Case Study 63
Case Study 63
Case Study 63
Kenneth Clark, MD
• This is a 79-year-old woman with a past medical
history significant for hypothyroidism who
presented to an outside hospital following
sudden onset of severe headache and left sided
weakness. A CT scan of the head was
• Describe the CT scan findings.
• A large heterogeneous intraparenchymal
hematoma in right frontotemporal lobe with
vasogenic edema, mass effect and right to left
• What is the differential diagnosis of a
spontaneous intracranial hemorrhage?
Primary CNS tumor
• The blood was evacuated and the tissue sent for
pathologic examination. Describe the findings.
• Click here to review the slide
• Sections show fresh blood clot with small islands
of entrapped micro-vacuolated, devitalized brain
parenchyma and leptomeninges. The medium
caliber arteries have markedly thickened,
multilaminar sclerotic walls. One vessel shows
penetrating hemorrhage into and through the
• What immunohistochemical stains would you
order to help better characterize the etiology of
• A-beta amyloid
• Smooth muscle actin
• Pankeratin (to rule out carcinoma not readily
apparent on the slide)
• PAS (to rule out CADASIL – see question XX)
• Click to see A-beta amyloid, Actin, PAS
• Based on the clinical history, H&E impression
and immunohistochemical findings (see below),
what is your diagnosis?
• A-beta Amyloid – intense concentric staining of arterial
walls; highlights numerous diffuse and neuritic plaques in
• Actin – reveals near-complete loss of the smooth muscle
from vascular media
• PAS – negative for positive granules
• A. Cerebral Amyloid Angiopathy
• B. Alzheimer’s Disease Pathology
• What causes cerebral amyloid angiopathy and
how is it related to other forms of amyloidosis?
• Cerebral amyloid angiopathy is not related to other forms
of systemic amyloidosis.
• It occurs in both sporadic and familial forms and is
caused mainly by the deposition of a specific type of
amyloid (Ab-amyloid) in the vessels walls.
• This is the same amyloid protein that is found in
Alzheimer’s disease, encoded on chromosome 21.
• Rare forms of CAA amyloid occur through mutations in
cystatin C, transthyretin, gelsolin, ABri-precursor protein,
ADan-precursor protein and prion protein (these are very
• What is amyloid?
• Amyloid is a pathologic protein aggregate that
forms from the abnormal cleavage and
subsequent abnormal folding of ab-amyloid
peptide that results in extensive b-pleated sheet
secondary structure. In this secondary structure,
proteins form insoluble fibrils that deposit in the
walls of vessels, leading to medial destruction
and loss of vascular integrity and function.
• What is the most common cause of spontaneous
intracranial hemorrhage and how is the clinical
presentation of cerebral amyloid angiopathy
• Hypertensive vasculopathy (HV) is the most common
cause of spontaneous intracranial hemorrhage (7090%).
• CAA most prominently involves the leptomeningeal and
cortical vessels (resulting in hemorrhages in these
regions), usually sparing the deep white matter and
brainstem vessels. Commonly found in demented
individuals with Alzheimer’s like pathology.
• HV typically causes hemorrhages in the basal ganglia
(40-50%), lobar regions (20-50%), thalamus (10-15%),
pons (5-12%), cerebellum (5-10%), and other brainstem
sites (1-5%). More commonly fatal (rapid).
• What is CADASIL?
• CADASIL (Cerebral Autosomal Dominant
Arteriopathy with Subcortical Infarcts and
Leukoencephalopathy) is a hereditary
cerebrovascular disorder that results in markedly
thickened cerebral vessels and can result in
migraines, strokes (with and without
hemorrhage) and dementia.
• How does CADASIL differ from CAA both
clinically and histologically?
• CADASIL affects patients at a younger age than
CAA (45 year vs 65 years)
• CADASIL usually associated with multiple
ischemic events (transient or stroke)
• CADASIL has a progressive course, whereas
CAA can present abruptly
• Histologically, CAA shows strong Ab-amyloid
staining of the vessel walls while CADASIL
vessels show marked deposition of PAS-positive
granular material in the walls
• This patient also had amyloid plaques deposited
in the surrounding cortex. How closely
associated is CAA with Alzheimer’s disease?
• Alzheimer’s disease pathology is clearly
associated with CAA. Recent studies have
shown that more than 90% of patients with
clinical AD have some degree of CAA.
However, it has also been shown that 30%
of all people with CAA have no additional
Alzheimer’s pathology (usually younger
• Mandybur TI. The incidence of cerebral amyloid angiopathy in
Alzheimer's disease (1975). Neurology. 25:120-126.
• Prayson RA. Neuropathology (A Volume in the Foundations of
Diagnostic Pathology Series). 2005. Elsevier, Inc.
• Attems J, Jellinger KA. Only cerebral capillary amyloid angiopathy
correlates with Alzheimer pathology - a pilot study (2004). Acta
• Arvanitakis Z, et al. Cerebral amyloid angiopathy pathology and
cognitive domains in older persons (2011). Annals of Neurology.
• Dietmar R, et al. Cerebral amyloid angiopathy and its relationship to
Alzheimer’s disease (2008). Acta Neuropathol. 115:599-609.