Cerebral Amyloid Angiopathy Cases Research Articles

The Pathology of Alzheimer Disease Elicits an In Vivo Immunological Response

The mechanism(s) responsible for the loss of neurons that characterizes Alzheimer disease is incompletely understood. Nonetheless, there is considerable evidence suggestive of immune abnormalities coupled to alterations in blood-brain barrier permeability that likely play a key role in both the etiology and progression of the disease. To examine these issues further, this study was designed to examine the presence of human antibodies within hippocampal regions of both diseased and normal brains. Specifically, using antibodies directed against either human lambda (λ) or kappa (κ) subunits of human IgG, we examined the amount and localization of endogenous human antibodies within the brain. In cases of Alzheimer disease, but not in age-matched controls, we found human antibodies associated with pyramidal neurons and dystrophic neurites surrounding amyloid plaques - pathological structures that characterize the disease. Since such human immunoglobulins likely originate in the vasculature, we also examined cases of cerebral amyloid angiopathy to further explore the importance of blood-brain barrier breaches and found high levels of antibodies associated with many blood vessels as well as pyramidal neurons. Taken together, these findings strengthen the notion that alterations in blood brain barrier permeability in both Alzheimer disease and cerebral amyloid angiopathy leads to the accumulation of antibodies that then may contribute to the inflammatory cascade within the brain.

Cerebral Amyloid Angiopathy: CT and MR Imaging Findings

Cerebral amyloid angiopathy (CAA) is an important but underrecognized cause of cerebrovascular disorders that predominantly affect elderly patients. CAA results from deposition of beta-amyloid protein in cortical, subcortical, and leptomeningeal vessels. This deposition is responsible for the wide spectrum of clinical symptoms and neuroimaging findings. Many cases of CAA are asymptomatic. However, when cases are symptomatic, patients can present with transient neurologic events, progressive cognitive decline, or potentially devastating intracranial hemorrhage. Computed tomography is the imaging study of choice for evaluation of suspected acute cortical hemorrhage, which may be accompanied by subarachnoid, subdural, or intraventricular hemorrhage. Magnetic resonance imaging is best suited for identification of small or chronic cortical hemorrhages and ischemic sequelae of this disease, exclusion of other causes of acute cortical-subcortical hemorrhage, and assessment of disease progression. Accurate recognition of imaging findings is important in guiding clinical decision making in patients with CAA.

Two types of sporadic cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a type of beta-amyloidosis that occurs in leptomeningeal and cortical vessels of the elderly. In a sample of 41 CAA cases including 16 Alzheimer disease (AD) cases and 28 controls, we show that 2 types of sporadic CAA exist: The first type is characterized by immunohistochemically detectable amyloid beta-protein (Abeta) in cortical capillaries, leptomeningeal and cortical arteries, arterioles, veins, and venules. It is referred to here as CAA-Type 1. The second type of CAA also exhibits immunohistochemically detectable Abeta deposits in leptomeningeal and cortical vessels, with the exception of cortical capillaries. This type is termed CAA-Type 2. In cases with CAA-Type 1, the frequency of the apolipoprotein E (ApoE) epsilon4 allele is more than 4 times greater than in CAA-Type 2 cases and in controls. CAA-Type 2 cases have a higher epsilon2 allele frequency than CAA-Type 1 cases and controls. The ratio of CAA-Type 2 to CAA-Type 1 cases does not shift significantly with respect to the severity of AD-related beta-amyloidosis, with respect to degrees of CAA-severity, or with increasing age. Therefore, CAA-Type 1 is unlikely to be the late stage of CAA-Type 2; rather, they represent 2 different entities. Since both the ApoE epsilon2 and the epsilon4 allele are known to be risk factors for CAA, we can assign the risk factor ApoE epsilon4 to a distinct morphological type of CAA. The ApoE epsilon4 allele constitutes a risk factor for CAA-Type 1 and, as such, for neuropil-associated dyshoric vascular Abeta deposition in capillaries, whereas the e2 allele does not. CAA-Type 2 is not associated with the epsilon4 allele as a risk factor but shows a higher epsilon2 allele frequency than CAA-Type 1 cases and controls in our sample.

Serial CT and MRI findings in a patient with isolated angiitis of the central nervous system associated with cerebral amyloid angiopathy

We report serial CT and MRI findings in a biopsy-proven case of cerebral amyloid angiopathy (CAA) with isolated angiitis of the central nervous system (CNS). A 69-year-old man had developed dizziness, dementia, and generalized seizure during the preceding 4 years. An initial examination by brain CT and MRI showed bilateral symmetrical periventricular lesions closely resembling those of Binswanger's disease. Subsequently, the lesions expanded slowly, involving a large area of the right cerebral hemisphere with an obvious mass effect. Since a primary brain tumor was suspected, a brain biopsy was performed, and histopathological examination revealed amyloid beta protein CAA within the meningocortical vessels associated with perivascular monocytic cuffing, indicating the presence of isolated angiitis of the CNS. Multinucleated giant cells containing intracytoplasmic beta protein amyloid around a heavily amyloid-laden cortical vessel were also observed. This is the first case report to show sequential radiographical studies of the leukoencephalopathy associated with CAA and isolated angiitis of the CNS.

Fibrillar Amyloid β-Protein Binds Protease Nexin-2/Amyloid β-Protein Precursor: Stimulation of Its Inhibition of Coagulation Factor XIa

Cerebrovascular deposition of fibrillar 39-42 amino acid amyloid beta-protein (Abeta), a condition known as cerebral amyloid angiopathy (CAA), is a key pathological feature of Alzheimer's disease and related disorders including hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). Severe cases of CAA, particularly in HCHWA-D, lead to recurrent and often fatal hemorrhagic strokes. Although the reasons for this pathological consequence remain unclear, alterations in proteolytic hemostasis mechanisms have been implicated. For example, the Abeta parent molecule protease nexin-2/amyloid beta-protein precursor (PN-2/AbetaPP), which is elevated in HCHWA-D cerebral vessels with Abeta deposits, is a potent inhibitor of coagulation factor XIa (FXIa). Here we show that fibrillar HCHWA-D Abeta binds PN-2/AbetaPP, but not its isolated Kunitz-type proteinase inhibitor (KPI) domain, in a saturable, dose-dependent manner with a K(d) of approximately 28 nM. Neither PN-2/AbetaPP nor its KPI domain bound to nonfibrillar HCHWA-D Abeta. The fibrillar Abeta binding domain on PN-2/AbetaPP was localized to residues 18-119. PN-2/AbetaPP that bound to fibrillar HCHWA-D Abeta immobilized either in plastic wells or on the surface of cultured cerebrovascular smooth muscle cells was active in inhibiting FXIa. Quantitative kinetic measurements revealed that fibrillar HCHWA-D Abeta caused a >5-fold enhancement of FXIa inhibition by PN-2/AbetaPP. Similar stimulatory effects on FXIa inhibition by PN-2/AbetaPP were also observed with fibrillar wild-type Abeta. However, fibrillar Abeta had no effect on the inhibition of trypsin by PN-2/AbetaPP. These findings suggest that fibrillar Abeta deposits in cerebral vessels can effectively localize and enhance the anticoagulant functions of PN-2/AbetaPP, thereby contributing to a microenvironment conducive to hemorrhaging.

Cholinergic deafferentation of the rabbit cortex: a new animal model of Aβ deposition

Brain deposition of the amyloid beta-peptide (Abeta) is a critical step in the pathogenesis of Alzheimer's disease (AD) and human cerebral amyloid angiopathy (CAA). A small fraction of AD and CAA cases are caused by gene mutations leading to increased production and deposition of Abeta, but for the majority, there is no known direct genetic cause. We have hypothesized that Abeta deposition in these sporadic cases occurs as a result of cortical cholinergic deafferentation. Here we show that cortical cholinergic deafferentation, induced in rabbits by a selective immunotoxin, leads to Abeta deposition in cerebral blood vessels and perivascular neuropil. Biochemical measurements confirmed that lesioned animals had 2.5- and 8-fold elevations of cortical Abeta40 and Abeta42, respectively. Cholinergic deafferentation may be one factor that can contribute to Abeta deposition.

Lack of independent associations of apolipoprotein E promoter and intron 1 polymorphisms with Alzheimer's disease

Several studies have demonstrated genetic associations between Alzheimer's disease (AD) and polymorphisms in the promoter/enhancer regions of the apolipoprotein E (APOE) gene. These studies raise the possibility that APOE transcription control may be involved in altered risks for AD. We evaluated polymorphic sites in the intron-1 enhancer element (IE-1G/C) and in the APOE promoter (−219G/T). For the IE-1 polymorphism, we analyzed 433 individuals (183 AD and 250 controls), and found a strong linkage between the IE-1G allele and APOE-ε4. When we controlled for this linkage using log-linear model analysis, we found no independent association between the IE-1 polymorphism and AD. For the −219 polymorphism, we analyzed 475 individuals (168 AD cases, 234 controls, and 73 cases of cerebral amyloid angiopathy (CAA)). We found strong linkages between the −219G allele and APOE-ε2 and between the −219 T allele and APOE-ε4. Controlling for these linkages, we found no independent association between the −219 polymorphism and AD or CAA. Thus, our studies do not support independent associations between AD and either the IE-1 or the −219 polymorphisms.

Characterization of New Polyclonal Antibodies Specific for 40 and 42 Amino Acid-Long Amyloid β Peptides: Their Use to Examine the Cell Biology of Presenilins and the Immunohistochemistry of Sporadic Alzheimer’s Disease and Cerebral Amyloid Angiopathy Cases

In Alzheimer's disease (AD), the main histological lesion is a proteinaceous deposit, the senile plaque, which is mainly composed of a peptide called A beta. The aggregation process is thought to occur through enhanced concentration of A beta 40 or increased production of the more readily aggregating 42 amino acid-long A beta 42 species. Specificity of the antibodies was assessed by dot blot, Western blot, ELISA, and immunoprecipitation procedures on synthetic and endogenous A beta produced by secreted HK293 cells. A beta and p3 production by wild-type and mutated presenilin 1-expressing cells transiently transfected with beta APP751 was monitored after metabolic labeling and immunoprecipitation procedures. Immunohistochemical analysis was performed on brains of sporadic and typical cerebrovascular amyloid angiopathy (CAA) cases. Dot and Western blot analyses indicate that IgG-purified fractions of antisera recognize native and denaturated A beta s. FCA3340 and FCA 3542 display full specificity for A beta 40 and A beta 42, respectively. Antibodies immunoprecipitate their respective synthetic A beta species but also A beta s and their related p3 counterparts endogenously secreted by transfected human kidney 293 cells. This allowed us to show that mutations on presenilin 1 triggered similar increased ratios of A beta 42 and its p 342 counterpart over total A beta and p3. ELISA assays allow detection of about 25-50 pg/ml of A beta s and remain linear up to 750 to 1500 pg/ml without any cross-reactivity. FCA18 and FCA3542 label diffuse and mature plaques of a sporadic AD case whereas FCA3340 only reveals the mature lesions and particularly labels their central dense core. In a CAA case, FCA18 and FCA3340 reveal leptomeningeal and cortical arterioles whereas FCA3542 only faintly labels such structures. Polyclonal antibodies exclusively recognizing A beta 40 (FCA 3340) or A beta 42 (FCA3542) were obtained. These demonstrated that FAD-linked presenilins similarly affect both p342 and A beta 42, suggesting that these mutations misroute the beta APP to a compartment where gamma-secretase, but not alpha-secretase, cleavages are modified. Overall, these antibodies should prove useful for fundamental and diagnostic approaches, as suggested by their usefulness for biochemical, cell biological, and immunohistochemical techniques.

Leukoencephalopathy-Related Cerebral Amyloid Angiopathy With Cystatin C Deposition

We have described sporadic cases of cerebral amyloid angiopathy with cerebral hemorrhage showing a low cystatin C level in the cerebrospinal fluid detected by enzyme-linked immunosorbent assay. Recently, several cases of leukoencephalopathy in patients with cerebral amyloid angiopathy have been reported. We describe a sporadic case of leukoencephalopathy with cystatin C-type cerebral amyloid angiopathy diagnosed during life by enzyme-linked immunosorbent assay. A 74-year-old man who had suffered from progressive dementia for 3 years was admitted with right hemiparesis, dysarthria, and ataxia. MRI revealed pontine infarction and multiple lacunar state with leukoaraiosis. We suspected cystatin C-type cerebral amyloid angiopathy because of the low level of cystatin C in the cerebrospinal fluid. The patient died of sepsis 3 months later, and the presence of leukoencephalopathy with cerebral amyloid angiopathy was confirmed by autopsy. Immunohistological examination disclosed cystatin C and beta-protein deposition in amyloid structures of the cortical cerebral arteries. Measurement of cystatin C in the cerebrospinal fluid by enzyme-linked immunosorbent assay is a useful method of diagnosing leukoencephalopathy related to sporadic cystatin C-type cerebral amyloid angiopathy.

Pathologic processes leading to cerebral hemorrhage in amyloid angiopathy

This report concerns a study undertaken to eluidate the pathogenesis of arterial rupture related to amyloid deposition. For this purpose, histochemical and immunohistochemical analyses were carried out on brain tissue specimens of a case of cerebral amyloid angiopathy (CAA) with multiple cortical hemorrhages. A small amount of amyloid β‐protein was found in the tunica media vasorum in which the smooth muscle cells were well preserved. with increases in amyloiod deposition, the entire arteriolar wall became concenmtrically thick, with amyloid largely occupying the tunica media; the number of smooth muscle cells was decreased and these cells were located in the intimal side of the vessel wall. Under these conditions, the elastic fibers and endothhelial cells were relatively well preserved. In the advanced stage of amyloid deposition, the arterioles became devoid of smooth muscle cells and underwent wither fibrous luminal occlusionor aneurysmal dilatation with fibrinoid necrosis and loss of elastic fibers; the latterwould eventually rupture causing the hemorrhage. These findings suggest that amyloid β‐protein‐related loss of arteriolar smooth muscle cells could be the initial event, with the subsequent damage of the vascular wall leading to cerebral hemorrhages in CAA patients.

Cortical Petechial Hemorrhage, Leukoencephalopathy, and Subacute Dementia Associated With Seizures Due to Cerebral Amyloid Angiopathy

Although cerebral amyloid angiopathy is a well-known cause of cerebral lobar hemorrhage, subacute dementia, seizures, and acute encephalopathy without lobar hemorrhage are infrequently recognized as manifestations of this disease. In this report, we describe a case of cerebral amyloid angiopathy in a 74-year-old woman who had subacute progressive dementia and a superimposed rapid acute neurologic deterioration associated with seizures and the presence of cerebral edema on computed tomographic scans and leukoencephalopathy and cortical petechial hemorrhages on magnetic resonance imaging. A diagnosis of cerebral amyloid angiopathy in conjunction with small cortical infarcts and petechial hemorrhages was confirmed by antemortem biopsy. This clinical and radiologic picture is being increasingly recognized as characteristic of cerebral amyloid angiopathy.

Senile plaques in cerebral amyloid angiopathy show accumulation of amyloid precursor protein without cytoskeletal abnormalities

The abnormal neurites that surround β-amyloid in senile plaques (SP) in Alzheimer disease contain β-amyloid precursor protein (βAPP) or abnormal filaments which react with antibodies to τ. Occasionally, βAPP and abnormal filaments are present in the same neurite. Whether both types of abnormal neurites are reactive to the presence of β-amyloid or they are instead independent from each other is unknown. To begin to clarify this issue, we comparatively studied βAPP and τ-epitopes in SP from cases of classical Alzheimer disease and cases of cerebral amyloid angiopathy, with SP but without neurofibrillary pathology. In subjects with cerebral amyloid angiopathy, about one-third of SP, the same percentage as in Alzheimer disease, were βAPPP reactive in the absence of τ-reactivity. βAPP epitopes were ultrastructurally localized in dense bodies of probable lysosomal origin, adjacent to the core of SP. These results demonstrate that βAPP and τ-reactive cytoskeletal alterations occur independently in the neurites of SP. The presence of βAPP in dystrophic neurites of SP and the localization of βAPP in lysosomes suggest that βAPP containing dystrophic neurites may play a role in the extracellular deposition of amyloid.

Ubiquitin in cerebral amyloid angiopathy

Immunohistological findings in cerebral blood vessels of 4 cases with cerebral amyloid angiopathy (CAA) were compared with those of 4 Alzheimer's (AD) cases. A panel of antibodies against 2 neurofilament subunits (BF10 and RT97), a microtubule-associated protein (TAU) and ubiquitin were used. CAA cases showed a strong immunoreactivity for ubiquitin in blood vessel wall. Senile plaques (SPs) in CAA cases showed strong ubiquitin positivity but the central amyloid core was negative. AD brains showed immunoreactivity with all antibodies in SPs and neurofibrillary tangles (NFTs); blood vessels were consistently negative for ubiquitin. Control brains showed few SPs and NFTs; these were positive for ubiquitin, but blood vessels were negative. These results indicate that vascular amyloid deposition in CAA and AD may have different pathophysiological mechanisms.

Characterization of amyloid fibril protein from a case of cerebral amyloid angiopathy showing immunohistochemical reactivity for both β protein and cystatin C

We isolated and carried out a chemical analysis of the amyloid fibril protein from the leptomeningeal vessels of a case with non-hereditary cerebral amyloid angiopathy (CAA) showing dual immunohistochemical reactivity with antibodies to both β-protein and cystatin C. A crude amyloid fibril fraction reacted only with anti-β-protein antibody, and cystatin C immunoreactivity was observed in the first PBS supernatant. Complete amino acid sequence of this cystatin C-immunoreactive protein showed a homologous structure to that of normal cystatin C. It is concluded that cystatin C is not an intrinsic component of the amyloid fibril in this type of CAA.

Surgical considerations in cerebral amyloid angiopathy

In cerebral amyloid angiopathy, the contractile elements of the leptomeningeal and cortical arteries are replaced by noncontractile amyloid beta protein. The incidence of amyloid angiopathy increases with advancing age. It is associated with Alzheimer's disease and spontaneous cerebral hemorrhage. The latter can have the characteristic acute computed tomographic appearance of a hematoma at the cortex-white matter junction with extension of blood into the subarachnoid, subdural, and intraventricular spaces. Multiple hemorrhages are frequent. Additional bleeding can occur after evacuation of the hematoma, and postoperative hemorrhage can occur after cortical biopsy. To elucidate the role of surgery in this condition, we have reviewed 20 consecutive operated cases of cerebral amyloid angiopathy. A first group of 8 patients with senila dementia underwent cortical biopsy without resultant hemorrhage. A second group of 6 patients in good clinical condition had delayed evacuation of a spontaneous cerebral hematoma from cerebral amyloid angiopathy because of the radiological misdiagnosis of a hemorrhage within a tumor. One patient died of a pulmonary embolism, and another had subsequent multiple hemorrhages that were ultimately fatal. A third group of 6 patients in poor neurological condition had the acute evacuation of a spontaneous cerebral hematoma to relieve intracranial hypertension. All died or were severely disabled. One had repeated hemorrhages which added a progressively more severe organic dementia onto an initial hemiplegia.(ABSTRACT TRUNCATED AT 250 WORDS)

Surgical Considerations in Cerebral Amyloid Angiopathy

Abstract In cerebral amyloid angiopathy, the contractile elements of the leptomeningeal and cortical arteries are replaced by noncontractile amyloid beta protein. The incidence of amyloid angiopathy increases with advancing age. It is associated with Alzheimer's disease and spontaneous cerebral hemorrhage. The latter can have the characteristic acute computed tomographic appearance of a hematoma at the cortex-white matter junction with extension of blood into the subarachnoid, subdural, and intraventricular spaces. Multiple hemorrhages are frequent. Additional bleeding can occur after evacuation of the hematoma, and postoperative hemorrhage can occur after cortical biopsy. To elucidate the role of surgery in this condition, we have reviewed 20 consecutive operated cases of cerebral amyloid angiopathy. A first group of 8 patients with senila dementia underwent cortical biopsy without resultant hemorrhage. A second group of 6 patients in good clinical condition had delayed evacuation of a spontaneous cerebral hematoma from cerebral amyloid angiopathy because of the radiological misdiagnosis of a hemorrhage within a tumor. One patient died of a pulmonary embolism, and another had subsequent multiple hemorrhages that were ultimately fatal. A third group of 6 patients in poor neurological condition had the acute evacuation of a spontaneous cerebral hematoma to relieve intracranial hypertension. All died or were severely disabled. One had repeated hemorrhages which added a progressively more severe organic dementia onto an initial hemiplegia. We conclude that acute evacuation of a spontaneous cerebral hematoma from amyloid angiopathy patients in poor clinical condition results in a high mortality and morbidity, that delayed surgery in patients in good condition is better tolerated, and that cortical surgery in the absence of a cerebral hemorrhage can be accomplished relatively safely with meticulous attention to hemostasis. The outcome of surgery is a function of both the severity of the cerebral amyloid angiopathy and the extent of the hemorrhage that it produces, especially as it involves multiple lobes and extends into the ventricles or subdural space. Survivors remain at risk for hemorrhages that are progressively more disabling.

Surgical risk of hemorrhage in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is increasingly recognized as a cause of lobar cerebral hemorrhage in normotensive elderly individuals. Isolated reports have suggested that neurosurgical intervention entails a high risk of precipitated hemorrhage. We identified 16 pathologically confirmed cases of cerebral amyloid angiopathy. Fourteen of these patients presented with lobar cerebral hemorrhage. Fifteen neurosurgical procedures in eight patients included eight clot evacuations, three abscess drainage procedures, two ventriculoperitoneal shunts, one biopsy, and one lobectomy. Recurrent postoperative cerebral hemorrhage was seen in four patients at 2 days, 9 days, 6 weeks, and 10 months, but surgery was thought to have precipitated the cerebral hemorrhage in only one patient. Recurrent cerebral hemorrhage also was seen in two of the eight nonoperated cases. Recurrent cerebral hemorrhage is characteristic of cerebral amyloid angiopathy, but we conclude that neurosurgical intervention, particularly evacuation of hematomas, is not associated with major risk of precipitated hemorrhage.

Stroke related to cerebral amyloid angiopathy: the significance of systemic vascular disease.

A retrospective postmortem analysis of 25 cases of cerebral amyloid angiopathy (CAA) in the setting of Alzheimer's disease or senile dementia of the Alzheimer type (AD/SDAT) is reported. Seven patients experienced clinically significant cerebral infarcts or hemorrhages or both. There was no statistically significant difference in the incidence of infarcts or hemorrhages in hypertensive and nonhypertensive patients. Hypertension does not appear to be an additional risk factor in the causation of cerebral infarct or hemorrhage associated with CAA in the setting of AD/SDAT. Just over half of patients with CAA and significant ischemic and/or hemorrhagic brain lesions showed atherosclerosis of the circle of Willis, sometimes in the context of severe disseminated atheromatous disease.

Ultrastructural features of cerebral amyloid angiopathy

Ultrastructural studies of the brain in three cases of cerebral amyloid angiopathy demonstrated that the vascular amyloid in this disease is composed of fibrils identical to those in systemic amyloid disease, mixed with a large amount of vesicular debris. Amyloid appears to be derived from circulating protein and is depostied in areas of vascular basement membrane degeneration. The initiating degenerative change is thickening of basement membrane with accumulation of debris. Inflammation, when present, tends to accelerate amyloid deposition locally. Amyloid transport from the vascular wall into the brain parenchyma proceeds by overflow when perivascular astroglial end-feet are disarranged. Structures of perivascular amyloid plaques are similar to the neuritic (senile) plaques in Alzheimer's disease, which were used as control, except that the amyloid core of the plaques in Alzheimer's disease is not related to blood vessels.