A Case of Severe Cerebral Amyloid Angiopathy-Related Inflammation in a 81-Year-Old Woman with Rapid Cognitive Decline

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.

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.

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

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.

Radiologically Isolated Cerebral Amyloid Angiopathy-Related Inflammation

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.

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.

Cognitive decline and falls in the elderly are common and are often accepted as natural and inevitable by relatives and health care professionals, but frequently there are specific and treatable diseases that should be revealed. In our case, cerebral amyloid angiopathy-related inflammation (CAA-RI) was causative for neuro-psychiatric symptoms and worsening of gait in a 71 year-old man with recurrent falls and decline of gait and cognition. Cerebral amyloidangiopathy (CAA) is an important cause of cerebrovascular disorders in the elderly, characterized by leukoencephalopathy combined with lobar or small cortical hemorrhage due to amyloid deposition in cortical and leptomeningeal vessels. In several conditions, amyloid deposition can provoke inflammation or edema that lead to -normally reversible- encephalopathy. CAA-RI is then characterized by subacute neurobehavioral symptoms, headache, seizures or stroke-like signs. The first therapeutic option after confirming the diagnosis is treatment with glucocorticoids. Despite treatment with prednisolone, our patient could not regain his unrestricted mobility and self-help competence. Our report aims to sharpen awareness for CAA and its inflammatory form (CAA-RI) in healthcare professionals involved in medical care of the elderly and provide a short summary of this disease.

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.

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.

Cerebral amyloid angiopathy (CAA) is characterised by β-amyloid deposition in the walls of small to medium sized arteries of the cerebral cortex and the leptomeninges. In a significant proportion of patients, CAA is the probable cause of non-traumatic primary cerebral haemorrhage, particularly in those who are over 55 years of age and have controlled blood pressure. Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an uncommon and aggressive subtype of CAA, which is thought to be caused by an immune reaction to the deposits of β-amyloid. It has a variety of presentations that can mimic other focal and diffuse neurological disorders. Radiographically, its classic presentation is asymmetric cortical or subcortical white matter hyperintense foci due to multiple microhaemorrhages on T2-weighted or fluid attenuated inversion recovery (FLAIR) images. Although definite diagnosis requires brain and leptomeningeal biopsy, diagnostic criteria for probable CAA-ri based on a combination of clinical and radiological features were validated in 2015. We describe a patient with probable CAA-ri mimicking stroke and review the clinical and radiological features important for a proper differential diagnosis between ischaemic stroke (IS) and CAA-ri, and its subsequent appropriate treatment.LEARNING POINTSMRI is a crucial tool for the diagnostic evaluation of cerebral amyloid angiopathy-related inflammation (CAA-ri).A high index of suspicion and awareness of CAA-ri is necessary for correct diagnosis in stroke-like presentations of the condition.The treatment of choice for CAA-ri is empirical corticosteroid therapy, which is associated with clinical and radiological improvement.

Cerebral amyloid angiopathy (CAA) is a common but often asymptomatic disease, characterized by the deposition of amyloid proteins within brain parenchyma and leptomeningeal-cortical vessels. It can occur as a sporadic disorder or accompany Alzheimer disease (AD). The usual presentation of CAA is spontaneous lobar hemorrhage, Unlike CAA, cerebral amyloid angiopathy-related inflammation (CAA-ri), a subtype of CAA, can show various presentations and responds to steroid (or immuno suppressive) treatment. We report a patient with mixed dementia who showed subacute progression in cognitive impairment and had a mass lesion on brain magnetic resonance imaging (MRI). The lesion was identified as CAA related inflammation and the cognitive status of the patient improved significantly after steroid treatment. In this case report, we aimed to emphasize that CAA-ri is one of the possible diagnoses that should be considered in demented patients with rapid cognitive deterioration and showing brain lesions resembling neoplasms on the MRI. Therefore, steroids or other immunosuppresive treatments, which may lead to a dramatic clinical improvement, could be administered without delay.

Cerebral amyloid angiopathy related inflammation (CAAri) is becoming increasingly recognised as a subset of cerebral amyloid angiopathy (CAA). CAAri generally presents with subacute cognitive decline, headaches, seizures, behavioral changes, and focal neurological deficits. We describe a patient who developed acute dysphasia and reversible cognitive decline due to probable CAAri. CT brain showed bilateral vasogenic edema in the cerebral hemispheres, predominantly involving the parietal and temporal lobes, left greater than right without enhancement. Magnetic resonance brain imaging showed extensive multifocal areas of subcortical white matter T2 hyperintensity in the frontal and temporal regions with associated mass effect, negligible enhancement, and multiple foci of microhemorrhage on susceptibility weighted imaging sequences consistent with a diagnosis of probable CAAri. She responded dramatically to a course of intravenous methylprednisolone followed by further immunosuppression with pulse intravenous cyclophosphamide. Her dysphasia resolved within 5 days of intravenous methylprednisolone therapy. Her MMSE improved from 11/30 at day 5 of admission to 28/30 at 6-month follow-up. The notable features of our case were the unusual CT findings, which were inconsistent with stroke and diagnostic utility of susceptibility-weighted magnetic resonance imaging in confirming the diagnosis which allowed for prompt institution of immunosuppression.

Cerebral amyloid angiopathy related inflammation: An under recognized but treatable complication of cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is a well-known pathology of Alzheimer’s disease among elderly individuals. CAA-related inflammation (CAAri) has been increasingly viewed as a rare presentation of CAA. We report the case a 65-year-old man who presented with subacute dementia and reversible delirium secondary to probable CAAri. His laboratory findings were negative except for elevated cerebrospinal fluid protein levels. Brain magnetic resonance imaging (MRI) revealed disseminated microbleeds in both the cerebral hemispheres on T2 weighted gradient images and prominent confluent T2-hyperintense white matter lesions in the bilateral temporo-occipital subcortical areas. Suspecting CAAri, we prescribed steroid pulse therapy with oral steroid tapering. The acute delirium and agitation improved after medication. However, the CAAri-induced damage to the brain function persisted, as evidenced in the follow-up clinical performance and serial Mini-Mental State Examination (MMSE). The identification and accurate diagnosis of CAAri are important because the disease may respond to immunosuppressive therapy. In clinical settings, the detection of CAA with diffuse microbleeds in the brain is essential for making a tentative diagnosis of CAAri. Immunosuppressive therapy is the cornerstone of treatment. However, the optimal treatment duration is currently uncertain and warrants further investigation. In conclusion, the possible diagnosis of CAAri should always be considered when a patient presents with sub-acute cognitive decline and compatible MRI findings (T2-hyperintense lesions with diffuse microbleeds).