60-150 60-150
Heart rate (mean 2 SD) 81.5 f 12 78.5 2 8.5 78.7 2 8 78.6 f 7
Range 45-152 50-120 45-165 56-110
264 ANNALS NEW YORK ACADEMY OF SCIENCES

TABLE LO. List of the 51 Adverse Events”

Total First Part Second Part
Heartburn 14 10 (3) 4 (1)
Nausea-vomit 10 9 (2) 1
Excitation-insomnia 9 5 (2) 4
Headache 4 3 1
Diarrhea 3 2 (1) 1(1)
Dizziness 2 2 (1)
Skin rash 2 1 10)
Gastric bleeding 1 1
Increased y G T 1 1
Increased ALATIASAT 1 1
Confusion 1 1(1)
Anemia and low vit. B12 1 1
Supraventriculararrhythmia 1 1
Repeated drop attacks 1 1(1)
“The number in parenthesis indicates number of drop-out patients.

SUMMARY

The clinical efficacy and the tolerability of a-glycerophosphocholine (a-GPC), a

drug able to provide high levels of choline for the nervous cells of the brain and to
protect their cell walls, have been tested in a clinical open multicenter trial on 2044
patients suffering from recent stroke or transient ischemic attacks. a-GPC was
administered after the attack at the daily dose of 1000 mg im for 28 days and orally at
the dose of 400 mg tid during the following 5 months after the first phase.
The evaluation of the efficacy on the psychic recovery was done by the Mathew
Scale (MS) during the period of im drug administration, and using the Mini Mental
State Test (MMST), the Crichton Rating Scale (CRS), and the Global Deterioration
Scale (GDS) during the following period of oral administration.
The MS mean increased 15.9 points in 28 days in a statistically significant way
(p < 0.001) from 58.7 to 74.6. At the end of the 5 month oral administration, the
CRS mean significantly decreased 4.3 points, from 20.2 to 15.9 (p < 0.001); the
MMST mean significantly increased (p < 0.001) from 21 to 24.3 at the end of the
trial, reaching the “normality’’ score at the 3rd month assessment. The GDS score at
the end of the trial corresponded to “no cognitive decline” or “forgetfulness” in 71%
of the patients. Adverse events were complained of by 44 patients (2.14%); in 14
(0.7%)the investigator preferred to discontinue therapy.
The most frequent complaints were heartburn (0.7%), nausea-vomit (0.5%),
insomnia-excitation (0.4%),and headache (0.2%).
The trial confirms the therapeutic role of a-GPC on the cognitive recovery of
patients with acute stroke or TIA, and the low percentage of adverse events confirms
its excellent tolerability.

REFERENCES

1. LOEB,C. 1986: La diagnosi di attacco ischemic0 transitorio: una diagnosi facile? Aggiorna-
mento del medico lO(2): 8689.
BARBAGALLO SANGIORGI el al.: CEREBRAL. ISCHEMIC AlTACKS 265

2. STAZI,C., F. CARPINTERI & F. STAZI.1986. Ictus cerebrale: dall’etiologia alla terapia. Clin.
Ter. I18 433447.
3. TATEMICHI, T. K., M. A. FOULKES, J. P. MOHR,J. R. HEWITT,D. B. HIER,T. R. PRICE&
P. A. WOLF.1990. Dementia in stroke survivors in the stroke data bank cohort. Stroke
21(6): 858-866.
4. SCHETIINI, G., C. VENTRA,T. FLORIO,M. GRIMALDI, et al. 1992. Molecular mechanisms
mediating the effect of a-glycerylphosphorylcholine,a new cognition-enhancing drug,
on behavioral and biochemical parameters in young and aged rats. Pharmacol. Bio-
chem. Behavior 4 3 139-151.
5. GOVONI, S., C. LOPEZ,F. BAITAINI, et al. 1990. Effetti di alfa-GFC sul comportamento di
evitamento passivo del ratto e sui livelli di acetilcolina. Basi Raz. Ter. 20( 1): 55-60.
6. DRAGO,F., L. NARDO,V. FRENI,er al. 1990. Effetti comportamentali di a-GFC in modelli
di invecchiamento cerebrale patologico. Basi Raz. Ter. 20( 1): 6548.
7. SPANO,P. F. & M. TRABUCCHI. 1990. Farmacocinetica e metabolismo di 14c colina
alfoscerato nel ratto. Basi Raz. Ter. 20( 1).
8. MISSALE,C., S. SIGALA& P. F. SPANO.1990. Effetto modulatore di a-GFC sulla
trasmissione colinergica nell’ippocampo di ratto. Basi Raz. Ter. tO( 1): 13-15.
9. AMENTA, F., E. BRONZETTI, M. DELVALLE,et al. 1990. Neuroanatomia dell’invecchiamento
cerebrale nell’animale da esperimento: effetto del trattamento con a-GFC. Basi Raz.
Ter. 20( 1): 31-38.
10. CANAL,N., M. FRANCESCHI, M. ALBERONI, et al. 1990. Effetto di a-GFC sulla amnesia
causata da scopolamina. Basi Raz. Ter. 20( 1): 75-78.
11. MOGLIA,A., S. BERGONZOLI & P. DE MOLINER.1990. Effetto di a-GFC nel modificare il
brain mapping in pazienti con Age Associated Memory Impairment (AAMI). Basi Raz.
Ter. 20( 1): 83-89.
12. BASSI,S., M. G. ALBIZZATI, R. PIOLTI& L. FRATTOLA.1990. Esperienza clinica con colina
alfoscerato in pazienti affetti da demenza degenerativa primaria e multiinfartuale.
Gnosis 5: 55-62.
13. DI PERRI,R., G. COPPOLA, L. A. AMBROSIO. A. GRASSO, F. M. PUCA& M. Rizzo. 1991. A
multicentre trial to evaluate the efficacy and tolerability of a-glycerylphosphoryohc-
line versus cytidine diphosphocholine in patients with vascular dementia. J. Int. Med.
Res. 1 9 330-341.
14. FRATTOLA, L., R. PIOLTI,S. BASSI,M. G. ALBIZZATI, G. GALETTI,B. GRUMELLI, N.
CANAL, et af. 1991. Multicenter clinical comparison of the effects of choline alphoscer-
ate and cytidine diphosphocholine in the treatment of multiinfarct dementia. Curr.
Ther. Res. 49(4): 683-693.
15. BAN,T. A., R. PANZARASA, S. BORRA,D. DELDUCHE-ITO& 0. FJETLAND. 1991. Choline
alphoscerate in elderly patients with cognitive decline due to dementing illness. New
trends Clin. Neuropharmacol. 5(3/4): 1-35.
16. MATHEW,N. T., J. S. MEYER,V. M. RIVERA,J. Z. CHARNEY & D. HARTMANN. 1972.
Double blind evaluation of glycerol therapy in acute cerebral infarction. Lancet 7791
(Dec. 23).
17. GELMERS, H. J., K. GORTER, C. J. DE WEERDT& H. J. A. WIEZER.1988. A controlled trial
of nimodipine in acute ischemic stroke. N. Engl. J. Med. 318(4): 203-207.
18. GELMERS, H. J., K. GORTER,C. J. DE WEERDT& H. J. A. WIEZER.1988. Assessment of
intraobserver variability in a Dutch multicenter study on acute ischemic stroke. Stroke
19(6): 709-711.
19. GUY,W. 1976. ECDEU Assessment Manual for Psychopharmacology. Revised 1976.
Department of Health, Education and Welfare Publication (ADM) 76338. Bethesda,
Md.
20. FOLSTEIN,M. F. 1983. The Mini Mental State Examination. In Assessment in Geriatric
Psychopharmacology. T. Crook, S. Ferris & R. Barbus, Eds. Mark Powley Ass., Inc.
New Canaan, Conn.
21. REISBERG, B., S. H. FERRIS, M. J. DE LEON& T. CROOK.1982. The Global Deterioration
Scale (GDS). An instrument for the assessment of primary degenerative dementia
(PDD). Am. J. Psych. 1 3 9 11361139.
266 ANNALS NEW YORK ACADEMY OF SCIENCES

APPENDIX

For contributing and assessing the patients, thanks are due to following investigators:
Addis L. Ospedale Dettori Tempio Pausania (SS)
Aguggia M. Ospedale S. Luigi Gonzaga Orbassano (TO)
Ambrosio L.A. Ospedale Dell’Annunziata Cosenza
Amedoro G. Ospedale Civile Rieti
Amodio E. Ospedale Umberto I Frosinone
Andreotti M. Presidio Ospedaliero Varallo Sesia (VC)
Angeletti R. Ospedale Civile Tarquinia (VT)
Ansaldi E. Ospedale Civile SS. Antonio e Biagio Alessandria
Appiotti A. Ospedale Mauriziano Torino
Arcara A. Casa Di Cura Sant’Anna Palermo
Bagnato F. Ospedale Civile G. Ciaccio Catanzaro
Barba V.R. Ospedale S.Giuseppe Da Copertino Copertino (LE)
Barbi G. Ospedale S. Anna Como
Bargnani C. Ospedale Di Chiari (BS)
Belfiore A. Ospedale Civile Ostuni (BA)
Bendandi P. Casa Di Cura S. Francesco Ravenna
Bernacchi G. Ospedale S. Leonard0 Castellammare Di Stabia (NA)
Bernadi A. Ospedale Di Rovereto (TN)
Bertuzzi A. Pascal G.C. Istituti Ospedalieri Carlo Poma Mantova
Bettini R. Ospedale Del Ponte Varese
Bonaduce V. Ospedale Consorziale Bari
Bonasera N. Ospedale Civic0 e Benfratelli Palermo
Bonincontro C. Ospedale Civile Vasto (CH)
Bosi L. Arcispedale S. Anna Ferrara
Cafagna D. Ospedale Cattinara Trieste
Calcara G. Ospedale S. Marta e. S. Venera Acireale (CT)
Camardella G. Ospedale Civile Rieti
Cassani P. Ospedale S. Biagio Domodossola (NO)
Castiglione R. Ospedale Villa Sofia Palerrno
Cataliotti C. Ospedale S. Giovanni Di Dio e Isidoro Giarre (CT)
Cella L. Ospedale S. Francesco Barga (LU)
Cerini G. Ospedale M. Sarcone Terlizzi (BA)
Cerri C. Ospedale Trabattoni Ronzoni Seregno (MI)
Cesareo E. Ospedale A. Tortora Pagani (SA)
Ciannella L. Ospedale G. Rummo Benevento
Clivati A. Ospedale Citta’ Di Sesto S. Giovanni (MI)
Codeluppi P. Ospedale Civile I. Caffi Poggiorusco (MN)
Conti A. Ospedale San Luca Firenze
Cortesi P.P. Ospedale Pierantoni Forli’
Curti A. Ospedale S. Giovanni Decoll. Andosilla Civitacastellana
(VT)
Cusumano V. Ospedale Civile Vittorio Emanuele 111 Monselice (PD)
D’Agnolo B. Ospedale Cattinara Trieste
D’Angelo D. Ospedale Generale Provinciale Giulianova (TE)
D’Auria N. Fond. Praxis S. Maria a Vico (CE)
D’Avanzo A. Ospedale Civile Avellino
De Angelis A. Fond. Praxis S. Maria a Vico (CE)
De Falco F.A. Ospedale Loreto Mare (NA)
Del Papa M. Ospedale Civile Civitanova Marche (MC)
Di Taranto A. Ospedale F. Lastaria Lucera (FG)
Fabriani P. Favilla A. Ospedale F. Lotti Pontedera (PI)
Fabrizi De Biani G. Ospedale Serristori Figline Valdarno (Fl)
Fabrizi G. Ospedale P. Burresi Poggibonsi (SI)
Facchini G. Ospedale Del Comprensorio Lug0 (RA)
BARBAGALLO SANGIORGI el al.: CEREBRAL ISCHEMIC AlTACKS 267

Faggi L. Aimone G. Ospedale Maggiore Lodi

Ferrari E. Ospedale S. Margherita Pavia
Ferrari L. Ospedale Civile Umberto I Enna
Ferrini L. Ospedale Della Misericordia Montegranaro (AF’)
Finocchiaro S. Presidio Ospedaliero Ferrarotto Alessi Catania
Fiorina L. Ospedale Civile Castellamonte (TO)
Galanti F. Ospedale San Giovanni Roma
Galbiati G. Galli G.C. Ospedale Di Lecco (CO)
Galeone F. Ospedale Della Val Di Nievole Pescia (PT)
Galvanini G.T. Presidio Ospedaliero Di Villafranca e Verona (VR)
Galzio R. Ospedali Ed Istituti Riuniti Teramo
Ganga A. Universita’ Degli Studi Sassari
Gelarda G. Ospedale Civic0 e Benfratelli Palermo
Gentile M. Policlinico Umberto I Roma
Giamundo A. I1 Policlinico Napoli
Giorgetti C. Ospedale S. Chiara Pisa
Gorgone G. Ospedale M. Raimondi S. Cataldo (CL)
Guerrieri G. Ospedale Maggiore Modica (RG)
Gugliucci N. Ospedale Civile Oliveto Citra (SA)
Guideri R. Ospedale S. Andrea Massa Marittima (SI)
Guizzardi G. Casa Di Cura De Cesaris Spoltore (PE)
Guizzaro A. I Policlinico Napoli
Gurioli L. Desiderato P. Ospedale Civile Cuorgne’ (TO)
Gusmaroli V. Ospedale Agnelli Pinerolo (TO)
Jorini G.M. Bazzani M. Ospedale Civile Asola (MN)
Italian0 F. Ospedale Martini Nuovo Torino
La Rosa G. Ospedale Regina Margherita Messina
Lagana’ G. Ospedale Morelli Reggio Calabria
Lai M. Casa Di Cura Tomasini Ierzu (NU)
Laperuta A. Ospedale A.Tortora Pagani (SA)
Lavitola G. Ospedale Dell’Annunziata Cosenza
Leo F. Ospedale G. Panico Tricase (LE)
Lipizer A. Stabilimento Ospedaliero Gorizia
Loni G. Ospedali Riuniti Livorno
Losi F. Casa Di Cura S. Antonino Piacenza
Maffei R. Ospedale S. Maria Della Pieta’ Nola (NA)
Maffini S. Ospedale Civile Cortemaggiore Piacenza
Maggi S. Ospedale Civile Modugno (BA)
Magoni M. Universita’ Degli Studi Brescia
Manca P. Ospedale Civile Sondrio
Mancini M. Bompani R. Ospedale G. Stuard Parma
Mandarini A. Ospedale Cardarelli Napoli
Mansoldo G. Centro Ospedaliero S. Chiara Trento
Marangolo M. Ospedale G. Garibaldi Catania
Marano R. Policlinico Bari
Marchesi D. Ospedale Domus Salutis Brescia
Mariella F. Ospedale Civile Martha Franca (TA)
Marinangeli B. Casa Di Cura Stella Maris S. Benedetto D. Tronto (AP)
Mengoli M. Ospedale Civile S. Sebastiano Correggio (RE)
Molinari E. Policlinico San Matteo Pavia
Morbelli E. Casa Di Cura Societa’ Esercizio Cesano Boscone (MI)
Morino U Ospedale Martini Nuovo Torino
Munari L. Ospedale Civile Padova
Murgia B. Ospedale S. Francesco Nuoro
Musco A. Ospedale Basso Ragusa Militello In Val Di Catania
(W
Napoli S. Ospedali Riuniti Sanremo e Bussana Sanremo (IM)
268 ANNALS NEW YORK ACADEMY OF SCIENCES

Neviani V. Casa Di Cura Hemeria Modena

Nevola C. Ospedale Civile Aiellino
Nicolino A. Fondaz. Clinica Del Lavoro Campoli Del Monte
Taburno (BN)
Orefice G. I1 PoliclinicoNapoli
Pacifici P. Ospedale Civile S. Maria Dei Laici Amelia (TR)
Pagano S. Casa Di Cura Orestano Palermo
Pagliano F. Ospedale Generale Carate Brianza (MI)
Palermo F. Ospedali Riuniti G. Melacrino e F. Bianchi Reggio
Calabria
Papuzzo M. Clinica S. Marco Latina
Pascalis L. Ospedale S. Giovanni Di Dio Cagliari
Pedace C. Ospedale S. Foiano Arezzo
Petroni A. Clinica Di Lorenzo Avezzano (AQ)
Pipicelli G. Ospedale Civile Soverato (CZ)
Pisani L. Pi0 Albergo Trivulzio Milano
Pittera A. Ospedale SS. Salvatore Paterno’ (CT)
Platania S. Tringale G. Ospedale Civile E Muscatello Augusta (SR)
Polizzi C. Ospedale S. Biagio Marsala (TP)
Pomante P. Clinica S. Anna Pomezia (ROMA)
PonseveroniA. Ospedale Misericordia e Dolce Prato (FI)
Porcellati C. Ospedale Civile R. Silvestrini Perugia
Pozzuoli L. Ospedale Civile Caserta
Principe M. Ospedale S. Camillo De Lellis Manfredonia (FG)
Princi R. Ospedale Civile Locri (RC)
Pumilia G. Ospedale Civic0 e Benfratelli Palermo
Puoti F. Cotrufo R. I Policlinico Napoli
Raganato G. Ospedale S. Giuseppe Da Copertino Copertino (LE)
Rampino A. Casa Di Cura Citta’ Di Udine
Rapex G. Ospedale M. Montessori Chiaravalle (AN)
Rascio L. Ospedale S. Camillo Roma
Rastelli G. Ospedale Civile Fidenza (PR)
Renzi D. Artese D. Ospedale SS. Trinita’ Popoli (PE)
Ricca M. Ospedale Di Camerata Firenze
Rizzo D. Ospedale Cardarelli Napoli
Rocchi G. StabilimentoOspedaliero Sacile (PN)
Rodari T. Ospedali Riuniti Verbania e Pallanza Verbania (NO)
Rollandi M. Ospedale Civile S. Andrea La Spezia
Rossini P.M. Ospedale Fatebenefratelli Roma
Salvi P. Ospedale Quarenghi S. Pellegrino (BG)
Sarapo G. Ospedale Civile Villa D’Agri (PZ)
Sardi A. Ospedale Civile Chivasso (TO)
Sarno A. Ospedale Villa Camaldoli Napoli
Scarda G. Neri A. Ospedale S. Filippo Neri Roma
Schioppa M. Ospedale Vecchio Pellegrini Napoli
Schisano G. Ospedale Nuovo Pellegrini Napoli
Sechi F. Molinu M. Testoni M. Ospedale Presidente A. Segni Ozieri (SS)
Sesti A.G. Casa Di Cura Villa Kraus Firenze
Sgro G. Ospedale Dell’Annunziata Sulmona (AQ)
Simone P. Casa Sollievo Della Sofferenza S. Giovanni Rotondo
(FG)
Solinas F. Ospedale Presidente A. Segni Ozieri (SS)
Spedo A. -
Ospedale Civile Migliorini e Balzan Badia Polesine
iRO)
Stella L. Os~edaleCardarelli Naooli
Tagliabue P. Balbis E. Ospedale S. Andrea Vekelli
Tavormina F. Ospedale S. Antonio Abate Trapani
BARBAGALLO SANGIORGI el al.: CEREBRAL ISCHEMIC ATTACKS 269

Tessitore A. Ospedale Cardarelli Napoli

Tirnpanaro S. Presidio Ospedaliero Vittorio Emanuele I1 Catania
Trarnpetti P. Ospedale Civile Montefalco (PG)
Travaglini A. Ospedale Civile S. Maria Terni
Tridico N. Ospedale Civile Rossano (CS)
Venco A. Serena G. Ospedale Di Circolo Varese
Vicari E. Ospedale V. Cervello Palermo
Viglierchio P. Ospedale San Paolo Savona
Vigna L. Ospedale G. Ferrari Castrovillari (CS)
Vivalda L. Ospedale Martini Nuovo Torino
Voglini C. Ospedale S. Ambrogio Mortara (PV)
Volpe D. Ospedale S. Raffaele Arcangelo e Fatebenefratelli
Venezia
Zanardi M.Morena M. Rossi M. Ospedale Civile Ge-Sarnpierdarena
Zit0 F. Ospedale SS. Annunziata Taranto