Cerebrospinal Fluid Biomarkers in Dementia Patients with Cerebral Amyloid Angiopathy

Yan-feng Li, Fang-fang Ge, Yong Zhang, Hui You, and Zhen-xin Zhang*

1Department of Neurology,2Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

Cerebrospinal Fluid Biomarkers in Dementia Patients with Cerebral Amyloid Angiopathy

Yan-feng Li1, Fang-fang Ge, Yong Zhang1, Hui You2, and Zhen-xin Zhang1*

1Department of Neurology,2Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

cerebral amyloid angiopathy; Alzheimer’s disease; cerebrospinal fluid biomarker

ObjectiveTo study the changes of biomarkers in cerebrospinal fluid (CSF) in cerebral amyloid angiopathy (CAA) dementia and Alzheimer’s disease.

MethodsLevels of amyloid protein β (Aβ42, Aβ40) and phosphorylated Tau-protein (P-tau) in CSF and ratio of Aβ42/Aβ40were tested in 5 cases with CAA dementia and 20 cases with Alzheimer’s disease collected at Peking Union Medical College Hospital from December 2001 to March 2011.

ResultsThe levels of Aβ42, Aβ40, and P-tau in CSF and ratio of Aβ42/Aβ40were (660.4±265.2) ng/L, (7111.0±1033.4) ng/L, (71.8±51.5) ng/L, and 0.077±0.033, respectively in CAA dementia and (663.6±365.6) ng/L, (5115.0±2931.1) ng/L, (47.7±38.8) ng/L, and 0.192±0.140, respectively in Alzheimer’s disease patients. There were no statistically significant differences between CAA dementia and Alzheimer’s disease in terms of these CSF biomarkers (all P＞0.05).

ConclusionMeasurements of CSF biomarkers may not be helpful in differential diagnosis of CAA and Alzheimer’s disease.

Chin Med Sci J 2015; 30(3):170-173

CEREBRAL amyloid angiopathy (CAA), which is clinically characterized by ischemic attack, cerebral hemorrhage and cognitive disorder, is a common cerebrovascular disease among the older people.1It is pathologically identified as deposition of amyloid β-protein (Aβ) on the small vessel walls in cerebral cortex and cerebral dura mater. The morbidity of CAA increases along with age, which was about 4% in people aged 50 years but over 60% in those at the age of over 90, as showed by autopsy.2-4Because this disease may pathologically and clinically overlap with Alzheimer’s disease (AD), differential diagnosis was urged to confirm the clinical diagnosis. Cerebrospinal fluid (CSF) biomarkers can help to diagnose AD, but we did not know their role in the diagnosis of CAA and differences between these two diseases. Therefore, we compared the levels of some biomarkers in the CSF in 5 cases with CAA dementia and 20 cases with AD and wished to find the biomarkers that could help distinguish the two diseases.

PATIENTS AND METHODS

Patient collection

We collected 5 cases with CAA who visited Peking Union Medical College Hospital from December 2001 to March 2011 due to chief complaints of loss of memory and social behavioral function and fulfilled the Boston criteria for Dutch-type cerebral amyloid angiopathy1for probable CAA (MRI findings demonstrated multiple lobar, cortical and sub-cortical hemorrhages, the patients were older than 55 years, and other causes of hemorrhage were ruled out). Dementia due to other causes such as human immunodeficiency virus infection, syphilis infection, nutrition metabolic disorder and poisoning were also excluded. All the 20 cases with AD in the same time period fulfilled the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) diagnostic criteria for AD.

Typical MRI findings (Case 1 and Case 2) were showed in Fig. 1.

Methods

Methods for determination of apolipoprotein E (APOE) genotype and the levels of CSF biomarker phosphorylated tau-protein (P-tau) and amyloid protein β (Aβ42and Aβ40) are described as follows.The conventional phenolchloroform method was adopted to extract genome DNA from peripheral white blood cells,5and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine APOE. Enzyme-linked immunosorbent assay (ELISA, InnoTest, Indianapolis, IN, USA) was used to detect and measure CSF levels of Tau and Aβ.

Statistical analysis

SPSS 12.0 software package was used for statistical analysis. T test was used for the comparison of CSF biomarkers between CAA dementia and AD. P＜0.05 was considered statistically significant.

RESULTS

The clinical information of the 5 CAA dementia patients was shown in Table 1, the levels of P-tau, Aβ42, Aβ40in the CSF and the ratio of Aβ42/Aβ40in each CAA dementia case were listed in Table 2. The 5 cases of CAA dementia were all male with the mean age of 74.4±4.82 years old, while the mean age of the AD patients was 67.3±7.79 years, smaller than that of the CAA dementia patients, although with no statistical significance (Table 3). The comparison between CAA dementia and AD patients in terms of levels of P-tau, Aβ42, Aβ40in the CSF and the ratio of Aβ42/Aβ40all showed no significant differences (all P＞0.05, Table 3).

Figure 1. T2-weighted imaging (T2WI) (A) and susceptibility weighted imaging (SWI) (B) of Case 1 of cerebral amyloid angiopathy (CAA) dementia. Fluid-attenuated inversion recovery (FLAIR) (C) and gradient echo image (D) of Case 2 of CAA dementia. White arrows in T2WI and FLAIR indicate preventricular multiple white matter demyelination, and black arrows in SWI and gradient echo image show small hemorrhage.

Table 1. Clinical data of the 5 selected CAA dementia cases

Table 2. The results of CSF biomarkers in CAA dementia

Table 3. Comparison of CSF biomarkers between CAA dementia and Alzheimer’s disease (AD) patients

DISCUSSION

The incidence of CAA is strongly age-dependent and presents with female predominance;6however, all the 5 cases of CAA dementia reported in the present study were male, which may be due to the small sample size with CSF specimens.

All the cases showed an insidious disease progression that was either fast or slow. Case 1 developed into a severe condition within one year after onset of CAA; while Case 2 and 3 had a longer course of disease progression. Among the cognitive function test results of all the cases, MMSE, MoCA and FOM scores declined, fulfilling the diagnosis of dementia. Because obvious vascular lesions were found in all the cases, susceptibility weighted imaging (SWI) or gradient echo imaging was further performed to demonstrate multiple small hemorrhagic focuses that distributed widely in multiple lobes, including the cerebral hemisphere cortex and sub-cortex, brain stem, and the cerebellar hemispheres. These focuses could not be discovered by the conventional T1/T2 scanning. Such findings in imaging were consistent with those previously reported and could help to confirm CAA.7

APOE ε2 allele may play a role in the severity and clinical course of CAA lobar intracranial hemorrhage.8APOE ε4 allele may be a risk factor in the development of CAA dementia.9However, there were no consistent reports on the relationship between APOE genotype and CAA.10Therefore, we did not analyze APOE genotype as a marker for the differential diagnosis of CAA and AD. The relationship between APOE genotype and CAA complicated by dementia still needs to be identified through further research.

Neuro-pathological studies suggest that vascular and parenchymal Aβ deposits can either occur relatively independently or overlap.11Aβ not only accumulates in the brain parenchyma as senile plaques in AD, but also in brain vessels in CAA.12CAA dementia is associated with both vascular mechanism and Aβ deposition.1-3The proportion of CAA complicated by dementia was over 40%, while that of AD complicated by CAA was greater than 80%. Because CAA may pathologically and clinically overlap with AD, it is important to differentiate in diagnosis.

In contrast to the parenchymal depositions with Aβ42in AD, CAA contains both Aβ40and Aβ42but primarily Aβ40. Some findings of previous studies confirm that the decreased CSF Aβ40concentrations in CAA were not significantly lower than that in controls, but significantly lower than that in AD.12,13

In this study, CSF biomarker measurement was performed for all the 5 CAA cases, showing that all the cases had an increased level of Aβ40in the CSF and decreased Aβ42/Aβ40ratio, but changes in their Tau protein were not characteristic. CSF biomarkers were not significantly different between AD and CAA dementia, indicating that CAA dementia may have the same pathological basis as AD. Therefore, amyloid substances that deposit in theblood vessels may be from the same sources as those deposit in the brain parenchyma and thus cause intelligencerelated demyelination. The finding of this study was not consistent with previous reports which showed that the Aβ40concentration in CSF was decreased in CAA dementia compared with AD. It may be due to this small sample size of CAA dementia in this study. Further study is need to confirm whether CSF biomarkers could help distinguish CAA dementia from AD.

REFERENCE

1. Yamada M. Cerebral amyloid angiopathy: emerging concepts. J Stroke 2015; 17: 17-30.

2. van Rooden S, van der Grond J, van den Boom R, et al. Descriptive analysis of the Boston criteria applied to a Dutch-type cerebral amyloid angiopathy population. Stroke 2009; 40: 3022-7.

3. Thanvi B, Robinson T. Sporadic cerebral amyloid angiopathyan important cause of cerebral haemorrhage in older people. Age Ageing 2006; 35: 565-71.

4. Chao CP, Kotsenas AL, Broderick DF. Cerebral amyloid angiopathy: CT and MR imaging findings. Radiographics 2006; 26: 1517-31.

5. Guo F, Zhang ZX, Xu Q, et al. Relationship between apolipoprotein E ε4, ε2 alleles and intrauterine growth. Chin J Neurol 2008; 41: 835-9.

6. Hirohata M, Yoshita M, Ishida C, et al. Clinical features of non-hypertensive lobar intracerebral hemorrhage related to cerebral amyloid angiopathy. Eur J Neurol 2010; 17: 823-9.

7. Haacke EM, DelProposto ZS, Chaturvedi S, et al. Imaging cerebral amyloid angiopathy with susceptibility-weighted imaging. AJNR Am J Neuroradiol 2007; 28: 316-7.

8. Biffi A, Anderson CD, Jagiella JM, et al. APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study. Lancet Neurol 2011; 10: 702-9.

9. Premkumar DR, Cohen DL, Hedera P, et al. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. Am J Pathol 1996; 148: 2083-95.

10. Verghese PB, Castellano JM, Holtzman DM. Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol 2011; 10: 241-52.

11. Viswanathan A, Greenberg SM. Cerebral amyloid angiopathy in the elderly. Annals of Neurology 2011; 70: 871-80.

12. Verbeek MM, Kremer BP, Rikkert MO, et al. Cerebrospinal fluid amyloid beta(40) is decreased in cerebral amyloid angiopathy. Ann Neurol 2009; 66: 245-9.

13. Renard D, Castelnovo G, Wacongne A, et al. Interest of CSF biomarker analysis in possible cerebral amyloid angiopathy cases defined by the modified Boston criteria. J Neurol 2012; 259: 2429-33.

Received for publication January 17, 2014.

*Corresponding author Tel: 86-10-69155095, E-mail: wuzhangzhenxin@ 163.com