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Journal of the Neurological Sciences 135( 19%) 13I - 139

Vascular pathology in three casesof progressive cognitive deterioration
Leonardo Pantoni a, Julio H. Garcia a,b,* , Gregory G. Brown a
’ Departments of Pathology (Neuropathology)

and Psychiatry (Neuropsych~logy), Henry Ford Hospital, K-6, 2799 West Grand Boulevard, Detroit, MI
48202. USA
b Case Western Reserve Uniuersity School of Medicine, Cleveland, OH, USA

Received 9 May 1995;revised 17 August 1995;accepted28 August 1995

Abstract
The clinical condition known as vascular dementia remains poorly defined. Few studies have attempted a correlative link between the
clinical syndrome and the structural abnormalities of the brain. Classically the clinical progression of the vasculardementing process is
thought to be a multi-step process punctated by repeated episodes of ischemia, that are clinically expressed as strokes. In most instances it
has been assumedthat the substrateof vascular dementiasconsists of atherothrombotic infarcts. The objective of this report is to illustrate
3 cases of progressive (rather than stepwise) cognitive deterioration without clinical evidence of stroke, evolving over a period of several
years, in which there were prominent vascular lesions. A complete autopsy and detailed neuropathologic examination demonstrated
cerebral vascular lesions involving small arterial vessels (< 200 pm in diameter). The lesions consisted of moderate-to-severe
arterioloscierosis in two cases, and mild-to-moderate arteriofosclerosis in a case of Alzheimer’s disease with severe cerebral amyloid
angiopathy. Parenchymal lesions consisted of small cortical and subcortical infarcts, most of them smaller than 0.1 cm in average
diameter, and subcortical leukoencephalopathy severe in two cases and mild-to-moderate in the third case. Severe atherosclerosis not
accompanied by large infarcts was also present in one case. Arterial changes affecting small, distal branches causing sometimes small
parenchymal lesions in association with diffuse cerebral white matter disease, appear to be the anatomical substrate that accompanies
progressive cognitive impairment in some patients who are frequently diagnosed with Alzheimer’s disease because in their clinical
records there is neither history of strokes nor stepwise progression of symptoms.
Keywords: Dementia; Vascular dementia; Alzheimer’s disease; Small vesselsdisease; Ischemic leukoencephalopathy;Brain ischemia

1. Introduction

The contribution of vascular pathology to the syndrome
of cognitive impairment is incompletely defined. Vascular
dementia (VaD) encompasses a wide spectrum of disease
processes (Scheinberg, 1988; Muiioz, 1991). Several
pathogenetic mechanisms have been proposed to explain
VaD (Garcia and Brown, 1992; Wallin and Blennow,
19931, but the pathological substrates of these diseases
remain incompletely defined. In particular, many studies of
patients with cognitive impairment of possible vascular
origin have failed to illustrate the pathological changes in
the cervical or cerebral vessels and in the brain parenchyma.
It is commonly believed that a minimum volume of cerebral tissue loss at specific locations determines cognitive
impairment in patients with vascular diseases (Tomlinson

l

Corresponding author. Tel.: (3 13) 876-2269;Fax: (313) 876-7120.

0022-510X/96/$15.00
0 1996 Elsevier Science B.V. All rights reserved
SSDI 0022-5 10X(95)00273I

et al., 1970; Erkinjuntti et al., 1988; de1 Ser et al., 1990).
Accordingly, VaD is often seen as a disease associated
with brain infarcts of presumed arterial etiology. However,
ischemic injury to the brain has more than one morphological expression, and lesions other than arterial territorial
infarcts, may be associated with deteriorating cognitive
functions (Garcia and Brown, 1992). In a series of 175
consecutive autopsy cases of dementia, pathology of small
vessels disease was the most important alteration described
among the cases with cerebrovascular diseases (Bnm,
1994).
We report a detailed neuropathological study of three
cases presenting with progressive, non-stepwise, cognitive
deterioration over a period of several years. In two cases
the pathological abnormalities were exclusively vascular;
both Alzheimer’s disease (AD) and vascular pathology
were present in the third case. Alterations in small cerebral
vessels accompanied by brain parenchymal changes, other
than large territorial infarcts, were present in all three

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cases; the parenchymal lesions were small or diffuse and
involved the cerebral cortex and white matter.

2. Methods
The brain and the spinal cord were removed in all three
cases about S-10 h after death and fixed in 10% buffered
formalin. Coronal sections of the whole cerebrum and
about 20 samples from several areas of the brain were
processed for histologic evaluation. In addition to hematoxylin-eosin, the following stains were utilized: Luxol fast
blue/periodic acid Schiff, Masson’s trichrome, Prussian
blue, Verhoeff-van Gieson, Congo red, and Bielschowski’s
silver impregnation. Immunohistochemical demonstration
of glial fibrillary acidic protein, P-A4 amyloid, and ubiquitin was done by the avidin-biotin peroxidase complex
method (Hsu et al., 1981).

3. Case reports and neuropathological

findings

Case I was a Caucasian normotensive man in his
mid-fifties when he began to exhibit changes in personality. Previously polite and well mannered, he became verbally abusive and unusually belligerent, hypersomnolent
and presented with diminished energy and libido. Subsequently he showed topographical memory loss even in
familiar places, and memory loss for new events as well as
his own actions. Because of this, the patient was forced to
retire from his job. He became less concerned with his
personal care, started to eat meals at irregular intervals and
gradually became unable to perform daily skills. There was
no history of stroke or transient ischemic attacks, arterial
hypertension, diabetes mellitus, cardiac dysrhytbmias, myocardial infarction, thyroid disease, or head trauma. A
neurologist who examined him on several occasions diagnosed possible AD. The patient was not known to take any
medication on a regular basis, according to his wife. At the
age of 59, he was taken to an emergency room because
according to his wife he suddenly fell down and when he
stood up he had “forgotten how to walk”. The patient had
been ambulatory until a few days before, when he complained of nausea and vomiting. On this occasion, the
neurologist described him as being awake and alert, ori-

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ented to person, but disoriented to time; judgement and
abstract thought were impaired, gait was apraxic, and
frontal releasing signs were present. Motor, sensory, and
cranial nerves examinations were normal. A computed
tomography (CT) scan of the brain showed an ill-defined
single site of low attenuation in the right basal ganglia
(suggestive of a lacunar infarct), and ill-defined irregular
areas of decreased attenuation in the periventricular white
matter of both cerebral hemispheres. A diagnosis of acute
myocardial infarct was followed by continuous deterioration of his general condition; death supervened four days
later.
The autopsy disclosed recent atherothrombotic occlusion of the right coronary artery and a recent, large myocardial infarct. The brain weighed, after fixation, 1210 g
(normal = 1307 g f 319) (Ho et al., 1980). There was
slight atrophy of the cerebral mantle with ventricular dilatation. Three lesions could be identified by direct examination: a 2.5 cm in diameter cavitary infarct in the left
middle frontal gyrus; a 2.0 cm in diameter, ill defined
subacute infarct in the head of the right caudate nucleus
extending into the adjacent fibers of the anterior limb of
the internal capsule (Fig. I); and a 1.0 cm in diameter
cavity surrounded by brown pigmentation in the dorsal
nucleus of the right thalamus. The hippocampus did not
appear atrophic. Microscopically, the large extracerebral
arteries contained large, partly calcified atheromatous
plaques that narrowed the lumen by an average of 30%.
The small intraparenchymal arterial vessels (15-20 pm in
diameter) in the basal ganglia, thalamic nuclei, subcortical
white matter, and base of pons appeared markedly thickened and hyalinized (Fig. 2). In the white matter, the
subcortical U fibers were normal. The periventricular white
matter, however, had extensive patchy areas of prominent
rarefaction with myelin pallor and marked reactive astrogliosis. There was multifocal parenchymal destruction
with cavitation and lipid-laden macrophages (Fig. 3). The
gliosis and rarefaction were more prominent around vessels, which displayed enlarged perivascular spaces. The
corpus callosum was of normal thickness; hippocampus,
thalamus, nucleus basalis, and mammillary bodies were
unremarkable. In the cerebral cortical, basal ganglia, cerebellar, and brain stem grey matter there were no neurodegenerative changes (neuritic plaques, fibrillary tangles,
granulo-vacuoles, Lewy bodies).

Fig. I. Case 1. Pallor of the white matter and several small infarcts are visible in the left middle frontal gyrus, in the right and left caudate nuclei. Multiple
enlarged perivascular spaces and subacute infarct in the anterior limb of the right internal capsule are also visible (Luxol fast blue/periodic acid SchiffJ.
Fig. 2. Case 1. Thickening and hyalinization of the wall of a small penetrating vessel in the white matter which appears rarefied. Existing glial cells appear
intact (Luxol fast blue/periodic acid Schiff, 50 X 1.
Fig. 3. Case 1. Hemispheric white matter: multiple areas of tissue destruction (cavitation)
subcortical U fibers am spared (Luxol fast blue/periodic acid Schiff, 2.5 X ).

and myelin rarefaction, as existed in the frontal lobes. The

Fig. 4. Case 2. Basilar artery: severe atherosclerosis with occlusion of lumen in the proximal segment of the artery (hematoxylin-eosin,

5 x).

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Case 2 was an obese (124 kg) 68 year-old black man
who was first diagnosed with arterial hypertension at the
age of 42. Marked and repeated postural hypotensive
episodes were described following anti-hypertensive treatment with a thiazide diuretic and a beta blocker. At the age
of 52, his clinical record revealed uncontrolled hypertension, non-insulin dependent diabetes, and congestive
heart failure. At the age of 60 he became belligerent and
aggressive towards his wife; over the next few years the
patient developed apraxic gait and urinary incontinence.
Several episodes of slurred speech resolving within a few
minutes were described by family members, but other
focal neurological deficits were never observed. He also
developed memory difficulties, confusion and tended to
wander. The onset of memory problems followed the onset
of irritability. The family described a generally progressive
downhill course for the memory problems, with some daily
fluctuations. A psychiatrist diagnosed probable AD. Because of his behavioral difficulties he was confined to a
chronic care facility for the last five years of his life where
he was described as being oriented only to person. At the
age of 65, his wife noted a left facial droop; over the next
days his condition declined and he was no longer able to
get up from his chair because of apparent gait apraxia.
Emesis prompted the final hospital admission. On his final
admission he was alert and awake, oriented to person, but
not to time or place, able to follow commands and answer
simple questions. Motor deficits were not detected; he
withdrew appropriately from noxious stimuli and there was
central palsy of the left facial nerve. Frontal releasing signs
were present. Two days later he was febrile and stuporous,
responding to verbal and physical stimuli but unable to
verbalize or follow commands. The quality of a CT of the
brain obtained at this time was somewhat impaired by the
patient’s motion; but, it showed moderate and diffuse
cerebral atrophy and low attenuation in the periventricular
white matter. Acute ischemic or hemorrhagic lesions were
not demonstrable. The patient’s condition deteriorated over
the next few hours and death supervened on the same day.
The autopsy disclosed bacterial pneumonitis and pulmonary congestion. There was cardiomegaly with left
ventricular hypertrophy (weight: 400 g), and coronary
atherosclerosis with 20-40% narrowing of the lumen in
the large arteries. Arteriolar nephrosclerosis was present in
both kidneys. The brain weighed 1260 g after fixation
(normal = 1262 g L- 293) (Ho et al., 1980). All brain arter-

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135

ies had extensive, calcific atherosclerosis. The distal third
of the basilar artery had 90-95% lumenal narrowing, and
its proximal segment was completely occluded over a
segment about 1.0 cm long (Fig. 4). The right posterior
communicating artery was also occluded, and both middle
cerebral arteries had 5060% narrowing of their lumen.
Coronal sections of the brain disclosed slight dilatation of
the lateral ventricles. Small, irregularly shaped patches of
grayish discoloration and increased granularity were visible in the corona radiata, and the corpus callosum was
markedly thinned (Fig. 5). Several lactnae (average diameter: 0.8 cm) were seen in the right putamen. The right
hippocampus was markedly atrophic while the left one was
grossly normal. A small area of softening (0.2 X 0.2 cm)
involved the left side of the base of the pons. A large
(4 X 1.5 cm> healed hemorrhagic infarct was visible on the
ventral surface of the right cerebellar hemisphere. The
microscopic evaluation demonstrated, in addition to the
complicated obstructing atherosclerotic lesions in the extracerebral arteries, marked medial thickening and hyalinization of arterioles (15-20 pm in diameter) in basal
ganglia and hemispheric white matter (Fig. 6). The white
matter had extensive patchy areas of rarefaction with
decreased number of myelinated fibers, diffuse astrocytic
gliosis, and small areas of tissue destruction with cavity
formation. The perivascular spaces were widened, especially around the hyalinized vessels. In the cerebral cortex
neurodegenerative findings of the AD type were not detected, except for occasional senile plaques of the diffuse
type as defined by Alafuzoff (1992) (Fig. 8). The right
Ammon’s horn showed almost complete absence of neurons and extensive reactive astrogliosis (Fig. 7). Multiple
cavitary lesions (lacunes) measuring 0.1 cm in average
diameter were present in the right thalamus and basal
ganglia. In the brain stem there were several lacunar
infarcts ( < 0.3 cm in diameter), one at the left crus cerebri
and three at the basis pontis, and a recent (0.6 X 0.3 cm)
infarct involved the left lateral medulla.
Case 3 was a Caucasian man, University professor,
who was first noted as being mentally impaired at the age
of 70 when he retired from the University. Significant past
medical history included chronic atria1 fibrillation (sick
sinus syndrome), not associated with either arterial hypertension or diabetes mellitus. Over the next several years,
the patient had developed a slowly progressive decline *n
cognitive functions accompanied by rigidity and tremor at

Fig. 5. Case 2. Pallor of the white matter, marked atrophy of the corpus callosum, atrophy of the right hippocampus, and mild dilatation of the lateral
ventricles (Luxol fast blue/periodic acid Schift).
Fig. 6. Case 2. Thickening and hyalinization of the tunica media of small arterioles (15-20 pm) of the white matter (hematoxylin-eosin,
Fig. 7. Case 2. Right hippocampus: loss of pyramidal cells with marked reactive astrogliosis (hematoxylin-eosin,
Fig. 8. Case 2. Cerebral cortex (superior temporal gyrus): senile plaques of the diffuse type (Bielschowski’s

21.25 X).

4.25 X).

silver impregnation, 21.25 X).

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rest, which severely impaired his locomotion; therapy with
L-Dopa was administered for several years without clear
evidence of beneficial effects. A history of stroke or focal
neurologic events was not recorded in any of the numerous
medical examinations the patient underwent over a period
of 12 years; a diagnosis of AD with complicating parkinsonism was advanced. A CT scan of the head obtained 14
months before death when he was completely incapacitated to care for himself showed “ill-defined hypodensity
within the right temporal lobe and brain, which may
represent areas of subacute infarct”, or may be ‘artifactual’. Cortical atrophy and bilateral periventricular white
matter lucencies were also visible. Despite these findings,
examinations on two separate occasions did not uncover
any focal neurological deficits. The patient died at the age
of 82 with bacterial pneumonitis.
At auiopsy there was cardiomegaly (400 g) with ventricular hypertrophy and mild coronary atherosclerosis,
bilateral extensive bacterial pneumonitis, and slight arteriolar nephrosclerosis. The brain was edematous and weighed
1500 g (normal = 1250 g f 280) (Ho et al., 1980). The
large arteries at the base of the brain had scattered small
atheromatous plaques. A large, recent hemorrhagic infarct
(4.5 cm in largest diameter) was visible in the right
occipital lobe in the territory supplied by a branch of the
posterior cerebral artery. No brain atrophy or remote infarcts could be detected grossly (Fig. 91, and the substantia
nigra was well pigmented. Microscopically, there were
more than 15 neuritic plaques per microscopic magnification X 200 field in the neocortex, and numerous neurofibrillary tangles, granulo-vacuoles and Hirano bodies more
abundant in the hippocampus, amygdala and nucleus
basalis. There were also frequent plaques in the striatum.
Most pial and cortical arteries had extensive amyloid
deposits in the tunica media (Fig. lo>, a few of them
displaying a classical ‘double barrel’ appearance. A few
intracortical arterioles showed hyalinization without amyloid deposits; similar hyalinizing change could be observed
in the white matter vessels. In the cerebral cortex there
were haphazardly distributed glial scars and multiple (as
many as 6 per block of neocortex) recent or subacute
( < 0.1 cm in average diameter) infarcts (Figs. 11 and 12).
The periventricular white matter was diffusely paler than
the subcortical zones, and had focal areas of cavitation
(< 0.5 cm in diameter) with gliovascular lumenal bridging. The substantia nigra was well pigmented. There were

137

no changes of Parkinson’s disease (Gibb, 1992) in the
brain stem or cerebrum.

4. Comment
We describe 3 patients with progressive cognitive decline, two of these with few lacunar infarcts and a third
with AD and cerebral cortical micro-infarcts, and all of
them with prominent leukoencephalopathy and arteriolar
sclerosis. We suggest that ischemic lesions involving cerebral cortex and periventricular white matter, alone or in
association with AD, may be responsible for progressive
mental deterioration in the absence of stepwise progression.
The progressive decline in cognitive function was associated in all three cases with pathological changes in the
small vessels and in the brain parenchyma. We suggest
that in all three cases the parenchymal lesions are of
ischemic origin and may be etiologically related to the
structural abnormalities of the pial and intraparenchymal
vessels. The nature of the vascular abnormalities has not
been entirely defined in previous publications dealing with
VaD and many authors imply that atherosclerosis and the
consequent large brain infarcts are the main cause of VaD
(Garcia and Brown, 1992). Severe intracranial atherosclerosis was present in case 2 but this condition was
accompanied by small infarcts in the cerebellum and the
brainstem; unilateral hippocampal sclerosis, also found in
this case, may have been the result of the atheromatous
occlusion of the ipsilateral posterior communicating artery
and the effects of the repeated hypotensive crises
(Schmidt-Kastner and Freund, 1991). Hyalinization of the
small intracerebral arterial vessels was prominent in Cases
1 and 2; this abnormality is usually accelerated by aging
and hypertension (Furuta et al., 1991; Ostrow and Miller,
1993). Remarkably, neither of these risk factors applied to
case 1. Amyloid deposits were abundant in the brain
vessels in case 3. The structural changes affecting the
small brain vessels can be the cause of structural changes
in gray matter (case 3) and white matter (all our cases).
The leukoencephalopathy in these three cases was characterized by loss of myelin fibers and gliosis; comparable
changes in AD brains have been interpreted as being the
result of ‘incomplete ischemic infarction’ (Brun and Englund, 1986). Interstitial edema (Feigin and Popoff, 1963)

Fig. 9. Case 3. Pallor of the hemispheric white matter and absence of infarcts detectable to the naked eye (Luxol fast blue/periodic

acid Schiff).

Fig. 10. Case 3. Immunohistochemical demonstration of amyloid deposits in the vessels of subarachnoid space and superficial cortical layers; most of the
senile plaques also contain amyloid deposits ( P/A4 amyloid antiserum, 8.5 X 1.
Fig. 11. Case 3. Cerebral cortex (inferior temporal gyrus): multiple microinfarcts of various age (Luxol fast blue/periodic
Fig. 12. Case 3. Cerebral cortex (inferior
blue/periodic acid Schiff, 13.6X ).

temporal gyms): detail of a microinfarct

acid Schiff, 3.4X).

in which abundant lipid-laden macrophages are present (Luxol fast

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and Wallerian degeneration (Leys et al., 1991) are altemative potential explanations for the white matter changes.
Hemispheric white matter abnormalities associated with
cerebral amyloid angiopathy has been reported in several
instances (Gray et al., 1985; Bogucki et al., 1988) and
microinfarcts in the cerebral cortex, of the type found in
Case 3, have been mentioned in at least one postmortem
analysis of cerebral amyloid angiopathy (Okazaki et al.,
1979). Repeated hypotensive crises, resulting from cardiac
arrhythmia, could be an additional contributing cause to
multiple cortical infarcts of microscopic size.
Only one (case 1) of the three patients had formal
repeated neuropsychological examinations, yet, the clinical
history of mental decline is well documented in all of
them. The correlation between the mental deterioration and
the pathological changes in case 3 appears obvious; but the
clinical significance of the white matter lesions in cases 1
and 2 is less clear. The clinical significance of white
matter abnormalities is still a matter of debate and controversy (Hachinski et al., 1987; Pantoni and Garcia, 1995).
The absence of neurodegenerative changes in case 1 suggests that the vascular changes (arteriolosclerosis) and the
associated leukoencephalopathy were in some way responsible for the dementing process. The small number and the
type of senile plaques in case 2 appear insufficient to
explain the cognitive changes (Crystal et al., 1993; Mirra
et al., 1993). In this case, three small infarcts, two in the
basal ganglia, and one in the left frontal lobe were also
present. These lesions, as well as the unilateral hippocampal sclerosis, seem to be an unlikely cause for the progressive cognitive impairment that developed in this patient. In
contrast, in patients with leukoaraiosis (Yamaguchi et al.,
1994) or multiple sclerosis (Huber et al., 1987) a significant correlation has been shown between atrophy of corpus
callosum (present in case 2) and cognitive impairment. In
case 3 the number and distribution of senile plaques was
adequate for a diagnosis of AD; yet, in this case the
contribution of multiple microinfarcts and periventricular
focal lesions and white matter degeneration to the cognitive deterioration cannot be ignored.
Cases 1 and 2 had in common personality change and
gait disturbances; both findings are suggestive, but not
diagnostic, of VaD (Ishii et al., 1986; Kotsoris et al.,
1987). New criteria for the diagnosis of VaD have been
formulated recently (Chui et al., 1992; Roman et al., 1993;
Wetterling et al., 1994). According to these consensus
papers multiple types of vascular lesions may be responsible for cognitive deterioration. Nevertheless the suggested
criteria for the clinical identification of patients with VaD
emphasize significant cerebrovascular accidents, that are
identifiable either clinically or radiologically; these criteria
focus mainly on the clinical correlates of large territorial
infarcts. A definite chronological association between development of cognitive impairment and a major cerebrovascular accident is lacking in all three cases. A stroke
occurred, in case 2, as a terminal event and the retro-

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spective diagnosis of transient ischemic attacks (episodes
of ‘slurred speech’) in the same patient may be questionable. The abrupt onset of ‘inability to walk’ in case 1 was
not accompanied by detectable focal neurological deficits;
therefore this episode can hardly be diagnosed as a stroke.
Case 3 could have been diagnosed as a case of AD with
cerebrovascular disease (Roman et al., 1993), but the
vascular changes were not accompanied by clinical signs
of stroke or neuroimaging changes, except for the unspecific white matter lucencies.
In addition to the type of ischemia leading to a territorial arterial infarct, other patterns of brain injury may
develop as a result of variations in either the severity or
the duration of the injury (Lassen, 1982; De Girolami et
al., 1984; Garcia et al., 1995). If one accepts the concept
that ischemic injury to the brain can impair cognitive
functions, then it seems logical that types of ischemic
injury (other than those secondary to arterial occlusions)
ought to be considered among those potentially responsible
for causing an encephalopathy, as we have previously
outlined (Garcia and Brown, 1992). It is probable that
ischemic brain lesions not falling in the category of global
ischemia or arterial territorial infarction could have subtle
clinical correlates and these would be difficult to detect
until the cumulative effect of many of these lesions develop. In these cases, the clinical evolution probably would
lack those features thought to be pathognomonic of cognitive impairment of vascular origin, namely: a history of
stroke and a stepwise progression.
At-present, we are unable to outline well defined clinical criteria for cases of progressive cognitive impairment
secondary to ischemic injury. However, overlooking a
possible vascular cause of cognitive impairment in patients
who have a progressive course can lead to the exclusion of
these patients from therapeutic treatment. We suggest that
clinico-pathological studies are required before we achieve
a more precise understanding of the vascular causes of
mental impairment.
A recently published review of subcortical leukoencephalopathy, based on the analysis of over 150 publications, concluded that the brief description of one case
provided by Binswanger in 1894 is inadequate to merit
attaching his name to a yet-to-be-defined nosological entity (Pantoni and Garcia, 1995).

Acknowledgements
Dr. J.A. Gutierrez made valuable suggestions that significantly improved the final version of this manuscript.
Ms. Lisa Pietrantoni HTL (ASCP) was responsible for the
histological preparations. Ms. Paula McGee, Ms. Kathy
Zajas and Ms. Shirley Labrenz provided excellent secretarial support. We thank them all.
Financial support was derived in part from. a USPHS
grant: NIH/NIA-AG-10677
(P.I.: Dr. G.G. Brown)

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