Cerebral amyloid angiopathy

Increasing number of data, including the existence of common risk factors, indicate an association between cerebrovascular disease and Alzheimer's disease (AD). AD is known to be often associated with cerebral hypoperfusion. Recent histopathological evidence showed a significant association between watershed cortical microinfarcts and AD indicating that cerebral hypoperfusion induces not only white matter damage, known as leuko-araiosis, but cortical border zone infarcts as well, further aggravating the degenerative process and worsening dementia. In late stages of Alzheimer's disease - in cases with neuropathologically confirmed definite AD - the occurrence of watershed cortical microinfarcts was ten times higher than in aged matched control cases. Congophilic angiopathy and perturbed hemodynamic factors were found to be important factors in the genesis of watershed microinfarcts. To consider the vulnerability of the cerebral blood flow and the perturbed cortical vascular network in AD is important. Neuroleptic and sedative treatments frequently employed in AD may further accentuate cerebral hypoperfusion by decreasing blood pressure. Therefore, to treat and prevent arterial hypotension and maintain cerebral perfusion at an appropriate level in AD is essential. [Neurol Res 2003; 25: 605-610]

Keywords: Alzheimer's disease; amyloid angiopathy; arterial hypotension; cerebral hypoperfusion; vascular disease; watershed cortical infarct

INTRODUCTION

The pathological hallmarks of Alzheimer's disease (AD), which is characterized by a slowly progressive dementia, consist of the accumulation of senile plaques and neurofibrillary tangles in the atrophic brain, particularly accentuated in the cerebral cortex. The amyloid substance that accumulates in senile plaques and in cortical and leptomeningeal vessel walls corresponds to a 4kDa peptide (A[beta]), which derives by proteolytic cleavage of a larger transmembrane amyloid beta precursor protein (A[beta]PP)1. The pathogenesis of amyloid formation and the aetiology of AD are subjects of debate and still remain unclear.

A variety of risk factors for vascular diseases, e.g. hypertension, increased cholesterol level, diabetes and smoking, constitute risk for AD as well, suggesting the coexistence and some common factors in the pathogenesis of AD and cerebrovascular diseases. Several types of vascular lesions were found to be associated with AD, including cerebral infarctions, lacunes, hemorrhages and ischemic white matter changes2-4. It was also shown that AD patients with brain infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts2-9, indicating the role of the vascular component in the severity of dementia.

Here, we would like to concentrate on the association of cerebral hypoperfusion and AD.

CEREBRAL HYPOPERFUSION

During the past two decades an increasing number of studies have reported reduced cerebral blood flow in AD5-8,10-14. Consequently, the knowledge of an association between cerebral hypoperfusion and AD is well established. In addition to the predominantly cortical atrophy caused by the degenerative process of AD, CT-scan and MRI analyses showed white matter lesions, described and named as leuko-araiosis by Hachinski et al.15. Many authors concluded that diffuse cerebral hypoperfusion is responsible for white matter damage15-24. Based on a histopathological analysis of leuko-araiosis in AD, Brun et al.25 demonstrated that the smallest arterioles and capillaries within the damaged white matter areas show a stenosing fibrohyalin sclerosis without hypertensive alterations. The ratio for leuko-araiosis to total brain volumes was greater among patients with AD than in age-matched controls26,27, and the blood flow to the frontal and parietal cortices was significantly lower in patients with leuko-araiosis than in those without28. In addition to white matter involvement, decreased whole-brain perfusion with a characteristic perfusion deficit in the temporoparietal cortex was also observed in AD29. Positron Emission Tomography (PET) analyses showed decreased regional cerebral blood flow and metabolic rates in AD. Reduced cerebral perfusion and decreased metabolism was found not only in white matter but also in the cerebral cortex, predominantly in the temporal and parietal regions and occasionally in the frontal areas in AD10,18,21. Pavics et al.30, studying regional cerebral blood flow showed bilateral hypoperfusion in the temporal and/or parietal region in 70% (23/33) of AD patients versus 33% (6/18) of subjects with cerebrovascular disease associated with dementia. Functional neuroimaging techniques demonstrated specific patterns of hypoperfusion and hypometabolism that are thought to be useful in the differential diagnosis between AD and other dementing disorders. The preservation of vascular reserve was proposed to be specific for AD, where it remained normal, while depleted in patients with cerebrovascular disease. The authors suggested that the preservation of the vascular reserve implicate the participation of a vascular factor, at the capillary level, in the pathogenesis of AD31,32. Not only cortical atrophy but also cerebral hypoperfusion and leuko-araiosis are correlated with cognitive decline in AD15-20,22,33,34.

It was proposed that two factors, namely advanced aging and conditions that lower cerebral perfusion must be present before cognitive dysfunction and cortical degeneration occur in AD6. As cerebral blood flow in AD patients is significantly lower than in age-matched control individuals and since the brain is known to be particularly vulnerable to oxygen and glucose depletion, it was suggested that cerebral hypoperfusion may represent a risk factor for AD and may contribute to the development of dementia5. Recently a 'critically attained threshold of cerebral hypoperfusion' (CATCH hypothesis) was proposed to play a pathogenic role in the neurodegenerative process of AD5-7.

CEREBRAL HYPOPERFUSION AND WATERSHED CORTICAL INFARCTS

It is well known that the three major cerebral arteries, the anterior, middle and posterior cerebral arteries are end-arteries, without significant collateral circulation. Therefore, in the event of cerebral hypoperfusion secondary e.g. to arterial hypotension, the vascular border zone areas are the first to be deprived of sufficient blood flow. Lesions secondary to cerebral hypoperfusion include not only white matter damage but cortical infarcts as well, specifically localized to the vascular boundary zones of these three major cerebral arteries and are known as watershed, boundary or border zone infarcts. Infarction of these watershed areas is generally attributed to perturbed hemodynamic factors35. Following Baldin et al.35 prolonged, severe hypotension causes bilateral watershed infarction. There is a high individual variation with respect to the size of watershed areas. Depending on these variations, but particularly, depending on the severity and extent of cerebral hypoperfusion the resulted watershed ischemic lesions correspond to larger macroscopic infarcts or more frequently, to numerous small microinfarcts. When watershed cortical infarcts accumulate, due to scar formation, the cortical surface becomes irregular, granular in appearance. Consequently, this pathological entity was named granular cerebral atrophy. Granular atrophy is usually limited to the middle frontal gyrus and to the parieto-occipital convolutions36 and was described as a paramedian sickle-shaped zone (Figure 1, upper right inset) extending from the frontal pole over the vertex to the occipital pole and sometimes onto the inferior surface of the hemisphere from the occipital to the temporal pole37. Granular cerebral atrophy may occur in association with hypertensive microangiopathy or thrombangiitis obliterans, and may lead to cognitive decline.

WATERSHED CORTICAL INFARCTS IN ALZHEIMER'S DISEASE

Despite the frequent association of cerebral hypoperfusion and AD and despite the known vulnerability of cortical watershed zones in response to cerebral hypoperfusion the involvement of the cortical boundary zones was only recently documented in AD38. This may be explained by the small, often microscopic size of the watershed cortical infarcts, which may remain undetectable with cerebral MRI, CT-scan or frequently even by macroscopic examination of the brain. Recently, the analysis of a representative number of neuropathologically characterized autopsy cases allowed us to conclude that cerebral hypoperfusion induces not only white matter damage, but cortical watershed infarcts as well38. A significant association was found between the occurrence of cortical watershed infarcts and AD, the number of small cortical watershed infarcts being ten times higher in AD than in age-matched control brains. The three-dimensional intra and interhemispheric (3-D) distribution of the watershed microinfarcts were restricted to the watershed cortical zones (Figure 1) defining that cerebral hypoperfusion is the determinant factor in the genesis of watershed infarct38. The percentage of AD cases with watershed cortical infarcts was significantly higher in AD cases associated with congophilic angiopathy than in AD cases without amyloid congophilic indicating that amyloid angiopathy is an important risk factor for the genesis of watershed cortical infarcts in AD. Similarly to hypertensive microangiopathy, amyloid angiopathy represents an occlusive angiopathy involving also cortical arterioles and may enhance the occurrence of cortical microinfarcts in the case of cortical hypoperfusion38. These observations fit well with those showing that white matter rarefaction and pallor (leuko-araiosis) coexist with cerebral amyloid angiopathy in the brains of patients with AD17. Therefore, in AD patients with cerebral hypoperfusion, amyloid angiopathy is an important risk factor in the genesis of both, cortical and white matter damage.

Watershed infarcts occur in a significant number of AD cases without amyloid angiopathy or other occlusive angiopathies indicating that disturbed hemodynamic factors (e.g. arterial hypotension) are important in the genesis of cortical watershed microinfarcts38.

AMYLOID ANGIOPATHY AND PERTURBED CORTICAL VASCULAR NETWORK IN ALZHEIMER'S DISEASE

Several previous observations showed that the cortical vascular network is strongly disturbed in AD5-7,38-44. Amyloid deposition causes important irregularity of the arterial wall, particularly in the medium and small sized leptomeningeal and cortical arteries38-43. Pathological features at the capillary level in aging and in AD brains was also reported by several authors9,38-40. Characteristic pathological changes including capillary basement membrane thickening with collagen accumulation were also observed40,41,44. When the morphology of the cortical vascular network was analyzed using silver impregnation technique, described by Gallyas45 for the visualization of cerebral capillaries, severe involvement of the cortical vascular network was visible in AD cases associated with congophilic angiopathy38 (compare Figure 2A,C with B, D). Dramatic changes of the vascular network, including irregularity of the vessel walls in medium and small sized arteries, including arterioles, which was particularly severe in cortical layers with high plaque count and important A[beta] deposition38. When compared to normal brains an increased number of collapsed capillaries (Figure 2C,D) were observed in the cerebral cortex in AD38,46.

In cases with severe congophilic amyloid angiopathy, the occurrence of cortical infarcts, mostly hemorrhagic lesions localized frequently in the cerebral cortex and the immediate subcortical areas, was reported by Regli et al.47, Okazaki et al.48 and Vonsattel et al.49. The frequency of these mostly small hemorrhagic lesions is generally considered to be low46,47. According to these observations, one may expect to find small hemorrhagic infarcts outside watershed cortical areas or even large, fatal cerebral hemorrhagic strokes in some AD cases with severe cerebral amyloid angiopathy. Thaddeus et al.50 analyzing 25 cases with cerebral amyloid angiopathy reported the occurrence of granular cortical atrophy in two cases.

The relative preservation of the hemodynamic integrity at the capillary level in AD as shown by recent PET studies31,32 may suggest that the increased number of collapsed cortical capillaries in AD38,46 (Figure 2C,D) may be functional and may be reopened for circulation if cerebral hypoperfusion is corrected and maintained at an appropriate level. For conclusive evidence future studies are necessary. Pro-inflammatory and vasoactive effects of A[beta] on the cerebrovasculature was demonstrated by in vitro and in vivo studies51-53. The relation between the acute pro-inflammatory and vasoconstriction properties of A[beta] and the chronic progressive hypoperfusion seen in AD is yet to be elucidated. Constitutively reduced cerebrovascular NOS-III expression and NO production could also lead to vasoconstriction and cerebral hypoperfusion due to impaired vasodilation responses54.

CEREBRAL HYPOPERFUSION IN PRE-CLINICAL STAGES OF AD

Hemodynamic microcirculatory insufficiency and declined blood pressure were suggested to appear years before the onset of AD55-7,29,43. It was reported that AD patients have a decreased blood pressure beginning one or two years before the onset of AD53. Decreased regional cerebral hypoperfusion as measured by single photon emission computed tomography (SPECT) was found to be one of the earliest clinical manifestations in both sporadic and familial AD. Deficit in cerebral glucose metabolism was demonstrated by PET analyses in asymptomatic individuals at risk of familial AD54. Reduced blood flow and metabolic rate of the posterior cingulate gyrus was observed in patients with mild cognitive impairment at least two years before they met the clinical diagnosis of AD11,57,58. When SPECT analysis of combined brain areas (cingulate gyrus, hippocampal-amygdaloid complex and thalamus) was performed, more than 80% of the subjects with hypoperfusion progressed to AD after a 16.7 months follow-up18. Therefore, SPECT is a promising tool for early detection of AD in a heterogeneous group of subjects with mild cognitive impairment.

PREVENTION AND TREATMENT OF CEREBRAL HYPOPERFUSION IS ESSENTIAL IN ALZHEIMER'S DISEASE

By decreased oxygen and nutritive support, cerebral hypoperfusion may create optimal conditions for the progression of the degenerative process, resulting in a vicious circle with progressive acceleration of the devastating disease. The white matter and cortical changes generated by cerebral hypoperfusion together with the severely disturbed cortical microcirculation will further worsen cognitive decline in AD. These observations should have important impact on the therapy of AD. Treatment with neuroleptics and other sedative drugs is frequently employed in AD, which may further worsen cerebral hypoperfusion by diminishing blood pressure and increasing the risk of microinfarcts in watershed cortical areas. To consider the presence of cerebral hypoperfusion and low blood pressure when applying sedative drugs in aged and AD patients should be important. Monitoring blood pressure and using an appropriate sedative therapy in maintaining systemic blood pressure at normal level is essential in AD. It would diminish the progression of cognitive decline.

There are increased numbers of elderly patients with evidence of post-operative diffuse brain encephalopathy, presenting as delirium, confusion, coma, and sometimes seizures in the immediate post-operative period59. Predictive models were developed for encephalopathy involving five pre-operative factors (age, past stroke, carotid bruit, hypertension, and diabetes) and one peri-operative factor (time on cardiopulmonary bypass)59. The model for stroke involved only three pre-operative risk factors (past stroke, hypertension, and diabetes)59. It is interesting to notice that the risk factors found in this study are similar to those for cerebral hypoperfusion in AD or in cerebrovascular diseases.

Several observations showed that therapy that improves cerebral perfusion improved cognitive functions in AD60-62, which further indicate that to consider the vulnerability of cerebral blood flow and to correct and prevent cerebral hypoperfusion in AD is important.

The analysis of the factors generating cerebral hypoperfusion in AD would be essential. Information resulting from such studies would have important implication for the development of an efficient therapy for the prevention of cerebral hypoperfusion and its consequences, namely leuko-araiosis and watershed cortical infarcts in AD. A prospective study, considering the clinical and neuroimaging correlates, together with the presence or absence of watershed cortical infarcts may add additional information concerning cerebral hypoperfusion and arterial blood pressure during life. The occurrence and severity of watershed cortical infarcts with respect to the progression and severity of dementia would be another important issue. The quantitative analysis of neuronal loss in watershed cortical areas in patients with decreased cerebral blood flow would also be of interest, as chronic cerebral hypoperfusion may well lead to neuronal loss, particularly localized to the watershed cortical areas, without infarction which may be difficult to assess by a simple histological examination. Such neuronal loss even in the absence of watershed infarcts may contribute to the severity of cognitive decline in AD patients with cerebral hypoperfusion. The analysis of the frequency and correlation between leuko-araiosis and cortical watershed microinfarcts would be another useful outcome of prospective studies.

The possible role of systemic disease, particularly, cardiovascular disease, hypertension and diabetes may also affect cerebral circulation and decrease cerebral blood flow in AD9,63. To elucidate the contribution of systemic factors is also important, as a higher prevalence of senile plaques and a significantly high plaque count in the inferior watershed area, dentate gyrus, subiculum, and transentorhinal cortex was observed in patients with cardiovascular disease when compared to controls63.

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Judith Miklossy

University Institute of Pathology, Division of Neuropathology, CHUV, Lausanne, Switzerland and Center for Neurovirology and Cancer Biology, Temple University, Philadelphia, PA, USA

Correspondence and reprint requests to: Judith Miklossy, MD, Center for Neurovirology and Cancer Biology, Temple University, 1200 N 12th Street, Philadelphia, PA, 19122, USA.

[judith.miklossy@verizon.net] Accepted for publication April 2003.

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