Cerebrospinal fluid biomarkers in cerebral amyloid angiopathy: insights from a clinical case series.

Cerebrospinal fluid biomarkers and apolipoprotein E genotype in cerebral amyloid angiopathy. A narrative review

Cerebrospinal fluid (CSF) biomarkers in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) have demonstrated inconsistent results. We investigated the relationship between CSF amyloid-β protein (Aβ) and vascular pathological findings to elucidate the mechanisms of Aβ elimination from the brain in CAA-ri. We examined Aβ 40 and Aβ 42 levels in CSF samples in 15 patients with CAA-ri and 15 patients with Alzheimer's disease and cerebral amyloid angiopathy (AD-CAA) using ELISA as a cross-sectional study. Furthermore, we pathologically examined Aβ 40 and Aβ 42 depositions on the leptomeningeal blood vessels (arteries, arterioles, and veins) using brain biopsy samples from six patients with acute CAA-ri and brain tissues of two autopsied patients with CAA-ri. The median Aβ40 and Aβ42 levels in the CSF showed no significant difference between pre-treatment CAA-ri (Aβ40, 6837 pg/ml; Aβ42, 324 pg/ml) and AD-CAA (Aβ40, 7669 pg/ml, p = 0.345; Aβ42, 355 pg/ml, p = 0.760). Aβ40 and Aβ42 levels in patients with post-treatment CAA-ri (Aβ40, 1770 pg/ml, p = 0.056; Aβ42, 167 pg/ml, p = 0.006) were lower than those in patients with pre-treatment CAA-ri. Regarding Aβ40 and Aβ42 positive arteries, acute CAA-ri cases showed a higher frequency of partially Aβ-deposited blood vessels than postmortem CAA-ri cases (Aβ40, 20.8% versus 3.9%, p = 0.0714; Aβ42, 27.4% versus 2.0%, p = 0.0714, respectively). Lower levels of CSF Aβ40 and Aβ42 could be biomarkers for the cessation of inflammation in CAA-ri reflecting the recovery of the intramural periarterial drainage pathway and vascular function.

To the Editor: The first priority of diagnostic evaluation of dementia syndrome is the identification of potentially treatable causes. Cerebral amyloid angiopathy-related inflammation is a recently described diagnostic entity that is characterized by a treatment-responsive, rapidly-progressive dementia syndrome. It has been suggested that it can be noninvasively diagnosed on the basis of a characteristic combination of clinical and radiological features. We present a representative case and discuss typical findings.

Elderly and forgetful with transient neurological spells: A story of two amyloids?

Cerebral amyloid angiopathy (CAA) related inflammation (CAA-ri) is considered to be a distinct syndrome caused by an inflammatory response to amyloid-β deposition in the walls of small leptomeningeal and cortical vessels in patients with sporadic CAA. However, recent data suggest that inflammation might contribute to a broader range of CAA subtypes. We describe a case of probable iatrogenic CAA (iCAA), which manifested with multiple intracerebral haemorrhages complicated by the development of clinical and radiological features of CAA-ri, which responded to steroids. Clinical, neuroimaging and CSF data suggested possible co-existing Alzheimer's pathology. CAA-ri may occur in association with iCAA, suggesting that a broader spectrum of patients might benefit from steroid treatment than previously assumed.

Introduction Cerebral amyloid angiopathy (CAA) is a vasculopathy characterized by amyloid-beta (Aβ) deposition in the walls of the leptomeningeal and cortical blood vessels. In a minority of patients with CAA, presence of amyloid-beta (Aβ) deposition triggers an autoimmune inflammatory reaction, referred to as CAA-related inflammation (CAA-RI). It can present in two forms, either as perivascular CAA-related inflammation (CAA-ri) or as Aβ-related angiitis (ABRA). The mechanism underlying CAA-RI remains unclear. Symptoms are subacute mental disorders and behavioral or cognitive changes, headaches, seizures and focal neurological deficits. Most commonly, CAA-ri is a monophasic illness. Relapses occur often years after the initial presentation and are correlated with corticosteroid tapering or immunosuppression cessation. Treatment is often prolonged, but effective. We present a rare and instructive case with CAA-ri characterized by rapid cognitive decline, therapy resistance and fatal outcome and discuss current literature. Case presentation We describe a case of an 81-year-old female who presented with progressive confusion, behaviour alterations, recurrent falls and vomiting since two weeks. There was a rapid cognitive decline and fatal outcome. The diagnosis of a probable CAA-ri was made based on the clinical presentation and brain MR imaging. To allow long-term corticosteroid replacement, azathioprine was initiated for second-line immunosuppression. Conclusion This case report of CAA-ri describes the diagnostic and therapeutic challenges in an elderly patient with rapid cognitive decline. It highlights the severe nature of the condition, the limitations of available treatments and the importance of early recognition based on the diagnostic criteria and MR imaging and start of the therapy, while acknowledging that outcomes may remain poor despite intervention.

Cerebral amyloid angiopathy is a common small vessel disease in the elderly involving vascular amyloid-β deposition. Cerebral amyloid angiopathy is one of the leading causes of intracerebral hemorrhage and a significant contributor to age-related cognitive decline. The awareness of a diagnosis of cerebral amyloid angiopathy is important in clinical practice as it impacts decisions to use lifelong anticoagulation or nonpharmacological alternatives to anticoagulation such as left atrial appendage closure in patients who have concurrent atrial fibrillation, another common condition in older adults. This review summarizes the latest literature regarding the management of patients with sporadic cerebral amyloid angiopathy, including diagnostic criteria, imaging biomarkers for cerebral amyloid angiopathy severity, and management strategies to decrease intracerebral hemorrhage risk. In a minority of patients, the presence of cerebral amyloid angiopathy triggers an autoimmune inflammatory reaction, referred to as cerebral amyloid angiopathy-related inflammation, which is often responsive to immunosuppressive treatment in the acute phase. Diagnosis and management of cerebral amyloid angiopathy-related inflammation will be presented separately. While there are currently no effective therapeutics available to cure or halt the progression of cerebral amyloid angiopathy, we discuss emerging avenues for potential future interventions.

Radiologically Isolated Cerebral Amyloid Angiopathy-Related Inflammation

La angiopatía amiloide cerebral (AAC) consiste en el depósito de amiloide en la pared de los vasos sanguíneos intracraneales, y conlleva a la aparición de hemorragia, isquemia o leucoencefalopatía. Las manifestaciones clínicas de la AAC son muy variables, tales como alteraciones cognitivas, alteraciones comportamentales, déficit neurológico focal, cefalea o crisis epilépticas. Un subtipo de angiopatía amiloide cerebral con inflamación relacionada (AAC-IR), se ha reportado recientemente en la literatura mundial. Presentamos el caso de una paciente de 74 años de edad, con un cuadro de demencia rápidamente progresiva de aproximadamente tres meses de evolución, asociada a cefalea, meningismo, disminución de la fuerza en hemicuerpo derecho, múltiples lesiones hemorrágicas parenquimatosas, hemosiderosis difusa, edema cerebral focal y estudio histológico con evidencia de amiloide intracerebral.
 El diagnóstico de la AAC se basa en una historia clínica compatible; neuroimagenes que demuestren hemosiderosis o múltiples hemorragias de predominio en fosa posterior, y en algunos casos estudio histológico que confirme la presencia de amiloide en la microcirculación intracraneal. Los criterios de Boston modificados unifican los hallazgos para el diagnóstico de AAC con diferentes grados de certeza. En algunas ocasiones, como en el caso presentado, la AAC se asocia a un componente inflamatorio, y se manifiesta con una demencia rápidamente progresiva, constituyéndose en un verdadero reto diagnóstico.

Cerebral Amyloid Angiopathy (CAA) is characterized by amyloid beta-peptide deposits within the small to medium-sized vessels of the brain and leptomeninges. CAA is an important cause of intracerebral hemorrhage in older adults. Cerebral Amyloid Angiopathy Related Inflammation (CAA-ri) is, however, a rare variant of CAA that results from an autoimmune response to the deposits and is characterized by acute or subacute encephalopathy, headache, or focal neurological deficits. We present a case of a 62-year-old female who presented with a generalized tonic-clonic seizure witnessed by a family member. The event was preceded by a worsening of her dementia in the past few months. The patient had features suggestive of CAA-ri on Magnetic Resonance Imaging of the brain and was treated with high dose IV steroids. With an improvement in her cognitive symptoms and no further seizure episodes, she was discharged on oral steroids. Although CAA is well studied and well documented, its subset CAA-ri is uncommon with its clinical course and complications mentioned infrequently in medical literature. In conclusion, CAA-ri is underdiagnosed because of its rarity and remains a potentially treatable cause of subacute cognitive decline and seizures demanding further research in this area.

Introduction: Cerebral amyloid angiopathy related inflammation (CAARI) is an autoimmune inflammatory condition that occurs in patients with cerebral amyloid angiopathy (CAA) and can lead to rapidly progressive cognitive decline. Little is known about the prevalence of subclinical and clinical CAARI. We sought to determine the prevalence of subclinical and clinical CAARI among patients with CAA and white matter hyperintensities (WMH). Methods: In this multicenter, single healthcare system, retrospective cohort study, we reviewed electronic medical records and MRI brain scans of patients presenting with a diagnosis code for amyloidosis or CAA that were evaluated between 1/2010 - 6/2020. We included patients meeting modified Boston criteria for CAA who had WMH on T2 FLAIR sequences. Patients without available hemosiderin sensitive sequences (SWI or GRE) and T2 FLAIR sequences and those without WMH on T2 FLAIR imaging were excluded. Two independent vascular neurologists blinded to background clinical information reviewed each MRI brain scan for the presence of CAARI. The clinical course and outcomes were reviewed and reported. Results: Out of 1100 patients reviewed, 511 met modified Boston criteria for CAA and 193 met the final study inclusion criteria. 55 (28.5% of those with CAA and WMH, and 10.8% of all CAA) patients had MRI brain imaging suggestive of CAA-RI. 21 (38.2%) were male, 38 (69.1%) were Caucasian, and the mean (SD) age was 72.9 (8.9) years. CAA-RI was recognized in only 10 (18.2%) patients initially while 20 (36.4%) were diagnosed up to 9 months later (median 0, IQR 0-9 months). At time of earliest detection of CAARI on imaging, common concurrent findings were cognitive impairment (74.5%), macro-hemorrhages (52.7%), headache (30.9%), seizures (14.5%), and ischemic infarcts (14.5%). Only 18 (32.7%) patients were started on immunosuppression. Nineteen (34.5%) patients expired during the observation period of which only 8 (42.1%) were ever diagnosed with CAA-RI by their treating clinician. Conclusion: The prevalence of subclinical CAA-RI in our study was high. Most cases of radiographic CAARI went unrecognized and untreated. Further studies are needed to assess if treatment of subclinical CAARI may prevent cognitive decline in these patients.

Background - Cerebral amyloid angiopathy-related inflammation (CAA-ri) is characterized by various neurological symptoms such as gradually developing confusion, progressive cognitive decline, seizure or headaches; T2 hyperintensities on magnetic resonance imaging (MRI); and neuropathological evidence of cerebral amyloid angiopathy (CAA) and associated vascular or perivascular inflammation. Although histological confirmation is necessary for accurate diagnosis, in case of typical clinical features and neuroimaging, the diagnosis can be established without biopsy. Case summary - We present the case of a 57-year-old man with a history of hypertension who presented to the emer¬gency department 3-week history of progressive headache and a gradually developing altered mental status. On examination, he was found to have left sided weakness and decreased pscyhomotility. Routine clinical work-up (lab investigations, CT, cerebrospinal fluid analysis) did not show obvious diagnosis, so we performed an MRI. It raised the suspicion of CAA-ri which diagnosis was verified by neuroradiological evaluation. High dose steroid treatment was initiated. The patient rapidly responded to treatment, his focal neurological signs resolved. Control MRI after 1.5 months showed multiple haemorrhagic laesions in the field of previous inflammation which posteriorly supported the previous supposed work-diagnosis. Conclusions - Although histopathology is the gold standard for the diagnosis of cerebral amyloid angiopathy, the typical clinical presentation, good response to steroids and accurate neuroradiological criteria make biopsy unnecessary to diagnose CAA-ri.

ABSTRACTIntroductionAmyloid related imaging abnormalities effusion/edema (ARIA‐E) is seen in patients treated with antiamyloid antibodies. It resembles cerebral amyloid angiopathy (CAA) related inflammation (CAA‐ri) caused by an inflammatory response to amyloid deposition in the walls of cortical and leptomeningeal vessels in patients with sporadic CAA. Recently, temporary inflammatory imaging findings that remained clinically silent have been described in patients with iatrogenic CAA (iCAA).ResultsWe describe a case of probable iatrogenic CAA (iCAA), which demonstrated radiological features of CAA‐ri that remained clinically silent and spontaneously resolved before the inaugural intracranial hemorrhage. Clinical and radiological features resembled ARIA‐E.DiscussionThis case adds to the clinical and radiological spectrum of iCAA and suggests an immune‐mediated response to amyloid deposition.

Cerebral amyloid angiopathy (CAA)-related inflammation (CAA-RI) is a rare CAA variant characterized by acute or subacute encephalopathy, headache, epilepsy, or focal neurological deficits. Radiologically, CAA-RI presents with widespread white matter lesions on brain magnetic resonance imaging (MRI) in addition to the hemorrhagic imaging features of CAA. Previous studies have found that the apolipoprotein E (ApoE) ε4 allele and ε4/ε4 genotype were over-represented in CAA-RI. The role of the ApoE ε2 allele in CAA-RI, however, is largely unknown, partly due to the rarity of the ε2/ε2 genotype in the general population. The authors report the first case of CAA-RI with the rare ApoE ε2/ε2 genotype. The patient presented with mild clinical symptoms but striking neuroimaging abnormalities. The response to small-dose glucocorticoids was satisfactory. Because ApoE ε2 promotes amyloid β accumulation and fibrinoid necrosis in the cerebral vasculature, the ε2/ε2 genotype, similar to ε4/ε4, may also be a precipitating factor for CAA-RI. To clarify the role of ApoE ε2 in CAA-RI, studies with large sample sizes investigating whether ε2 is more common in patients with CAA-RI than in those with CAA only are warranted.

Integrating cerebrospinal fluid-biomarkers into diagnostic workup of patients with sporadic cerebral amyloid angiopathy may support early and correct identification. We aimed to identify and validate clinical- and cerebrospinal fluid-biomarkers for in vivo diagnosis of cerebral amyloid angiopathy. This observational cohort study screened 2795 consecutive patients admitted for cognitive complaints to the academic departments of neurology and psychiatry over a 10-year period (2009-2018). We included 372 patients with available hemosiderin-sensitive MR imaging and cerebrospinal fluid-based neurochemical dementia diagnostics, i.e. Aβ40, Aβ42, t-tau, p-tau. We investigated the association of clinical- and cerebrospinal fluid-biomarkers with the MRI-based diagnosis of cerebral amyloid angiopathy, applying confounder-adjusted modelling, receiver operating characteristic and unsupervised cluster analyses. We identified 67 patients with cerebral amyloid angiopathy, 76 patients with Alzheimer's disease, 75 patients with mild cognitive impairment due to Alzheimer's disease, 76 patients with mild cognitive impairment with unlikely Alzheimer's disease and 78 healthy controls. Patients with cerebral amyloid angiopathy showed a specific cerebrospinal fluid pattern: average concentration of Aß40 [13 792 pg/ml (10 081-18 063)] was decreased compared to all controls (P < 0.05); Aß42 [634 pg/ml (492-834)] was comparable to Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease (P = 0.10, P = 0.93) but decreased compared to mild cognitive impairment and healthy controls (both P < 0.001); p-tau [67.3 pg/ml (42.9-91.9)] and t-tau [468 pg/ml (275-698)] were decreased compared to Alzheimer's disease (P < 0.001, P = 0.001) and mild cognitive impairment due to Alzheimer's disease (P = 0.001, P = 0.07), but elevated compared to mild cognitive impairment and healthy controls (both P < 0.001). Multivariate modelling validated independent clinical association of cerebral amyloid angiopathy with older age [odds-ratio: 1.06, 95% confidence interval (1.02-1.10), P < 0.01], prior lobar intracerebral haemorrhage [14.00 (2.64-74.19), P < 0.01], prior ischaemic stroke [3.36 (1.58-7.11), P < 0.01], transient focal neurologic episodes (TFNEs) [4.19 (1.06-16.64), P = 0.04] and gait disturbance [2.82 (1.11-7.15), P = 0.03]. For cerebrospinal fluid-biomarkers per 1 pg/ml, both lower Aß40 [0.9999 (0.9998-1.0000), P < 0.01] and lower Aß42 levels [0.9989 (0.9980-0.9998), P = 0.01] provided an independent association with cerebral amyloid angiopathy controlled for all aforementioned clinical confounders. Both amyloid biomarkers showed good discrimination for diagnosis of cerebral amyloid angiopathy among adjusted receiver operating characteristic analyses (area under the receiver operating characteristic curves, Aß40: 0.80 (0.73-0.86), P < 0.001; Aß42: 0.81 (0.75-0.88), P < 0.001). Unsupervised Euclidian clustering of all cerebrospinal fluid-biomarker-profiles resulted in distinct segregation of cerebral amyloid angiopathy patients from all controls. Together, we demonstrate that a distinctive set of cerebrospinal fluid-biomarkers effectively differentiate cerebral amyloid angiopathy patients from patients with Alzheimer's disease, mild cognitive impairment with or without underlying Alzheimer's disease, and healthy controls. Integrating our findings into a multiparametric approach may facilitate diagnosing cerebral amyloid angiopathy, and may aid clinical decision-making, but warrants future prospective validation.