Leukoencephalopathy-Related Cerebral Amyloid Angiopathy With Cystatin C Deposition
Background 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.
Case Description 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 β-protein deposition in amyloid structures of the cortical cerebral arteries.
Conclusions 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.
In 1972, Gudmundsson et al1 first described families with HCHWA-I. Ghiso et al2 reported that amyloid protein is a variant of cystatin C (γ-trace), which is a cysteine proteinase inhibitor. Grubb et al3 reported in 1984 that the cystatin C concentration in the CSF of patients with HCHWA-I was abnormally low. We have reported that the measurement of cystatin C concentrations in the CSF by a new enzyme-linked immunosorbent assay was a useful tool for the diagnosis of sporadic cerebral hemorrhage caused by CAA with deposition of cystatin C.4 In the present report we describe a case of leukoencephalopathy with dementia, which was suspected to be cystatin C-type CAA because of the abnormally low cystatin C concentration in the CSF. We also confirmed the leukoencephalopathy related to CAA with deposition of cystatin C by histopathological examinations.
A 74-year-old man with a history of mild hypertension and diabetes mellitus showed slowly progressive dementia during the last 3 years before his admission. He was admitted to the hospital because of sudden onset of vomiting, urinary incontinence, dysarthria, and right hemiparesis. His blood pressure was 180/100 mm Hg at admission. Neurological examinations revealed an apathetic and demented mental condition and right-sided ataxic hemiparesis. MRI demonstrated left pontine infarction with multiple small infarctions in the corona radiata and basal ganglia and marked leukoaraiosis with brain atrophy. The cystatin C concentration of CSF measured by the enzyme-linked immunosorbent assay method was decreased to 56 ng/mL (control values ranged from 70 to 600 ng/mL),4 and therefore cystatin C-type CAA was suspected. The patient's mental condition deteriorated, and he became bedridden. He died of sepsis 3 months after the admission. We received permission to perform an autopsy.
The brain weighed 1125 g. We noted brain atrophy and moderate atherosclerosis in the arteries of the circle of Willis. Macroscopic observation of the brain manifested left pontine base infarction and multiple lacunes in the basal ganglia and deep white matter. Microscopic examination of specimens stained with hematoxylin and eosin and Klüver-Barrera revealed diffuse demyelination mainly located in the frontoparietal lobes. However, U fibers were well preserved (Fig 1⇓). Alkaline Congo red staining disclosed deposition of amyloid in leptomeningeal and cortical small arteries. However, amyloid deposition was not seen in the vessels of the deep white matter and basal ganglia. Hyaline changes and fibrinoid necrosis were seldom seen. Thickening of the wall of arterioles in the deep white matter was rarely observed. Immunohistochemical study by the avidin biotin complex method disclosed the amyloid deposition in the cortical and leptomeningeal small arteries. These arteries were positively stained for both anti-cystatin C antibody, which was kindly provided by Dr Andres Grubb, University of Lund (Fig 2⇓, left panel), and anti-β/A4 antibody, which was kindly provided by Dr George Glenner, University of California at San Diego (Fig 2⇓, right panel). A small number of senile plaques, mainly in the temporal lobe, were positively stained for β/A4; however, no neurofibrillar tangles were observed. The patient did not fulfill Khachaturian's criteria for senile dementia of the Alzheimer type.5
We believe that this is the first case confirmed as cystatin C-type CAA during life and postmortem examinations.
Gray et al6 have reported several cases of leukoencephalopathy with sporadic CAA. They explained that amyloid depositions in the cortical long perforating arterioles caused obstructive changes and resulted in ischemia in the white matter. It has been demonstrated that HCHWA-D showed not only lobar hemorrhages but also marked leukoencephalopathy. Vinters et al7 8 9 reported that the amyloid proteins that were deposited in sporadic CAA and Alzheimer's disease were both β/A4 protein and cystatin C by immunohistochemical studies. Hann et al10 reported colocalization of β/A4 and cystatin C in the cortical blood vessels of patients with HCHWA-D but not in patients with HCHWA-I. We previously reported a low cystatin C level in the CSF of patients with cerebral hemorrhage who had CAA, and we noted that it was a useful diagnostic indicator of cystatin C-type CAA.4 We also detected a low concentration of cystatin C in the CSF in the present patient, and we therefore suspected that leukoencephalopathy was related to CAA. We confirmed the diagnosis of CAA with cystatin C deposition by postmortem histopathological examination. We ruled out a diagnosis of senile dementia of the Alzheimer type by pathological examination findings. This case indicates that measurement of cystatin C in the CSF may be a very useful method of premortem diagnosis of leukoencephalopathy associated with cystatin C-type CAA. Hypertension is considered one of the critical causes of leukoencephalopathy, whereas additional findings in CAA also need to be identified.
The mechanism of amyloid deposition in CAA has not been clearly elucidated. It has been reported that β/A4 protein (4 kD) was found in the CSF not only in patients with Alzheimer's disease but also in normal subjects.11 It has been established that cystatin C is higher in CSF than in serum. Therefore, we presume that abnormal levels of β/A4 protein and cystatin C might result in the formation of insoluble amyloid from soluble protein in the CSF. The insoluble amyloid will be deposited in the cerebral vessels to induce CAA, with consequent occurrence of subcortical hemorrhage and leukoencephalopathy. Hann et al10 reported that the possibility of preceding deposition of β/A4 protein promotes deposition of cystatin C. Since both β/A4 protein and cystatin C are proteinase inhibitors, we speculate that the abnormal metabolisms of proteinases and proteinase inhibitors are deeply involved in the initiation mechanism of CAA. Amyloid deposition in the meningeal arterioles and the cortical long perforating arterioles could be a cause of recurrent subcortical hemorrhages. We concluded that the present patient had evidence of amyloid depositions in the small arteries of the cerebral cortex and the subcortex, which induced obstruction of the small arteries in combination with advanced (for his age of 74 years) arteriostenosis. This symptom and chronic widespread arteriostenoses may have resulted in leukoencephalopathy associated with a partial cerebral infarction.
Selected Abbreviations and Acronyms
|CAA||=||cerebral amyloid angiopathy|
|HCHWA-D||=||hereditary cerebral hemorrhage with amyloidosis, Dutch type|
|HCHWA-I||=||hereditary cerebral hemorrhage with amyloidosis, Icelandic type|
We wish to express our gratitude to Dr Andres Grubb (University of Lund) and Dr George Glenner (University of California at San Diego) for kindly providing us with antibodies and antigens. We also express our sincere thanks to Dr Shigeyoshi Fujihara (Jusei Hospital) for advice.
- Received October 26, 1995.
- Revision received April 30, 1996.
- Accepted April 30, 1996.
- Copyright © 1996 by American Heart Association
Gudmundsson G, Hallgrimsson J, Jonasson TA, Bjarnasson O. Hereditary cerebral hemorrhage with amyloidosis. Brain. 1972;95:387-404.
Ghiso J, Jensson O, Frangione B. Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C). Proc Natl Acad Sci U S A. 1986;83:2974-2978.
Shimode K, Fujihara S, Nakamura M, Kobayashi S, Tsunematsu T. Diagnosis of cerebral amyloid angiopathy by enzyme-linked immunosorbent assay of cystatin C in cerebrospinal fluid. Stroke. 1991;22:860-866.
Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai XD, Mckay DM, Tintner R, Frangione B, Younkin SG. Production of Alzheimer amyloid β protein by normal proteolytic processing. Science. 1992;258:126-129.