
==== Front
Eur J Neurol
Eur J Neurol
10.1111/(ISSN)1468-1331
ENE
European Journal of Neurology
1351-5101
1468-1331
John Wiley and Sons Inc. Hoboken

39105407
10.1111/ene.16425
ENE16425
EJoN-24-0642.R1
Original Article
Stroke
Clinical and neuroimaging precursors in cerebral amyloid angiopathy: impact of the Boston criteria version 2.0
Precursors in cerebral amyloid angiopathy
Weidauer et al.
Weidauer Stefan https://orcid.org/0000-0001-6437-6793
1 weidauer@em.uni-frankfurt.de

Tafreshi Mona 1
Förch Christian https://orcid.org/0000-0002-3770-7857
2
Hattingen Elke https://orcid.org/0000-0002-8392-9004
1
Arendt Christophe T. https://orcid.org/0000-0003-3300-3729
1
Friedauer Lucie https://orcid.org/0000-0001-9427-1271
2
1 Institute of Neuroradiology, University Hospital Goethe University Frankfurt Frankfurt am Main Germany
2 Department of Neurology, University Hospital Goethe University Frankfurt Frankfurt am Main Germany
* Correspondence
Stefan Weidauer, Institute of Neuroradiology, Goethe University Frankfurt, Schleusenweg 2‐16, Frankfurt am Main 60528, Germany.
Email: weidauer@em.uni-frankfurt.de

06 8 2024
10 2024
31 10 10.1111/ene.v31.10 e1642508 7 2024
02 4 2024
17 7 2024
© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

Abstract

Background and purpose

Although the Boston criteria version 2.0 facilitates the sensitivity of cerebral amyloid angiopathy (CAA) diagnosis, there are only limited data about precursor symptoms. This study aimed to determine the impact of neurological and imaging features in relation to the time of CAA diagnosis.

Methods

Patients diagnosed with probable CAA according to the Boston criteria version 1.5, treated between 2010 and 2020 in our neurocentre, were identified through a keyword search in our medical database. Neuroimaging was assessed using Boston criteria versions 1.5 and 2.0. Medical records with primary focus on the clinical course and the occurrence of transient focal neurological episodes were prospectively evaluated.

Results

Thirty‐eight out of 81 patients (46.9%) exhibited transient focal neurological episodes, most often sensory (13.2%) or aphasic disorders (13.2%), or permanent deficits at a mean time interval of 31.1 months (SD ±26.3; range 1–108 months) before diagnosis of probable CAA (Boston criteria version 1.5). If using Boston criteria version 2.0, all patients receiving magnetic resonance imaging (MRI) met the criteria for probable CAA, and diagnosis could have been made on average 44 months earlier. Four patients were younger than 50 years, three of them with supporting pathology. Cognitive deficits were most common (34.6%) at the time of diagnosis.

Conclusions

Non‐haemorrhagic MRI markers enhance the sensitivity of diagnosing probable CAA; however, further prospective studies are proposed to establish a minimum age for inclusion. As the neurological overture of CAA may occur several years before clinical diagnosis, early clarification by MRI including haemosensitive sequences are suggested.

cerebral amyloid angiopathy
cerebral microbleeds
MR imaging
neurological precursors
superficial siderosis
source-schema-version-number2.0
cover-dateOctober 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:20.09.2024
Weidauer S , Tafreshi M , Förch C , Hattingen E , Arendt CT , Friedauer L . Clinical and neuroimaging precursors in cerebral amyloid angiopathy: impact of the Boston criteria version 2.0. Eur J Neurol. 2024;31 :e16425. doi:10.1111/ene.16425
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pmcINTRODUCTION

Cerebral amyloid angiopathy (CAA) refers to a genetic and biochemical inhomogeneous group of age‐related small vessel diseases, in which the reduced perivascular clearance of amyloid‐β (Aβ) from the interstitial fluid plays a key role in the pathogenesis [1, 2, 3, 4, 5, 6]. The impairment of the intramural periarterial drainage is part of an insufficient perivascular transport via the glymphatic system [3, 5, 7]. As a consequence, there are deposits especially in the small sized arteries in the cortex and the leptomeninges with preference for the posterior lobar brain regions [3, 4, 5]. Whereas capillary involvement is classified as CAA type 1, type 2 reflects CAA without capillary amyloid deposits [3, 4, 8]. However, the exact mechanisms for perivascular clearance of Aβ are up to now incompletely understood and further studies are necessary [3, 9]. A neuroradiological hallmark of CAA is multiple cortical and subcortical lobar microbleeds (MBs) [1, 10, 11, 12, 13]. CAA‐related intracerebral haemorrhages (ICHs) are consecutively in the cerebral lobes, with a high risk of recurrence [1, 2, 6]. Moreover, CAA is independently associated with age‐related cognitive impairment [13] and therefore accurate in vivo diagnosis is important for clinical treatment and prognostic assessment [3, 14].

The definitive diagnosis of CAA is still based on histological features presented in biopsy or autopsy [3, 14]. The first formulated in 1995, the Boston criteria (version 1.0), defined a probable CAA using neurological features in addition to specific magnetic resonance imaging (MRI) findings, that is, two or more haemorrhagic lesions (ICH and cortical or subcortical MBs) [2, 15]. The later modification of the Boston criteria [16, 17, 18, 19, 20, 21, 22] included singular haemorrhagic manifestation, focal (involving three sulci or fewer) or disseminated (involving four sulci or more) cortical superficial siderosis (cSS). This version 1.5 was linked to increased sensitivity for CAA‐related haemorrhage [16, 17]. In the most recent Boston criteria version 2.0 established in 2022 [14], additional non‐haemorrhagic MRI markers were added, namely white matter hyperintensities in a multispot pattern (WMH MS) and severe centrum semiovale perivascular spaces (CSO PVS) [14, 23, 24, 25]. The WMH MS disclose CAA‐related brain injuries resulting in a particularly severe loss of structural connectivity [3, 26]. Both possible and probable CAA are clinically defined by an age onset ≥50 years and presentation with spontaneous lobar ICH, cognitive impairment up to dementia or transient focal neurological episodes (TFNEs) [13, 27]. Even though clinical radiological criteria such as the Boston criteria or the Edinburgh criteria facilitate the diagnosis of possible or probable CAA, neuropathological evidence in biopsy or autopsy still remains the gold standard [28]. However, further validation in studies including healthy elderly control groups would be helpful [29], because radiological evidence of the disease is often incidentally encountered in approximately 16% of asymptomatic older patients and there are limited data in the presumed initial pathophysiological changes in CAA [30]. Although the Boston criteria version 2.0 forwards the sensitivity of CAA diagnosis without specificity decline [14, 31, 32], the recent literature exhibits only limited data about precursor neurological symptoms. This study aimed to determine the impact of neurological features in relation to the time of diagnosis of possible or probable CAA and the corresponding scope of agreement with the latest Boston criteria version 2.0.

MATERIALS AND METHODS

Research design and subjects

This is a single‐centre retrospective study that was approved by the ethics committee of the Faculty of Medicine of the Goethe‐University Frankfurt (2000‐1042) with a waiver for informed consent. Patients diagnosed with probable CAA according to the Boston criteria version 1.5, treated between 2010 and 2020 at our tertiary care neurocentre (Goethe University, Department of Neurology and Institute of Neuroradiology), were identified through a keyword search (cerebral amyloid angiopathy/CAA, MRI, CT) in our medical database, which included the neurological and neuroradiological reports. The keyword search resulted also in inclusion of patients with CAA‐related inflammation (CAA‐ri).

MRI analysis

Neuroimaging datasets were acquired on different MR scanners with a magnetic field strength of 3 T (MAGNETOM Skyra, Siemens Healthineers, Germany) and 1.5 T (MAGNETOM Vision & Aera, Siemens Healthineers; Achieva dStream, Philips, Netherlands). Two experienced neuroradiologists (S.W., C.T.A.) analysed the following sequences in all patients receiving MRI: T2‐weighted imaging, T2 fluid attenuated inversion recovery (FLAIR) imaging, diffusion weighted imaging, T1‐weighted imaging, T2*‐weighted imaging and if available susceptibility weighted imaging (SWI). All sequences were acquired in a two‐dimensional way. Imaging features of CAA were defined as the presence of signal loss either on SWI with blood‐equivalent signals on the corresponding phase map or on T2*‐weighted imaging; that is, haemorrhage, including MBs defined as a size of <5 mm diameter; band‐like sulcal affection, that is, focal (restricted to three or fewer sulci) or disseminated (four or more sulci) cSS [16]. Hyperintense signal changes on axial T2‐weighted imaging and T2 FLAIR imaging in the centrum semiovale and the basal ganglia were evaluated in line with STRIVE recommendations regarding enlarged PVS and WMH [33, 34, 35].

Neurological assessment

Two experienced neurologists (C.F., L.F.) reviewed the medical records of the patients with primary focus on the clinical course and the occurrence of (a) TFNEs [27], for example aphasia, dysarthria, motor and/or sensory deficits or temporary symptoms atypical for TFNEs such as vertigo, confusion or dizziness, or (b) persistent neurological deficits, for example aphasia, apraxia, dysarthria, cognitive impairment up to dementia, impairment of consciousness, dizziness, compromised vigilance, ataxia and gait disturbances. Moreover, it was evaluated whether the aetiology of the neurological symptoms was known and plausible. In a first step results of the standardized neurological assessment performed at the time of diagnosis of CAA were reviewed and analysed (including standardized neurological physical examination, neuropsychological examination, electroencephalography, Doppler ultrasonography of the cerebral vessels and cardiac diagnostics such as electrocardiogram and echocardiography to exclude competing pathologies). In a second step, patients' medical records were screened for CAA‐suspicious symptoms prior to the time of the CAA diagnosis. In a few cases, these symptoms had been purely anamnestic descriptions not leading to further medical examination. These symptoms were retrospectively classified as potential CAA‐related symptoms. If MRI had been performed at the time of symptom onset, an attempt was made to explain these symptoms by a corresponding imaging correlate of CAA and thereby to support the aetiology.

Statistical analysis

Variables are presented as absolute frequencies, proportions and percentages, ranges, and means with one standard deviation (SD), as applicable. The significance level α for statistical tests was set to 5%, and p < 0.05 were considered statistically significant. The McNemar test was employed to statistically evaluate changes of clinical features between the two moments before and at clinical diagnosis of probable CAA (Table 1) and was based on the chi‐squared approximation for paired binary data. Computations were performed using SPSS software version 27.0 (IBM SPSS Statistics, IBM Corporation, Armonk, NY, USA).

TABLE 1 Initial neurological symptoms before and at the time of clinical cerebral amyloid angiopathy (CAA) diagnosis.

Clinical features	Before clinical diagnosis of probable CAA (Δt = 31.1 months)	At clinical diagnosis of probable CAA	
N	(%)	N	(%)	
Patients	38	46.9	81	100	
Transient focal neurological episodes (TFNEs, amyloid spells)	19	10 (p = 0.004)	
Typical	14	5 (p = 0.004)	
Sensory deficits	5	13.2	1	1.2	
Aphasia	5	13.2	3	3.7	
Paresis	3	7.9	1	1.2	
Visual disturbances	1	2.6	–	–	
Atypical	5	5 (n.s.)	
Confusion	4	10.5	1	1.2	
Dizziness	1	2.6	2	2.5	
Vertigo	–	–	2	2.5	
Persistent neurological deficits b	17	Persistent neurological deficits a , b 71 (p < 0.001)	
Aphasia b	1	2.6	22	27.2	
Apraxia b	–	–	4	4.9	
Cognitive impairment/dementia	15	39.5	28	34.6	
Consciousness impairment, dizziness	–	–	14	17.3	
Gait disturbance, gait apraxia b	–	–	3	3.7	
Neglect	–	–	7	8.6	
Sensory deficits	1	2.6	3	3.7	
Paresis b	–	–	22	27.2	
Visual disturbances	–	–	11	13.6	
Headache	2	5.3	11	13.6	
p < 0.004	
Structural epilepsy	–	–	4	4.9	
a Multiple entries possible.

b May be due to lobar intracerebral haemorrhage (ICH).

RESULTS

The patient cohort consisted of a total of 81 subjects with clinically confirmed probable CAA according to the Boston criteria version 1.5 diagnosed between January 2010 and December 2020. The mean age was 72.8 ± 9.5 years (mean, SD; range 44–89 years) and the group predominantly encompassed men (n = 49/81, 60.5%).

Thirty‐eight out of 81 patients (46.9%) exhibited TFNEs or permanent neurological deficits at a mean time interval of 31.1 months (SD ±26.3; range 1–108 months) before clinical diagnosis of probable CAA (Boston criteria version 1.5) (Table 1). Referring to TFNEs, most common typical temporary symptoms were aphasic disorders (n = 5; 13.2%) and sensory hemisyndromes (n = 5; 13.2%; p = 0.004), followed by hemiparesis (n = 3; 7.9%) and visual disturbances (n = 1; 2.6%). Temporary symptoms atypical for TFNEs encompass confusion and/or dizziness (n = 5; 11.5%; n.s.). In contrast, cognitive impairment up to dementia (n = 15; 39.5%) was the clinically leading symptom of permanent or progressive neurological disorders before setting the diagnosis of probable CAA. Neuroradiological assessment was performed by computed tomography (CT) in 28 (70%) and by MRI in 12 patients (30%).

All patients assessed by MRI (n = 12; 30%) showed characteristic imaging features suggesting CAA (Table 2). According to Boston criteria version 1.5 applied without considering age, nine out of these 12 patients showed neuroradiological findings compatible with probable CAA (possible CAA, n = 3). If using Boston criteria version 2.0, all 12 patients met the criteria for probable CAA (Figure 1). However, four patients were younger than 50 years (Boston criteria version 2.0) and 55 years (Boston criteria version 1.5), respectively (Table 2, patients 7–10). In three of these four patients, a leptomeningeal biopsy was performed which confirmed the diagnosis of CAA (i.e., probable CAA with supporting pathology) (Figures 2 and 3).

TABLE 2 MRI in patients (n = 12) with previous neurological symptoms before clinical diagnosis of CAA.

No.	MRI findings	Neurological symptoms	Diagnosis/Boston criteria a	Age (years) at first symptoms	Age (years) at diagnosis	Δt (months)	
Version 1.5	Version 2.0	
1	Focal cSS, >2 MBs	TFNE, ataxic gait, dizziness	Probable CAA	Probable CAA	85	89	48	
2	CSO PVS, WMH MS, >2 MBs	TFNE, dizziness, impairment of consciousness	Probable CAA	Probable CAA	69	76	84	
3	CSO PVS, WMH MS, >2 MBs	Progressive dementia	Probable CAA	Probable CAA‐ri	70	71	15	
4	Extensive CSO PVS, WMH MS, >2 MBs	TFNE, aphasia	Probable CAA	Probable CAA	68	73	60	
5	CSO PVS, WMH MS, lobar ICH	Hemiparesis left	Possible CAA	Probable CAA	74	78	48	
6	Focal cSS, multiple MBs	Several TFNE b , sensory deficits	Probable CAA	Probable CAA	74	75	12	
7	Focal cSS, CSO PVS, multiple MBs	TFNE b , sensory deficit	Probable CAA	Probable CAA	44	49	60	
8	Multiple MBs, lobar ICH	TFNE, visual disturbances	Probable CAA	Probable CAA with supporting pathology	47	49	30	
9	Disseminated cSS, CSO PVS	TFNE, progressive disorientation	Possible CAA; after biopsy: probable CAA with supporting pathology	Probable CAA with supporting pathology	47	53	72	
10	Extensive CSO PVS, WMH MS, focal cSS, >2 MBs	Several TFNE b , aphasia, dizziness, visual deficits, cognitive impairment	Probable CAA	Probable CAA with supporting pathology	49	52	27	
11	Extensive CSO PVS, WMH MS, >2 MBs	TFNE, dizziness, impairment of consciousness	Probable CAA	Probable CAA	75	78	30	
12	CSO PVS, WMH MS, lobar ICH	TFNE, aphasia	Possible CAA	Probable CAA	59	60	12	
					∅ 63.4	∅ 66.9	∅ 41.5	
Abbreviations: CAA, cerebral amyloid angiopathy; CAA‐ri, CAA‐related inflammation; ; CSO PVS, centrum semiovale perivascular spaces; cSS, cortical superficial siderosis; ICH, intracerebral haemorrhage; MB, microbleed (cortical/subcortical location); MRI, magnetic resonance imaging; TFNE, transient focal neurological episode; WMH MS, white matter hyperintensity multispot.

a Boston criteria version 1.5/2.0 without minimum age ≥50 years.

b Misdiagnosed as epileptic seizures.

∅: Mean.

FIGURE 1 A 75‐year‐old man (patient 11, Table 2) suffering from a transient focal neurological episode 30 months before diagnosis of probable CAA. (a)–(c) Axial T2 weighted images showing several cortical and subcortical microbleeds ((a), (b) black arrowhead), enlarged centrum semiovale perivascular spaces ((a)–(c) arrow) sparing the basal ganglia (c) and white matter hyperintensity multispot ((a), (b) white arrowhead).

FIGURE 2 A 47‐year‐old man (patient 9, Table 2) with transient focal neurological episodes and progressive disorientation 72 months before an established diagnosis of probable CAA with supporting pathology in leptomeningeal biopsy. (a)–(c) Axial susceptibility weighted imaging disclosing disseminated chronic cortical superficial siderosis (cSS) with characteristic bilinear track‐line appearance (arrow) and multiple cortical microbleeds (MBs) (arrowhead). (d)–(i) Axial T2‐weighted images (d)–(f) and axial fluid attenuated inversion recovery images (g)–(i) showing white matter hyperintensity multispot ((d), (e), (g), (h) arrow) and multiple centrum semiovale perivascular spaces ((d), (e) arrowhead) sparing the basal ganglia (f), (i).

FIGURE 3 A 47‐year‐old man (patient 8, Table 2) suffering from recurrent temporary visual deficits, that is, transient focal neurological episodes, 30 months before an established diagnosis of probable CAA with supporting pathology. (a)–(c) Axial T2*‐weighted images representing disseminated chronic cortical superficial siderosis (cSS) with bilinear track‐line appearance (black arrowhead; (d) axial T2‐weighted images) and subacute cSS ((a) white arrowhead), multifocal cortical microbleeds ((b), (c) arrow). (d)–(f) Axial T2‐weighted images exhibiting multiple enlarged perivascular spaces ((d)–(f) white arrow) and white matter hyperintensity multispot ((e) white arrowhead) sparing the basal ganglia (f). (g), (h) Slight perifocal hyperintense signal changes on axial fluid attenuated inversion recovery images ((g) arrow) with leptomeningeal enhancement on axial post‐contrast T1‐weighted image ((h) arrow) due to subacute cSS and absent bilinear track‐line signal loss on T2*‐weighted image ((a) white arrowhead).

The mean age at onset of initial neurological symptoms (typical/atypical TFNEs, n = 10/12; persistent symptoms, n = 2/12; i.e., progressive cognitive decline, hemiparesis) was 63.4 ± 13.7 years (mean, SD; range 44–85 years) (Table 2). If the Boston criteria version 2.0 had been applied, the diagnosis of probable CAA could have been made on average 44 months earlier in three patients (Table 2, patients 5, 9, 12).

In contrast to the clinical precursors of CAA with TFNEs in the focus, persistent neurological deficits were leading at the time of diagnosis. Cognitive deficits up to dementia were most common (n = 28/81; 34.6%), followed by aphasia (n = 22/81; 27.2%) and paretic symptoms (n = 22/81; 27.2%) (Table 1). On the other hand, only 12.3% (p = 0.004) suffered from TFNEs at the time of diagnosis of probable CAA. One patient fulfilled clinical and neuroradiological features of CAA‐ri.

DISCUSSION

The implementation of non‐haemorrhagic MRI markers [23, 24] in the Boston criteria version 2.0 [14] for the diagnosis of probable CAA significantly improved the sensitivity for neuropathologically proven CAA compared to the Boston criteria version 1.5 established in 2010 [15] whilst maintaining the same specificity. The non‐haemorrhagic MRI criteria include CSO PVS and WMH MS on T2‐weighted sequences as a result of multifocal distributed microangiopathy [23, 24].

In the present study, transient or permanent neurological deficits attributable to CAA occurred in 38 patients (46.9%) 31.1 months on average before the clinical diagnosis of probable CAA according to the Boston criteria version 1.5 [16]. Whilst temporary neurological deficits, that is, TFNEs or ‘amyloid spells’ [27, 36], were dominated by aphasic disorders and sensory hemisyndromes (26.4%), permanent and/or progressive neurological symptoms were most often cognitive impairment up to dementia. However, several precursor symptoms recorded were primarily of an anamnestic nature and were retrospectively classified as suspicious for CAA. In particular, none of the symptoms of cognitive impairment resulted in further diagnostic procedures. To what extent the perception of temporary aphasic disorders are related to the side dominance in the hemispheric representation of language cannot be conclusively assessed at this point. However, it should be noted that, in earlier studies, functional disorders caused by ischaemia in the dominant hemisphere, that is, predominantly localized on the left, were perceived as clinically significantly more frequently than in the non‐dominant hemisphere [37].

In 12 out of the 40 patients suffering from precursor neurological deficits attributable to CAA an MRI examination was performed for the diagnostic clarification. According to the MRI criteria using the Boston criteria version 1.5 [16], nine patients met the criteria for CAA. In comparison, all 12 patients met the MRI criteria for probable CAA using Boston criteria version 2.0 [14, 31, 32]. However, four out of these 12 patients were <50 years of age and therefore diagnostic criteria for probable CAA according to the Boston criteria version 2.0 were not met. Comparable to the results of Charidimou et al. [14] the additional inclusion of non‐haemorrhagic MRI markers showed a higher sensitivity regarding the clinical diagnosis of probable CAA [14, 31]. However, it should be noted that four of these 12 patients were <50 years of age and characteristic neuropathological features were present in the leptomeningeal biopsy in three of them, that is, probable CAA with supporting pathology.

Although the minimum age of onset was lowered in the Boston criteria version 2.0 [14] from ≥55 years in version 1.5 [16] to ≥50 years, the present study shows that a relevant percentage of patients may present with clinical and neuroradiological features of probable CAA at a younger age. These findings suggest the performance of further prospective studies to analyse the impact of lowering the minimum age in the Boston criteria for the diagnosis of CAA. In this context, it is interesting to note that, in spontaneously CAA‐ri [38, 39], the minimum age of inclusion for both possible and probable CAA‐ri is ≥40 years, that is, 10 years younger than in the recent Boston criteria version 2.0 [14].

This CAA subtype along with rapidly progressive cognitive decline is associated with autoantibodies against Aβ‐40 deposits in the vessel walls of cortical and leptomeningeal small sized arteries, arterioles and capillaries [39, 40, 41]. The perivascular and vascular autoimmune‐induced inflammation causes vasogenic oedema and sulcal effusions, that is, amyloid‐related imaging abnormality oedema [39, 42, 43, 44]. Another manifestation, the haemorrhagic type, exhibits cerebral MBs, cortical subarachnoid haemorrhage and cSS [42, 43, 45, 46, 47, 48]. Similar imaging findings occurred in several randomized clinical trials within the investigational use of monoclonal antibodies targeting the less soluble Aβ‐42 in Alzheimer's disease. As a consequence, this suggests that immunotherapy‐related amyloid‐related imaging abnormalities are an iatrogenic version of CAA‐ri due to a far more soluble Aβ‐40 overflow in the vessel wall [3, 49, 50].

An important limitation of the present study is that only 12 out of 40 patients with neurological precursor symptoms underwent MRI assessment prior to the clinical diagnosis of probable CAA according to the Boston criteria version 1.5 [16]. Another limitation is the retrospective design of the study. Although a standardized neurological assessment was carried out at the time of diagnosis of CAA, some of the precursor symptoms recorded were primarily of a purely anamnestic nature without corresponding exclusion diagnostics being available, limiting the validity of this retrospective diagnosis. Moreover, despite accurate differential diagnostic work‐up, various other pathophysiological aetiologies that provoke temporary neurological deficits, for example focal epileptic seizures or ischaemia, might be misdiagnosed as TFNEs, that is, ‘amyloid spells’ [27, 36]. With regard to the latest introduction of non‐haemorrhagic MRI markers [23, 24], the improved sensitivity for the diagnosis of probable CAA could only be evaluated in a small number of patients. However, the present study suggests that MRI, preferably with susceptibility‐sensitive sequences besides T2‐weighted imaging and T2‐FLAIR imaging, should be favoured over initial CT examinations. Although SWI or T2*‐weighted imaging was performed in all patients, SWI is recommended instead of T2*‐weighted imaging in terms of higher detectability for signal loss due to blood breakdown products [51, 52, 53].

Since TFNEs represent stereotypical positive or negative neurological symptoms, differential diagnosis should include focal epileptic seizures, for example sensory or motor Jacksonian seizures, or ischaemia, for example transient ischaemic attacks [19, 21]. Neuroradiological mimics encompass cortical vein thrombosis [19], haemorrhagic transformation of cortical infarcts [19], hypointensity due to mineralization, for example calcifying microangiopathy, Sturge–Weber syndrome, reversible cerebral vasoconstriction syndrome, laminar cortical necrosis, multiple cavernomas and residuals of traumatic brain injury [13, 54, 55, 56, 57], amongst others.

In conclusion, the non‐haemorrhagic MRI markers enhance the sensitivity of diagnosing probable CAA. Nevertheless, further prospective studies are necessary to establish a minimum age for inclusion, currently set at ≥50 years in the Boston criteria version 2.0. As the neurological overture of probable CAA may occur several years before clinical diagnosis, earlier clarification by MRI including haemosensitive sequences, that is, SWI or at least T2*‐weighted imaging, rather than CT should be recommended, especially with regard to possible future availability of causal therapeutic approaches to lower the cerebral amyloid load.

AUTHOR CONTRIBUTIONS

Stefan Weidauer: Conceptualization; writing – original draft; methodology; data curation; investigation; supervision; visualization; software; validation. Mona Tafreshi: Investigation; formal analysis; data curation; project administration; software. Christian Förch: Conceptualization; supervision. Elke Hattingen: Writing – review and editing; formal analysis; supervision. Christophe T. Arendt: Writing – review and editing; formal analysis; supervision. Lucie Friedauer: Conceptualization; methodology; writing – review and editing; project administration; resources; supervision; data curation; investigation; validation; visualization; software.

FUNDING INFORMATION

None.

CONFLICT OF INTEREST STATEMENT

All authors declare that they have no competing interests.

DATA AVAILABILITY STATEMENT

The authors had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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