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Cerebral Hypoperfusion Generates Cortical Watershed Microinfarcts in
Oda-Christina Suter, Thanomphone Sunthorn, Rudolf Kraftsik, Joel Straubel, Pushpa
Darekar, Kamel Khalili and Judith Miklossy
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Cerebral Hypoperfusion Generates Cortical Watershed
Microinfarcts in Alzheimer Disease
Oda-Christina Suter, MD; Thanomphone Sunthorn; Rudolf Kraftsik; Joel Straubel;
Pushpa Darekar, BSc; Kamel Khalili, PhD; Judith Miklossy, MD
Background and Purpose
—The watershed cortical areas are the first to be deprived of sufficient blood flow in the event
of cerebral hypoperfusion and will be the sites of watershed microinfarcts. Cerebral hypoperfusion is associated withAlzheimer disease (AD), but information regarding the occurrence of watershed cortical infarcts in AD is lacking.
—Brains of 184 autopsy cases (105 definite AD cases and 79 age-matched controls) were selected and analyzed
by histochemical and immunohistochemical techniques. The 3-dimensional reconstruction of the whole cerebrum, with3-mm spaced serial sections, was performed in 6 AD cases to study the intrahemispheric and interhemisphericdistribution of the cortical microinfarcts.
—A significant association (P
⫽0.001) was found between the occurrence of watershed cortical infarcts and AD
(32.4% versus 2.5% in controls). The microinfarcts were restricted to the watershed cortical zones. Congophilicangiopathy was revealed to be an important risk factor. Perturbed hemodynamic factors (eg, decreased blood pressure)may play a role in the genesis of cortical watershed microinfarcts.
—In AD, cerebral hypoperfusion induces not only white matter changes but cortical watershed microinfarcts
as well, further aggravating the degenerative process and worsening dementia. To prevent the formation of watershed
cortical microinfarcts in AD, monitoring blood pressure and treating arterial hypotension are essential. (Stroke. 2002;
Alzheimer disease 䡲 amyloid 䡲 angiopathy 䡲 cerebral infarction 䡲 hypoperfusion
The association of cerebral hypoperfusion and Alzheimer cerebral hypoperfusion secondary to conditions such as arte-
disease (AD) is well established. In addition to the
rial hypotension. Lesions secondary to cerebral hypoperfu-
predominantly cortical atrophy shown on CT scan,1 MRI has
sion include not only white matter changes but cortical
demonstrated white matter lesions induced by cerebral hypo-
infarcts as well, specifically localized to the vascular water-
perfusion known as leukoaraiosis. It has been reported that
shed zones of the major cerebral arteries; they are known as
between 7.5% and 100% of AD patients have leukoaraiosis.2
watershed, boundary zone, or border zone infarcts.
With the use of positron emission tomography, decreased
If cerebral hypoperfusion is frequently associated with AD,
regional cerebral blood flow and metabolic rates were ob-
one would expect to find watershed zone cortical infarcts in a
served in AD. Reduced cerebral perfusion and decreased
significant percentage of AD cases. The involvement of cortical
metabolism in white matter and cerebral cortex were reported
watershed areas was not documented in AD. Therefore, the aim
to occur predominantly in the temporal, parietal, and frontal
of this study was to analyze, in a representative number of
areas.3–5 Recent observations showed that reduced cerebral
definite AD cases and age-matched control cases, whether
blood flow is rather global in AD, without significant varia-
cortical watershed zone infarcts are associated with AD.
tion between different brain regions.5 Reduction in metabolicactivity was also observed in several other cortical areas, such
as the posterior cingulate gyrus and occipital cortex.6,7 Cere-
To analyze the occurrence of cortical watershed infarcts in AD, 184
bral hypoperfusion, progressive and diffuse cortical atrophy,
autopsy cases (105 definite AD cases [aged 54 to 98 years; mean age,
and leukoaraiosis were all correlated with cognitive
78 years] and 79 age-matched control cases [aged 57 to 87 years;mean age, 72 years]) were selected (Table 1). For the definite
diagnosis of AD, criteria proposed by Khachaturian,11 the guidelines
It is well established that vascular watershed zones are the
of the Consortium to Establish a Registry for Alzheimer's Disease,12
first to be deprived of sufficient blood flow in the event of
and the guidelines of the National Institute of Aging–Reagan
Received February 11, 2002; final revision received March 26, 2002; accepted April 8, 2002.
From the University Institute of Pathology, Division of Neuropathology, University Medical School (O-C.S., T.S., J.S., P.D., J.M.), and Institute of
Cellular Biology and Morphology, University of Lausanne (R.K.), Lausanne, Switzerland; and Center for Neurovirology and Cancer Biology, Collegeof Science and Technology, Temple University, Philadelphia, Pa (K.K., J.M.).
Correspondence to Judith Miklossy, MD, Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, 1900
N 12th St, Philadelphia, PA 19122. E-mail email@example.com
2002 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
Suter et al
Cortical Watershed Infarcts in Alzheimer Disease
Cortical Watershed Microinfarcts in AD
AD Cases (n⫽105)
The presence of congophilic angiopathy (A⫹), the presence of atherosclerosis (ATS⫹), the
concurrent presence of congophilic angiopathy and atherosclerosis (A⫹/ATS⫹), and the absence ofatherosclerosis and congophilic angiopathy (A⫺/ATS⫺) were considered in the 185 autopsy casesanalyzed. The occurrence of cortical watershed infarcts (WI⫹) was ⬎10-fold higher in the group ofAD cases (34/105) than in the controls (2/79).
Institute13 were considered. In the 105 AD cases, dementia was
slice at the right parieto-occipital region (Figure 1) was also studied,
clinically documented. The 79 controls did not suffer from dementia
which included watershed areas of the 3 major cerebral arteries.
and were without cortical AD-type histological changes. Cases with
After they were embedded in paraffin, 5-m-thick sections were
moderate AD-type changes may be considered to have preclinical
cut and stained with hematoxylin and eosin (H&E), van Gieson–
stages of AD but also to be normal aging cases. Because criteria for
Luxol fast blue, Congo red, thioflavin-S, and the Gallyas technique
normal aging are not clearly established,11 all cases with discrete or
for neurofibrillary tangles. Paraffin sections were also immuno-
moderate AD-type cortical changes were excluded from this study.
stained with monoclonal antibody to ␤-amyloid (DAKO, M 872;
We expected that selecting the cases in this way would allow us to
dilution 1:100) with the avidin-biotin-peroxidase technique.
more accurately answer the question of whether cortical watershed
The neuropathological assessment of the AD-type cortical changes
infarcts are associated with AD.
was made by 2 different investigators following criteria previously
Because occlusive angiopathies, particularly hypertensive mi-
described in detail.14 The analysis of watershed cortical infarcts was
croangiopathy, represent a risk for developing watershed microin-
also performed in all cases and in all sections independently by 2
farcts, all cases with arterial hypertension and with cerebral infarcts
different investigators. One of the investigators participated in both
localized outside the cortical vascular watershed zones, including
lacunar infarcts, were excluded from this study.
In the 184 cases, we also analyzed the presence or absence of
From the formalin-fixed brains, in all cases at least 12 different
atherosclerosis and congophilic angiopathy. Atherosclerosis of the
samples, including cortical areas outside of watershed zones, basal
large cerebral arteries was noted on macroscopic examination, and
ganglia, thalamus, cerebellum, and at least 1 level of the brain stem,
the detection of congophilic angiopathy was performed on sections
were taken for a detailed neuropathological investigation. In addi-
stained with Congo red, stained with thioflavin S, and immuno-
tion, blocks from the frontal, parietal, and temporal regions, includ-
stained with monoclonal antibody to ␤-amyloid. We defined as
ing hippocampus and entorhinal cortex, were systematically taken
congophilic angiopathy only those cases in which the leptomeningeal
from all cases. The samples of the frontal and parietal watershed
and/or cortical arteries showed positive staining with Congo red.
cortical areas taken for analysis are illustrated in Figure 1. Finally, in
Cases with discrete vascular amyloid deposition visible with
76 AD cases and 45 control cases, a large, 5-mm-thick coronal brain
␤-amyloid immunostaining or thioflavin S, but negative for Congored, were not considered to exhibit congophilic angiopathy.
Statistical analysis was performed with the use of the 2 test to
determine whether a significant association exists between theoccurrence of watershed zone cortical infarcts and AD. The signif-icance of the role of congophilic angiopathy in the genesis ofwatershed infarcts in AD was also tested.
To analyze the intrahemispheric and interhemispheric distribution
of the small cortical infarcts, their 3-dimensional (3-D) localizationwas visualized in 5 randomly selected AD brains from the group ofAD cases in which standard analysis revealed the presence ofwatershed infarcts. Analysis of serial sections of a randomly selectedAD case, from the AD group without microinfarcts on standardsamples, was also performed to test whether serial brain sections willreveal microinfarcts in or outside watershed areas. In these 6 cases,30-m-thick, 3-mm-spaced serial sections were cut from the wholecerebrum (Polycat macrotome) and stained with H&E. The 3-Dreconstruction of cortical outlines and infarcts was performed withthe use of Silicon Graphics Indigo 2 workstation and the volumeprogram (see Acknowledgments).
We expected that congophilic angiopathy as an occlusive angiop-
athy may play a role in the genesis of cortical microinfarcts innarrowing the lumen of small arteries and arterioles. To analyze the
Figure 1. Illustration of watershed cortical areas from which
morphology of the cortical vascular network, from formalin-fixed
samples were taken for histological analysis. Gray areas indicate
brains, 3⫻2⫻1-cm samples were taken from the frontal and parietal
watershed cortical regions, and framed areas indicate the sites
cortical regions of 3 AD cases with congophilic angiopathy and in 1
of the samples taken for analysis. The vertical line in A shows
age-matched control case without AD and without congophilic
the level of the large parieto-occipital block. A schematic coro-nal view of this large sample in the right upper corner shows
angiopathy. Frozen sections (100 m thick) were stained with a
that watershed areas between the anterior (A), middle (M), and
Gallyas silver technique specifically described to visualize cerebral
posterior (P) cerebral arteries are included in this sample.
frequency of cortical infarcts in the group of AD cases withcongophilic angiopathy with the frequency in the AD groupwithout atherosclerosis and without congophilic angiopathy(Table 1). In the group of AD cases with congophilicangiopathy, 60% (18/30) showed watershed cortical infarcts(Figure 2B). This percentage was ⬎4-fold higher than in theAD group without any occlusive angiopathy. The associationbetween the occurrence of cortical watershed microinfarctsand the presence of congophilic angiopathy was statisticallysignificant (2⫽15.3; P⫽0.001). Cortical watershed microin-farcts were observed in 6 of 8 AD cases with both congophilicangiopathy and atherosclerosis. Despite the absence of ath-erosclerosis and vascular amyloid (by Congo red staining) in thatparticular AD group, we found watershed zone cortical infarctsin 14.6% (6/41) of the cases, which is 5-fold higher than in thecorresponding control group (2.7%; 1/37) (Table 1).
The size (diameter of the maximum extent) of the small
watershed cortical infarcts varied from 300 m to 2 mm(Figure 3B). The number of watershed zone cortical infarctsvaried from case to case and generally consisted of 1 to 4 perwatershed zone area (Figure 3C; see partial 3-D reconstruc-tion). In the majority of cases they corresponded to subacuteor old microinfarcts. In some cases concomitant occurrence
Figure 2. Relative frequency of watershed cortical infarcts in
AD. A, Occurrence of cortical infarcts in AD group (AD⫹) is
of acute, subacute, and old microinfarcts was observed.
⬎10-fold higher than in the control group (AD⫺) and corre-
The 3-D distribution of the watershed zone cortical infarcts
sponds to 32.8% (34/105) and 2.5% (2/79), respectively. Statis-
in the 5 AD cerebrums known to contain cortical watershed
tical analysis showed that the difference was significant(
infarcts also showed that the microinfarcts were restricted to
2⫽17.3; P⫽0.001). B, In the group of AD cases with congo-
philic angiopathy (A⫹), the number of cases with watershed cor-
the watershed cortical areas (Figure 3A and 3C). The intra-
tical infarcts was significantly higher (60%) than in AD cases
hemispheric and interhemispheric distribution of the cortical
without atherosclerosis and congophilic angiopathy (ATS⫺&A⫺)
microinfarcts, with respect to the watershed zones of the
(15%). ATS⫹ indicates group with atherosclerosis.
anterior, middle, and posterior cerebral arteries of the 6 ADcases, is detailed in Table 2. The intrahemispheric and
interhemispheric distribution of cortical watershed infarcts
Small cortical microinfarcts were found in the vascular
varied from case to case. The microinfarcts were more
watershed zones in 32.4% (34/105) of the neuropathologi-
numerous in the parieto-occipital region, particularly in the
cally confirmed, definite AD cases versus 2.5% (2/79) of the
watershed zones of anterior and middle cerebral arteries. In
controls (Figure 2A). The statistical analysis showed a strong
the frontal region, with respect to the watershed zone of
association between the occurrence of cortical watershed
anterior and middle cerebral arteries, the right side was more
infarcts and AD (2⫽17.3; P⫽0.001).
frequently affected. In the parieto-occipital region, the in-
To analyze the contribution of atherosclerosis and congo-
volvement of the watershed zone between the posterior and
philic angiopathy, the 105 AD cases were divided into 4
middle cerebral arteries was observed on the left side in 4 of
groups (Table 1). There were 30 cases with congophilic
the 5 cases (Table 2). We did not observe any cortical
angiopathy, 26 cases with atherosclerosis of the large cerebral
microinfarcts in or outside watershed areas in the sixth case
arteries, 8 cases with both amyloid angiopathy and athero-
selected from the AD group, in which cortical infarct was not
sclerosis, and 41 cases without occlusive angiopathy, namely,
found by the standard procedure.
without atherosclerosis and without congophilic angiopathy.
When the morphology of the cortical capillary network
To rigorously rule out the possibility that atherosclerosis
was analyzed by the silver impregnation technique described
may play a role in the association between AD and cortical
by Gallyas for the visualization of cerebral capillaries, severe
watershed infarcts, a second statistical analysis was also
involvement of the cortical vascular network was found in the
performed by eliminating all AD and control cases in which
3 AD cases with congophilic angiopathy. The alteration of the
the neuropathological examination showed the presence of
cortical arterial and capillary network is particularly striking
atherosclerosis, including those with both atherosclerosis and
when compared with the spared vascular architecture of the
amyloid angiopathy (Table 1). From the remaining AD cases,
control (Figure 4). Severe distortion and irregularity of the
33.8% (24/71) showed cortical watershed zone infarcts versus
wall of large penetrating cortical arteries (compare Figure 4D
2.6% (1/39) of the control group. The statistical analysis
and 4E) as well as of the smaller arterioles (compare Figure
showed that the association between AD and cortical water-
4B and 4C) were seen. Dramatic changes of the capillary
shed infarcts remained significant (P⬍0.001).
network were observed, particularly in cortical layers with
To analyze the role of congophilic angiopathy in the
severe plaque accumulation and amyloid deposition. In these
genesis of cortical watershed zone infarcts, we compared the
severely affected cortical regions, the number of small corti-
Suter et al
Cortical Watershed Infarcts in Alzheimer Disease
Figure 3. Histology and 3-D distribu-
tion of watershed cortical infarcts in
AD. B, Photomicrographs, from top to
bottom, show a watershed cortical
microinfarct (arrows) and the accumu-
lation of senile plaques and neurofibril-
lary tangles, respectively, in the parietal
cortex of the same AD case. Paraffin
sections were stained with H&E, immu-
nostained with monoclonal antibody to
␤-amyloid, and stained with thioflavinS, respectively. Bars⫽300 m, 100
m, 50 m, respectively. A and C, 3-Dreconstructions of the cortical outlinesand microinfarcts observed on H&E-stained, serial (spaced at 3 mm) sec-tions of the cerebrums of 2 AD caseswith watershed infarcts using computermaps. On the right upper corner of C,the partial 3-D reconstruction showsthe exact localization of cortical micro-infarcts, bilaterally, in the watershedzone of anterior and middle cerebralarteries. The limit between cortex andwhite matter is shown by a pale greenline, and the microinfarcts are shownby yellow dots. The sites of the corticalmicroinfarcts were perpendicularly proj-ected to the cortical surface andentered in yellow (A) and pink (C) dots,respectively. The 3-D reconstructionshows that the cortical microinfarctswere restricted to the watershed corti-cal zones in both AD cases (comparetheir distribution in C with the sche-matic illustration of watershed zones inFigure 1). The cortical infarcts werenumerous in the parieto-occipitalregion. There were no cortical infarctson the convexity of the occipital polessupplied by the posterior cerebralartery.
cal arterioles and capillaries was also decreased. In addition,
hypertension or thromboangiitis obliterans and may lead to
an increased number of collapsed cortical capillaries was
found in the AD cases (Figure 4F and 4G) compared with
Increasing evidence indicates a coexistence and a poten-
control (Figure 4C).
tially causal relationship between AD and cerebrovasculardiseases.19–27 AD patients with brain infarcts had a higher
prevalence of dementia than those without infarcts.19–25
Small cortical infarctions in watershed zones between the
Several earlier studies reported reduced cerebral blood
major cerebral arteries are known to occur in cerebral
flow in AD.5–7,22–25,28,29 Pavics et al,30 studying regional
hypoperfusion. Infarction of cerebral watershed areas is
cerebral blood flow, showed that bilateral cerebral hypoper-
generally attributed to perturbed hemodynamic factors.16 As
fusion occurs in the temporal and/or parietal region in 70%
described by Bladin and Chambers,16 prolonged and severe
(23/33) of patients with AD and in 33% (6/18) of patients
hypotension causes bilateral watershed infarction histologi-
with vascular dementia. Many authors have concluded that
cally corresponding to numerous cortical microinfarcts. As a
diffuse cerebral hypoperfusion is responsible for leukoaraio-
result of scar formation, the cortical surface becomes irregu-
sis in AD.10 Brun and Englund31 demonstrated that the
lar, which explains why this pathological entity was termed
smallest arterioles and capillaries within the damaged white
granular cerebral atrophy. It is usually limited to the middle
matter areas showed stenosing fibrohyalin sclerosis without
frontal gyrus and parieto-occipital convolutions17 and has
been described as a paramedian sickle-shaped zone of gran-
Recently, a "critically attained threshold of cerebral hypo-
ular atrophy extending from the frontal pole over the vertex to
perfusion" (CATCH hypothesis) was proposed to play a
the occipital pole and sometimes onto the inferior surface of
pathogenic role in the neurodegenerative process of AD.23–25
the hemisphere from the occipital to the temporal pole.18
Despite the association of cerebral hypoperfusion and AD
Granular cerebral atrophy may occur in association with
and the known vulnerability of cortical watershed zones in
Intrahemispheric and Interhemispheric Distribution
angiopathy. The frequency of these primarily small, hemor-
of Cortical Microinfarcts With Respect to Watershed Zones of
rhagic lesions is generally considered to be low.33,34 Further-
the Anterior, Middle, and Posterior Cerebral Arteries in the 6
more, occurrence of granular cortical atrophy was reported in
AD Cases Analyzed
2 of 25 cases with cerebral amyloid angiopathy.36 According
to these observations, one may expect to find hemorrhagicinfarcts outside watershed cortical areas or even large, fatal
cerebral hemorrhages in some AD cases with severe congo-
Cortical watershed microinfarcts were present in 6 of the 8
cases with both congophilic angiopathy and atherosclerosis.
The small number of cases in this group does not allow us to
consider this high percentage as conclusive, even if it is in
agreement with the findings that congophilic angiopathyalone significantly increases the percentage of cortical micro-
infarcts in AD.
The small, often microscopic size of these watershed
cortical microinfarcts, which remain undetectable with cere-
bral MRI or CT scan or by macroscopic examination of the
brain, may explain why watershed cortical infarcts were not
A/M indicates watershed zone of anterior and middle cerebral arteries; M/P,
described in AD.
watershed zone of middle and posterior cerebral arteries; ⫹, 1–2 cortical
Our results indicate that there is also an association
microinfarcts/watershed zone; ⫹⫹, 3–5 microinfarcts/watershed zone. We did
between cortical watershed infarcts and AD in cases without
not find microinfarcts in watershed zones of the anterior and posterior arteries
atherosclerosis and without vascular amyloid as defined by
in any cases. There was a variation in the distribution of watershed infarcts in
Congo red staining. The 15% of AD cases without athero-
the 5 AD cases. The microinfarcts were more frequent in the parieto-occipitalregion, particularly in the watershed zone between the anterior and middle
sclerosis and congophilic angiopathy showing watershed
cortical infarcts suggests that disturbed hemodynamic factors(eg, arterial hypotension) are important in the genesis of
response to cerebral hypoperfusion,20 the involvement of the
cortical microinfarcts. These results are in agreement with
cortical watershed zones was not documented in AD. Our
recent observations showing a higher prevalence of senile
results show that the incidence of small cortical watershed
plaques in patients with cardiovascular disease than in con-
infarcts in definite AD is ⬎10-fold higher than in age-
trols and with the significantly high plaque counts in the
matched controls without any AD-type cortical changes.
inferior watershed area, dentate gyrus, subiculum, and
Because hypertensive microangiopathy represents a risk
for generating watershed cortical infarcts, we eliminated all
Hemodynamic microcirculatory insufficiency and decline
AD and control cases with arterial hypertension. In addition,
in blood pressure have been suggested to appear years before
to rigorously eliminate the possibility that the presence of
the onset of AD.22–24,38,39 A prospective study considering the
atherosclerosis influenced the significant association found
clinical and neuroimaging correlates of the presence or
between AD and watershed cortical infarcts, the statistical
absence of watershed cortical infarcts may add additional
analysis was also performed after elimination of all AD and
data concerning cerebral hypoperfusion and arterial blood
control cases with atherosclerosis. The association remained
pressure during life. Further information about the occurrence
and severity of watershed cortical infarcts with respect to the
The percentage of cases with watershed cortical infarcts
progression and severity of dementia is warranted.
was significantly higher (60%) in the AD group with congo-
Our results show that cerebral hypoperfusion may generate
philic angiopathy, indicating that congophilic angiopathy is
not only white matter changes but cortical watershed infarcts
an important risk factor for the genesis of watershed cortical
as well and, together with the severely disturbed cortical
infarcts. In agreement with previous observations,22–24,32 the
microcirculation, will further worsen cognitive decline in
morphological analysis of the cortical vascular network
AD. The restriction of cortical microinfarcts to watershed
showed a strongly disturbed capillary network. As seen on the
cortical areas indicates that cerebral hypoperfusion is the
silver-impregnated sections in the Gallyas technique, the
determinant factor in their genesis. Treatment with neurolep-
amyloid deposition causes important irregularity of the arte-
tics and other sedative drugs, frequently employed in AD,
rial wall, particularly of the medium and small leptomenin-
may further worsen cerebral hypoperfusion by diminishing
geal and cortical arteries. Therefore, in the event of cerebral
blood pressure and will increase the risk of cortical watershed
hypoperfusion, in a manner similar to that which occurs with
zone infarcts. Monitoring blood pressure and using appropri-
hypertensive microangiopathy, congophilic angiopathy will
ate therapy for the maintenance of systemic blood pressure at
facilitate the occurrence of cortical watershed infarcts.
normal levels in AD are important in preventing cortical
The occurrence of cortical infarcts, mostly hemorrhagic
watershed infarcts and diminishing the progression of cogni-
lesions, localized frequently in the cortex and in the imme-
diate subcortical areas, was reported by Regli et al,33 Okazaki
As suggested by other authors,22–25,37 cerebral hypoperfu-
et al,34 and Vonsattel et al35 in cases with congophilic
sion, by decreasing the oxygen and nutritive support, may
Suter et al
Cortical Watershed Infarcts in Alzheimer Disease
Figure 4. Severely disturbed cortical vascular
network in AD. Parietal frozen sections from an
AD case with congophilic angiopathy were
stained with Gallyas silver technique, visualizing
brain capillaries. A and B show the strongly
damaged cortical vascular network, which is
particularly injured in upper cortical layers with
high number of senile plaques (A). In deep cor-
tical layers with smaller number of plaques, the
vascular system is relatively well preserved.
Arrow in B points to a cortical vessel showing
irregularity of its wall. The difference between
the morphology of the cortical vascular network
in AD and control is striking when B and C are
compared. D and E illustrate a larger penetrat-
ing cortical artery in AD (D) and in control (E)
subjects. Note the irregularity of the arterial wall
in AD. F and G, At high magnification several
collapsed capillaries (arrows) are visible in the
severely damaged cortical area. Scale bars: A,
B, C⫽200 m; D, E⫽300 m; F, G⫽50 m.
create optimal conditions for the progression of the degener-
comments. We are sincerely grateful for the strong support they
ative process of AD. The persistence of cerebral hypoperfu-
manifested with respect to this work. We thank E. Bernardi for hishelp with photography and B. Bolliger, who developed the volume
sion may result in a vicious circle with progressive acceler-
program in the framework of a joint project between the Institute of
ation of the devastating illness.
Anatomy, University of Lausanne and the Computer Graphics
In conclusion, cerebral hypoperfusion, which may lead to
Laboratory of the Swiss Federal Institute of Technology (EPFL,
watershed cortical infarcts, is known to be often associated
with AD. However, until now the histopathological demon-
stration of the occurrence of watershed cortical infarcts in AD
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LOS ACTOS DE CONFUSIÓN E IMITACIÓN EN EL PROYECTO DE LEY POR EL QUE SE MODIFICA EL RÉGIMEN LEGAL DE LA COMPETENCIA DESLEAL. A. Jorge Viera González Profesor Titular de Derecho Mercantil Universidad Rey Juan Carlos 1. Introducción. El presente trabajo tiene por objetivo exponer de una forma crítica el contenido de la reforma de los actos de confusión e imitación que se contiene en el Proyecto de Ley por
POSTTRANSPLANT TREATMENT AND MEDICATIONS Methylprednisolone (Solu-Medrol®)/Prednisone Day 1: 2 x 50 mg Day 2: 2 x 40 mg Day 3: 2 x 30 mg Day 4: 2 x 20 mg Day 5: 2 x 10 mg Day 6 to end of third week: 20 mg Week 4: 17.5 mg Month 2: 15 mg Month 3: 10 mg Month 4: 7.5 mg Month 6: 5 mg which is then titrated down to 2.5 mg at a time every two weeks until discontinued **Specific patients may be tapered off at 6 months