Anti-Aβ autoantibodies in the CSF of a patient with CAA-related inflammation: A case report

Abstract

A 68-year-old man presented with a 4-month history of progressive memory loss and mood disorders. Neurologic examination revealed severe impairment of attention and verbal skills, without motor and sensory deficits. His medical history included mild arterial hypertension, idiopathic partial epilepsy, and obsessive compulsive disorder.Brain MRI showed the presence of bilateral, asymmetric, swollen white matter lesions in the cerebral hemispheres, hyperintense in T2-weighted images, that partially involved the left frontal cortex (figure). On diffusion-weighted sequences, the white matter abnormalities were consistent with vasogenic edema. No pathologic contrast enhancement was present.Routine blood tests, inflammatory markers, autoantibodies, neoplastic markers, and paraneoplastic antibodies were within normal limits. CSF examination revealed increased level of proteins (152 mg/dL) and cell count (14 leukocyte/L), without intrathecal synthesis of oligoclonal bands. Bacterioscopic and virologic tests (including HIV and JCV) were negative, both on CSF and serum. Search for tumor or infection by total body CT scan was negative.Stereotactic biopsy of the left frontal white matter lesion showed gliosis without signs of infections or neoplasm.After the biopsy, the patient was treated with dexamethasone 24 mg/day IV for 20 days with marked clinical improvement. A control CSF analysis performed 3 months later was within normal limits (Ͻ1 leukocyte/ L, protein 27 mg/dL). Brain MRI demonstrated a reduction in number and extension of the white matter T2-hyperintense lesions (figure). T2*-weighted gradient echo images showed the presence of multiple microhemorrhages scattered over the entire cerebral cortex. No microbleeds were present in basal ganglia, thalami, and posterior fossa (figure).Diagnosis of probable cerebral amyloid angiopathy-related inflammation (CAA-ri) was made upon clinical and MRI findings, supported by the demonstration of APOE ⑀4 homozygosity.A search for A␤ deposits in brain tissue and vessel walls on the biopsy sample was negative; a possible explanation is the deep white matter target, with absence of cortex and leptomeninges in the specimen. The A␤ 1-42 protein in the CSF was reduced both in the first (129 pg/mL) and second (125 pg/mL) lumbar puncture compared to normal values (682-1,063 pg/mL). The A␤ 1-40 protein was also investigated (457 pg/mL in the first CSF; 238 pg/mL in the second); however, due to the large variability of this assay as reported in literature, the meaning of these values is unclear.We hypothesized a spontaneous autoimmune process against CNS A␤ proteins, and assessed the levels of anti-A␤ 1-40 and 1-42 autoantibodies in our patient's CSF, both before and after steroid treatment, compared to 6 age-matched controls (mean age: 63 Ϯ 19 years) and 4 patients with MS (mean age: 45 Ϯ 17 years). We used our ELISA, as described, 1 and detected a marked increase of anti-A␤ 1-40 and 1-42 autoantibodies in the CSF of our CAA-ri patient obtained prior to treatment compared to controls and ...

Immune Activation in Amyloid-β-Related Angiitis Correlates with Decreased Parenchymal Amyloid-β Plaque Load

“…Since reduced Aβ burden has been shown to correlate with enhanced immune activation, and ABRA patients have been shown to mount an immune response to Aβ, we assessed immune activation in ABRA patients and CAA controls [13,14,17,18]. We counted CD68-positive macrophages and HLA-DR-positive microglia in brain parenchyma distant from sites of vascular inflammation and determined percentages of brain parenchyma showing positivity for the above-mentioned markers.…”

“…ABRA is thought to be caused by an inflammatory response to Aβ deposited in vessel walls [5,17,18,28]. The objective of this study was to investigate whether the inflammatory response to Aβ has any effect on the status of immune activation in the brain parenchyma at sites distant from vessels.…”

“…Subsequent studies have shown that inflammation is specific to vessels with significant Aβ deposition [8,16]. Furthermore, autoantibodies to Aβ can be observed in cerebrospinal fluid and are produced by expanded B cells derived from an ABRA patient [17,18]. Finally, ABRA seems to occur spontaneously in a murine model with excessive production of vascular Aβ [19].…”

Immune Mediated Diseases and Immune Modulation in the Neurocritical Care Unit

“…This hypothesis is supported by the observation that a subset of patients with Alzheimer's disease undergoing experimental therapy with an antibody directed toward Aβ developed a syndrome closely resembling spontaneous CAA-related inflammation [125]. Further, recent reports indicate that patients with CCA-related inflammation have antibodies directed toward Aβ, suggesting that an aberrant immunological response is responsible for the inflammation [126,127].…”

Clinical Reasoning: A case of subacute cognitive decline in a 76-year-old man

“…Case studies have shown that titers of b-amyloid autoantibodies are elevated in the CSF of patients with CAA-RI, with return to near baseline levels following immunosuppressive treatment. 4 Further evidence is inferred from b-amyloid immunization studies performed in patients with Alzheimer dementia in which patients developed a subacute meningoencephalitis following immunization with b-amyloid antibodies, very similar to the leukoencephalopathy described in CAA-RI. 5 The gold standard for diagnosis is neuropathologic examination.…”