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Abstract Objective Elevated levels of anti‐amyloid‐β (anti‐Aβ) autoantibodies in cerebrospinal fluid (CSF) have been proposed as a diagnostic biomarker for cerebral amyloid angiopathy‐related inflammation (CAA‐RI). We aimed to independently validate the immunoassay for quantifying these antibodies and evaluate its diagnostic value for CAA‐RI. Methods We replicated the immunoassay to detect CSF anti‐Aβ autoantibodies using CSF from CAA‐RI patients and non‐CAA controls with unrelated disorders and further characterized its performance. Moreover, we conducted a literature review of CAA‐RI case reports to investigate neuropathological and CSF evidence of the nature of the inflammatory reaction in CAA‐RI. Results The assay demonstrated a high background signal in CSF, which increased and corresponded with higher total immunoglobulin G (IgG) concentration in CSF (rsp = 0.51, p = 0.02). Assay levels were not elevated in CAA‐RI patients (n = 6) compared to non‐CAA controls (n = 20; p = 0.64). Literature review indicated only occasional presence of B‐lymphocytes and plasma cells (i.e., antibody‐producing cells), alongside the abundant presence of activated microglial cells, T‐cells, and other monocyte lineage cells. CSF analysis did not convincingly indicate intrathecal IgG production. Interpretation We were unable to reproduce the reported elevation of anti‐Aβ autoantibody concentration in CSF of CAA‐RI patients. Our findings instead support nonspecific detection of IgG levels in CSF by the assay. Reviewed CAA‐RI case reports suggested a widespread cerebral inflammatory reaction. In conclusion, our findings do not support anti‐Aβ autoantibodies as a diagnostic biomarker for CAA‐RI.

Background White matter hyperintensities (WMHs) are frequently observed on magnetic resonance imaging (MRI) in patients with cerebral amyloid angiopathy (CAA). The neuropathological substrates that underlie WMHs in CAA are unclear, and it remains largely unexplored whether the different WMH distribution patterns associated with CAA (posterior confluent and subcortical multispot) reflect alternative pathophysiological mechanisms. Methods and Results We performed a combined in vivo MRI—ex vivo MRI—neuropathological study in patients with definite CAA. Formalin‐fixed hemispheres from 19 patients with CAA, most of whom also had in vivo MRI available, underwent 3T MRI, followed by standard neuropathological examination of the hemispheres and targeted neuropathological assessment of WMH patterns. Ex vivo WMH volume was independently associated with CAA severity (P=0.046) but not with arteriolosclerosis (P=0.743). In targeted neuropathological examination, compared with normal‐appearing white matter, posterior confluent WMHs were associated with activated microglia (P=0.043) and clasmatodendrosis (P=0.031), a form of astrocytic injury. Trends were found for an association with white matter rarefaction (P=0.074) and arteriolosclerosis (P=0.094). An exploratory descriptive analysis suggested that the histopathological correlates of WMH multispots were similar to those underlying posterior confluent WMHs. Conclusions This study confirmed that vascular amyloid β severity in the cortex is significantly associated with WMH volume in patients with definite CAA. The histopathological substrates of both posterior confluent and WMH multispots were comparable, suggesting overlapping pathophysiological mechanisms, although these exploratory observations require confirmation in larger studies.

Background Evidence from animal studies suggests that minocycline may reduce lobar intracerebral hemorrhage (ICH) recurrence in cerebral amyloid angiopathy, possibly by inhibiting perivascular extracellular matrix degradation in cerebral small vessels. There is currently no evidence of its safety or efficacy in humans with cerebral amyloid angiopathy. Methods and Results To provide preliminary data to support future studies of minocycline's efficacy, the authors performed a retrospective single‐center cohort study to assess the incidence of recurrent ICH in patients with an aggressive clinical course of probable cerebral amyloid angiopathy who had been prescribed minocycline off‐label via shared decision‐making. Crude incidence rate ratios were calculated to compare incidence rates before versus after treatment. Sixteen patients (mean age at minocycline initiation, 66.3±3.5 years; women 62.5%; median of 3 lobar ICHs [range, 1–6]) were initiated on minocycline and followed for a median of 12.4 months (range, 1.8–61.4 months). Adverse events were reported in 4 of 16 patients (gastroenteric, n=3; dizziness, n=1) and were considered mild. ICH incidence sharply increased the year before minocycline initiation compared with the preceding years (2.18 [95% CI, 1.50–3.07] versus 0.40 [95% CI, 0.25–0.60] events per patient‐year) and fell to 0.46 (95% CI, 0.23–0.83) events per patient‐year afterwards. Incidence rate ratios of recurrent ICH after minocycline was lower (0.21 [95% CI, 0.11–0.42], P

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid β, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed.