# Differentiating cerebral amyloid angiopathy from Alzheimer disease using dual amyloid and Tau Positron Emission Tomography

Hsin-Hsi Tsai, Marco Pasi, Chia-Ju Liu, Ya-Chin Tsai, Ruoh-Fang Yen, Ya-Fang Chen, Jiann-Shing Jeng, Li-Kai Tsai, Andreas Charidimou, Jean-Claude Baron

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Hsin-Hsi Tsai, Marco Pasi, Chia-Ju Liu, Ya-Chin Tsai, Ruoh-Fang Yen, et al.. Differentiating cerebral amyloid angiopathy from Alzheimer disease using dual amyloid and Tau Positron Emission Tomography. Journal of Stroke, 2025, 27 (1), pp.65-74. 10.5853/jos.2024.02376. inserm-04927905

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Original Article

# Differentiating Cerebral Amyloid Angiopathy From Alzheimer's Disease Using Dual Amyloid and Tau Positron Emission Tomography

Hsin-Hsi Tsai,¹ Marco Pasi,² Chia-Ju Liu,³ Ya-Chin Tsai,⁴ Ruoh-Fang Yen,³ Ya-Fang Chen,⁵
Jiann-Shing Jeng,¹ Li-Kai Tsai,¹ Andreas Charidimou,⁶ Jean-Claude Baron⁷

¹Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan

²Department of Neurology, University Hospital of Tours, INSERM U1253, Tours, France

³Department of Nuclear Medicine, National Taiwan University Hospital, Taipei, Taiwan

⁴Department of Nuclear Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan

⁵Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan

⁶Department of Neurology, Boston University Medical Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

⁷GHU-Paris Psychiatrie et Neurosciences, Department of Neurology, Inserm U1266, Université Paris Cité, Paris, France

**Background and Purpose** Although amyloid positron emission tomography (PET) might provide a molecular diagnosis for cerebral amyloid angiopathy (CAA), it does not have sufficient specificity for this condition relative to incipient Alzheimer's disease (AD). To identify a regional amyloid uptake pattern specific to CAA, we attempted to reduce this overlap by selecting "pure CAA" (i.e., fulfilling the criteria for probable CAA but without tau PET AD signature) and "pure AD" (i.e., positive amyloid PET and presence of tau PET AD signature, but without lobar hemorrhagic lesions). We hypothesized that occipital tracer uptake relative to the whole cortex (WC) would be higher in patients with pure CAA and may serve as a specific diagnostic marker.

**Methods** Patients who fulfilled these criteria were identified. In addition to the occipital region of interest (ROI), we assessed the frontal and posterior cingulate cortex (PCC) ROIs that are sensitive to AD. Amyloid PET uptake was expressed as the absolute standardized uptake value ratio (SUVR) and ROI/WC ratio. The diagnostic utility of amyloid PET was assessed using the Youden index cutoff.

**Results** Eighteen patients with AD and 42 patients with CAAs of comparable age were eligible. The occipital/WC was significantly higher in CAA than AD (1.02 [0.97-1.06] vs. 0.95 [0.87-1.01], P= 0.001), with an area under curve of 0.762 (95% confidence interval [CI] 0.635-0.889) and a specificity of 72.2% (95% CI 46.5-90.3) at Youden cutoff (0.98). The occipital lobe, frontal lobe, PCC and WC SUVRs were significantly lower in CAA than in AD. The frontal/WC and PCC/WC ratios did not differ significantly between the groups.

**Conclusion** Using stringent patient selection to minimize between-condition overlap, this study demonstrated the specificity of higher relative occipital amyloid uptake in CAA than in AD.

**Keywords** Cerebral amyloid angiopathy; Alzheimer disease; Positron emission tomography

**Correspondence:** Jean-Claude Baron
GHU Paris Psychiatrie et Neurosciences,
Department of Neurology, Inserm U1266,
Université Paris Cité, 102, rue de la Santé,
Paris, 75014, France
Tel: +33-14565-6268
E-mail: jean-claude.baron@inserm.fr
https://orcid.org/0000-0002-5264-2588

**Co-correspondence:** Andreas Charidimou
Department of Neurology, Boston
University Medical Center, Boston
University Chobanian & Avedisian School
of Medicine, 85 East Concord Street,
2nd Floor, 02118, Boston, MA, USA
Tel: +1-617-638-5351
E-mail: andreas.charidimou.09@alumni.ucl.ac.uk
https://orcid.org/0000-0001-5891-337X

Received: June 18, 2024

Revised: December 21, 2024

Accepted: December 23, 2024
Introduction

Sporadic cerebral amyloid angiopathy (CAA) is the main cause
of spontaneous lobar intracerebral hemorrhage (ICH) and is an
important contributor to cognitive decline in the elderly.¹ Ac-
curate diagnosis of CAA has major implications for patient prog-
nosis, management, and therapeutic trials. Positron emission
tomography (PET) imaging with amyloid-binding tracers has po-
tential as a molecular diagnosis of CAA because it detects not
just parenchymal but also cerebrovascular Aβ deposition.² Pre-
vious studies, at the group level, showed significantly higher
tracer retention in CAA compared to non-demented healthy
controls or patients with hypertensive deep ICH, suggesting that
a negative amyloid scan reasonably excludes CAA.³

However, the specificity of high amyloid uptake for CAA has
been questioned, compromising the potential routine applica-
tion of amyloid PET as a rule-in for CAA.⁴ This is thought to re-
flect the wide prevalence of incipient Alzheimer's disease (AD).
Indeed, the finding of positive amyloid PET steeply increases af-
ter age 60, in cognitively normal individuals.⁵ CAA and AD do
have pathological overlap, further complicating matters.²,⁴,⁶,⁷
Apart from global cortical uptake or visual assessment, regional
amyloid tracer uptake relative to the whole cortex (WC) has
been investigated as a potential discriminator between CAA and
AD, focusing on the occipital cortex, which shows the highest
vascular amyloid burden in post-mortem studies.⁸ Accordingly,
higher relative occipital uptake has been reported in CAA as com-
pared to AD, but sensitivity and specificity are considered insuf-
ficient for clinical application.²,³,⁹⁻¹³ Besides, tau PET detects *in vivo*
intracellular abnormal hyperphosphorylated tau,¹⁴ a histopath-
ologic hallmark for AD, and affords around 90% sensitivity and
specificity using an AD regional tau PET uptake "signature."¹⁵,¹⁶

To reassess the value of amyloid PET for differentiating CAA
from AD, we aimed in the present study to compare subsets of
patients with CAA and AD expected to have the lowest possible
chance of overlap. To achieve this, we selected patients fulfilling
the Boston diagnostic criteria for probable CAA¹⁷,¹⁸ without tau
PET AD signature ("pure CAA") and those fulfilling the current
diagnostic criteria for probable AD, including positive amyloid
PET and tau PET AD signature, but without lobar hemorrhagic
lesions on magnetic resonance imaging (MRI) ("pure AD"). Our
main goal was to assess the specificity of relative occipital cor-
tex tracer uptake for differentiating pure CAA from pure AD. Our
primary hypothesis was that this ratio would be significantly
higher in the former. Based on the previously reported lower
global cerebral uptake of amyloid tracers in CAA compared to
AD,³ our secondary hypothesis was that cerebral cortex uptake,
particularly the posterior cingulate cortex (PCC) and frontal lobe

uptake, two regions known to have the highest amyloid uptake
in AD,¹³ will have good sensitivity for differentiating pure AD
from pure CAA.

Methods

Data availability

All data were obtained from the National Taiwan University Hos-
pital (NTUH). Anonymized data not published in this article will
be made available upon request by any qualified investigator.

Patient enrollment

Starting in October 2018, we prospectively enrolled patients
attending the Memory Clinic or the Stroke Clinic of NTUH and
NTUH Bei-Hu Branch who presented with cognitive complaints
or spontaneous lobar ICH and fulfilled the clinical diagnosis of
probable CAA based on the Boston criteria v1.5¹⁷ until May 2022
and the 2.0 criteria thereafter.¹⁸ Patients who fulfilled a diagno-
sis of probable AD dementia based on the diagnostic criteria of
the National Institute on Aging-Alzheimer's Association¹⁹ were
recruited as the comparison group. All patients who agreed to
participate in this study underwent brain MRI, amyloid PET, and
tau PET. Patients with CAA were categorized as CAA-ICH or CAA-
cognitive impairment (CAA-CI) according to their initial pre-
senting symptoms of spontaneous lobar ICH or cognitive com-
plaints with objective cognitive impairment, respectively.

The following demographic characteristics and clinical data
were prospectively collected: age, sex, years of education, and
diagnoses of chronic hypertension, diabetes, or hypercholester-
olemia. At enrollment, cognitive status was assessed in each
patient through a combination of history-taking and objective
cognitive assessment by trained clinical psychologists and in-
cluded the Mini-Mental State Examination (MMSE) and Clinical
Dementia Rating (CDR) scale, a 5-point scale that assesses cog-
nition and functional autonomy in subjects with neurocognitive
disorders.²⁰,²¹

MRI acquisition and analysis

Brain MRI was performed using a 3-Tesla scanner (Siemens Verio, TIM, or mMR; Siemens Medical Solutions, Erlangen, Germany). The imaging protocol included T1-weighted magnetization-prepared rapid gradient-echo imaging (flip angle 9, repetition time/echo time=1,460/2.39 ms, field of view=25.6 cm, and slice thickness=1 mm), T2-weighted imaging (repetition time/echo time=3,530/83 ms, field of view=23 cm, and slice thickness=5 mm), fluid attenuated inversion recovery (FLAIR) (repetition time/echo time=10,000/89 ms, field of view=23 cm, and slice thickness=5 mm), susceptibility-weighted imaging (SWI) (flip
angle 15, repetition time/echo time=28/20 ms, matrix number=221x320, field of view=23 cm, and slice thickness=2 mm), diffusion-weighted imaging, and apparent diffusion coefficient maps, as we previously described.²²

MRI markers were evaluated based on the Standards for Reporting Vascular Changes on Neuroimaging criteria.²³ Briefly, the number of cerebral microbleeds (CMBs) and the presence of cortical superficial siderosis (cSS) were evaluated using axial SWI sequences according to current standards.²⁴,²⁵ CMBs in the lobar regions, deep regions, and cerebellum were counted. Lacunes were evaluated in the supratentorial region and defined as "round or ovoid, subcortical, fluid-filled cavities, from 3 to 15 mm in diameter." White matter hyperintense (WMH) lesion volume was calculated based on FLAIR imaging of the ICH-free hemisphere and multiplied by two, as previously proposed.²⁶ Perivascular spaces (PVS) were evaluated on T2-weighted imaging and defined as sharply delineated structures measuring less than 3 mm following the course of perforating or medullary vessels.²⁷ High-degree PVS was defined as more than 20 visible PVS in the centrum semiovale or in the basal ganglia on the side of the brain with more severe involvement.²⁷

## PET acquisition and analysis

Radiotracers were prepared at the Cyclotron and Radiopharmaceutical Laboratory at NTUH. PET images (Discovery ST; GE Healthcare, Chicago, IL, USA) were acquired over 30 min, starting 40 min after the injection of 10 mCi ¹¹C-Pittsburgh compound B (PiB) or ¹⁸F-T807. As previously described,²² PET data were reconstructed via ordered set expectation maximization and corrected for attenuation.

For probable AD samples, amyloid scan positivity was determined by two nuclear medicine specialists using a previously proposed visual assessment.²⁸ Any discordant results were resolved by consensus.

Using the PMOD software (PNEURO module; PMOD Technologies, Zurich, Switzerland), high-resolution T1-weighted MRI was auto-segmented using Montreal Neurological Institute space/coordinates based on the maximum probability Anatomical Automated Labeling (AAL) atlas. PET data were matched and normalized to the corresponding T1 images. Standardized uptake values (SUV) were extracted from the cerebellar cortex, pons, and cortical ribbon regions of interest (ROIs). As per our primary and secondary hypotheses, for the PiB scans, the ROIs included the occipital cortex, frontal cortex, PCC, and WC. PiB images were semi-quantitatively analyzed and expressed as SUV ratios (SUVRs). We chose the pons as the reference region in preference to the cerebellar cortex, given that CAA could involve the cerebellar cortex, resulting in increased cerebellar PiB up-

take.²⁹,³⁰ We did not apply the centiloid method to quantify the amyloid load in the present study because this method is based on a voxel-of-interest mask that includes all brain regions with high uptake in AD,³¹ which may miss regions that are more sensitive to CAA.

Regarding T807 scans, a meta-temporal ROI was created as an AD signature, which included the entorhinal cortex, amygdala, parahippocampal gyrus, fusiform gyrus, and inferior and middle temporal gyri.³²,³³ A cutoff of SUVR 1.26 (reference: cerebellar cortex) was applied to determine tau PET positivity based on results in previous cohorts using the mean and two standard deviations (SD) of T807 uptake in the meta-temporal ROI from amyloid-negative and cognitively unimpaired participants.²¹

## Statistical analysis

The baseline demographic information and neuroimaging variables of patients with CAA and AD were compared. Discrete variables are presented as counts (%) and continuous variables as mean (±SD) or median (interquartile range), as appropriate, based on their distribution. Categorical variables were analyzed using Fisher's exact test, and continuous variables were analyzed using the Mann-Whitney U-test. For PiB scans, we compared the absolute and relative uptake ratios in the CAA-sensitive (occipital cortex) and AD-sensitive regions (frontal cortex, PCC). For the sensitivity analysis, we compared AD to the pre-specified CAA subgroups: CAA-ICH and CAA-Cl.

We used the Youden index to determine the best cutoff value for the diagnostic utility of amyloid PET findings. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the area under curve (AUC) were determined for these ROIs. We primarily focused on the specificity of the occipital to WC ratio to differentiate CAA from AD. Our secondary focus was on the frontal cortex and PCC to differentiate AD from CAA.

All statistical analyses were performed using SPSS version 25 (IBM Corp., Armonk, NY, USA). Significance was established as a two-tailed less than 0.05.

## Standard protocol approvals, registrations, and patient consent

This study was approved by the Institutional Review Board (201903069RINB) of NTUH and was conducted in accordance with their guidelines. Written informed consent was obtained from all participants or their family members.
# Results

## Patients

A flowchart of the study is shown in Supplementary Figure 1. A sample of 60 patients fulfilled the eligibility criteria for the present study, including 42 patients with pure CAA (mean age, 73.8±6.9 years, 54.8% male; 24 with ICH and 18 with cognitive presentation) and 18 patients with pure AD patients (mean age, 73.4±8.2 years, 38.9% male). All pure CAA cases retrospectively fulfilled the Boston v2.0 criteria for probable CAA.¹⁸ Figure 1 shows images of illustrative patients from the two groups.

Table 1 presents the main demographic, clinical, and MRI data. The two groups had similar age and sex distributions. As expected, patients with AD had significantly lower MMSE scores (18.1±6.5 vs. 24.3±6.5, P=0.001) and higher CDR (1 [0.5-1] vs. 0.5 [0.5-0.5], P<0.001). On MRI, patients with CAA also as expected had more lobar CMBs (11.6±23.8 vs. 0.0±0.0, P=0.003) and a higher prevalence of cSS (26.2% vs. 0.0%, P=0.024), as well as more WMHs (13.6±11.9 mL vs. 4.2±3.4 mL, P<0.001).

## Amyloid PET data

Amyloid PET data for the CAA and AD groups are presented in Table 2. Compared to AD, the occipital/WC ratio was significant-

ly higher in CAA (1.02 [0.97-1.06] vs. 0.95 [0.87-1.01], respectively; P=0.001) (Figure 2A). The occipital cortex SUVR was significantly lower in CAA (0.78 [0.66-1.01] vs. 1.07 [0.81-1.19], respectively; P=0.002) (Figure 2B).

The WC SUVR was significantly higher in AD than in CAA (SUVR=1.15 [0.98-1.26] vs. 0.79 [0.64-0.99]; P<0.001) (Figure 2C). Likewise, the frontal cortex and PCC SUVRs were significantly higher in AD (frontal cortex: 1.16 [0.97-1.30] vs. 0.80 [0.63-0.98], respectively; P<0.001) and PCC: 1.35 [1.11-1.49] vs. 0.94 [0.73-1.19], respectively; P<0.001), but not the corresponding ROI/WC ratios (all P>0.05) (Supplementary Figure 2).

Regarding the pre-specified CAA subgroup analysis, the results were essentially unchanged from the whole sample regarding both the CAA-CI (n=18) and CAA-ICH subgroups (n=24), with slightly stronger P-values for the former (Table 3).

## Diagnostic performance of amyloid PET in the differentiation between CAA and AD

Regarding the occipital/WC ratio, the best cutoff for discriminating CAA from AD based on the Youden index was more than 0.98. This cutoff provides a specificity of 72.2% (95% confidence interval [CI], 46.5-90.3) with AUC of 0.762 (95% CI 0.635-0.889) (Table 4). The diagnostic performance of the occipital/WC ratio

<figure><img src="image_2.png" /><figcaption>**Figure 1.** Representative MRI, amyloid and tau scans in CAA and AD. (A) A patient with probable "pure" CAA with numerous lobar cerebral microbleeds but negative tau PET scan. (B) A patient with "pure" AD with positive amyloid and AD-signature tau PET scans. No lobar hemorrhagic lesions were found on SWI. MRI, magnetic resonance imaging; SWI, susceptibility-weighted imaging; PiB, Pittsburgh compound B; PET, positron emission tomography; CAA, cerebral amyloid angiopathy; AD, Alzheimer's disease.</figcaption></figure>
<table><caption>**Table 1.** Comparison of the demographics between the pure CAA and pure AD groups</caption><thead><tr><th></th><th>Pure CAA (n=42)</th><th>Pure AD (n=18)</th><th>P</th></tr></thead><tbody><tr><td>Male sex</td><td>23 (54.8)</td><td>7 (38.9)</td><td>0.399</td></tr><tr><td>Age (yr)</td><td>73.8±6.9</td><td>73.4±8.2</td><td>0.881</td></tr><tr><td>Years of education (yr)</td><td>11.4±4.9</td><td>10.4±5.2</td><td>0.459</td></tr><tr><td>Hypertension</td><td>30 (71.4)</td><td>7 (38.9)</td><td>0.023*</td></tr><tr><td>Diabetes</td><td>5 (11.9)</td><td>1 (5.6)</td><td>0.658</td></tr><tr><td>Hypercholesterolemia</td><td>10 (23.8)</td><td>4 (22.2)</td><td>&gt;0.999</td></tr><tr><td>eGFR (mL/min)</td><td>75.9±28.0</td><td>77.9±17.0</td><td>0.738</td></tr><tr><td>MMSE</td><td>24.3±6.5</td><td>18.1±6.5</td><td>0.001*</td></tr><tr><td>CDR</td><td>0.5 (0.5–0.5)</td><td>1 (0.5–1)</td><td>&lt;0.001*</td></tr><tr><td>Cognitive impairment/ICH</td><td>18/24</td><td>18/0</td><td>&lt;0.001*</td></tr><tr><td>CMBs</td><td></td><td></td><td></td></tr><tr><td>Lobar CMBs (+)</td><td>38 (90.5)†</td><td>0 (0.0)</td><td>&lt;0.001*</td></tr><tr><td>Number of lobar CMBs</td><td>11.6±23.8</td><td>0.0±0.0</td><td>0.003*</td></tr><tr><td>Deep CMBs (+)</td><td>0 (0.0)</td><td>1 (5.6)</td><td>0.300</td></tr><tr><td>WMH</td><td></td><td></td><td></td></tr><tr><td>Fazekas scale (≥2)</td><td>22 (52.4)</td><td>5 (27.8)</td><td>0.096</td></tr><tr><td>Volume (mL)</td><td>13.6±11.9</td><td>4.2±3.4</td><td>&lt;0.001*</td></tr><tr><td>Lacunes</td><td>13 (31.0)</td><td>2 (11.1)</td><td>0.192</td></tr><tr><td>MRI-visible enlarged perivascular spaces</td><td></td><td></td><td></td></tr><tr><td>Basal ganglia (&gt;20)</td><td>15 (35.7)</td><td>4 (22.2)</td><td>0.375</td></tr><tr><td>Centrum semiovale (&gt;20)</td><td>18 (42.9)</td><td>7 (38.9)</td><td>&gt;0.999</td></tr><tr><td>Cortical superficial siderosis</td><td>11 (26.2)</td><td>0 (0.0)</td><td>0.024*</td></tr></tbody></table>

Values are presented as n (%), mean±standard deviation, or median (interquartile range).

CAA, cerebral amyloid angiopathy; AD, Alzheimer's disease; eGRF, estimated glomerular filtration rate; MMSE, Mini-Mental Status Examination; CDR, Clinical Dementia Rating; ICH, intracerebral hemorrhage; CMBs, cerebral microbleeds; WMH, white matter hyperintensities; MRI, magnetic resonance imaging.

*P<0.05; †4 CAA cases without lobar CMBs: 3 had both 1 lobar ICH and cortical superficial siderosis, and 1 had 2 lobar hematomas.

in the two pre-specified CAA subgroups (CAA-Cl and CAA-ICH) is shown in Supplementary Table 1. We observed similar specificities for differentiating the two presentation subgroups of AD.

The best SUVR cutoffs to differentiate pure AD from pure CAA for WC, frontal cortex, and PCC were >1.00, >1.07, and >1.20, respectively. The diagnostic performance of these ROIs is presented in Table 5. Overall, the SUVR cutoffs provided a sensitivity of 72.2%–77.8%, specificity of 78.6%–83.3%, and AUC of 0.803–0.823.

Discussion

In this study, we used dual amyloid and tau PET to optimize the distinction between "pure" CAA and AD groups, with presumably

<table><caption>**Table 2.** Whole cortex and regional PET amyloid uptake in pure CAA versus pure AD</caption><thead><tr><th></th><th>Pure CAA (n=42)</th><th>Pure AD (n=18)</th><th>P</th></tr></thead><tbody><tr><td colspan="4">Absolute uptake (SUVR)</td></tr><tr><td>Occipital cortex</td><td>0.78 (0.66–1.01)</td><td>1.07 (0.81–1.19)</td><td>0.002*</td></tr><tr><td>Frontal cortex</td><td>0.80 (0.63–0.98)</td><td>1.16 (0.97–1.30)</td><td>&lt;0.001*</td></tr><tr><td>Posterior cingulate</td><td>0.94 (0.73–1.19)</td><td>1.35 (1.11–1.49)</td><td>&lt;0.001*</td></tr><tr><td>Whole cortex</td><td>0.79 (0.64–0.99)</td><td>1.15 (0.98–1.26)</td><td>&lt;0.001*</td></tr><tr><td colspan="4">Regional-to-whole cortex amyloid PET ratio</td></tr><tr><td>Occipital cortex</td><td>1.02 (0.97–1.06)</td><td>0.95 (0.87–1.01)</td><td>0.001*</td></tr><tr><td>Frontal cortex</td><td>0.99 (0.96–1.02)</td><td>1.01 (0.97–1.10)</td><td>0.087</td></tr><tr><td>Posterior cingulate</td><td>1.17 (1.09–1.27)</td><td>1.18 (1.10–1.24)</td><td>0.949</td></tr></tbody></table>

Values are median (interquartile range).

PET, positron emission tomography; CAA, cerebral amyloid angiopathy; AD, Alzheimer's disease; SUVR, standardized uptake value ratio.

*P<0.05.

predominant vascular versus parenchymal Aβ, respectively. Consistent with our hypothesis, we found significantly higher relative PiB uptake in the occipital cortex in the CAA group than in the AD group. Furthermore, the occipital/WC ratio on amyloid PET provided fair diagnostic specificity (72.2%) for differentiating CAA from AD. Additionally, the WC, frontal cortex, and PCC exhibited markedly lower absolute PiB uptake in pure CAA than in pure AD, with SUVR cutoffs providing good diagnostic accuracy. Therefore, this study establishes that amyloid tracer uptake is much lower in absolute terms in CAA than in AD and furthermore shows a predominantly occipital relative distribution in CAA. In turn, these amyloid patterns may have diagnostic utility in clinical practice, particularly for the cognitive subtype where distinction from AD is more difficult and in which the performance of the current Boston criteria is being questioned.³⁴

Previous studies and a pooled meta-analysis suggested higher relative occipital uptake may differentiate CAA from AD, but the effect size was low and was considered insufficient for clinical application.²,³,¹¹,¹² This was attributed to the presence of substantial incipient AD pathology in the CAA cohorts studied.⁵,³⁵ Despite the present attempt to reduce as far as possible the odds of such overlap by means of selecting patients with "pure" CAA and AD, the difference in relative occipital tracer uptake between CAA and AD, although statistically significant, remained small (mean value: 1.02 vs. 0.95, respectively), with individual values exhibiting substantial overlap. This situation may reflect a high topographical correlation between vascular and parenchymal Aβ pathologies.³⁶ A study in an aged cohort with available postmortem data reported that *in vivo* amyloid uptake correlated more closely with parenchymal than vascular Aβ.³⁷ However, amyloid tracers do significantly bind to vascular amyloid uptake *in vivo*, as shown by work in both asymptomatic and less than
<figure><img src="image_3.png" /><figcaption>**Figure 2.** Comparisons of amyloid PET uptake in the occipital cortex and whole cortex. Box plots show (A) relative amyloid uptake in the occipital cortex (occipital/whole cortex ratio), (B) absolute amyloid burden in the occipital cortex, and (C) absolute amyloid burden in the whole cortex. SUVR, standardized uptake value ratio; AD, Alzheimer's disease; CAA, cerebral amyloid angiopathy; PET, positron emission tomography. \*P<0.05.</figcaption></figure>

<table><caption>**Table 3.** Whole cortex and regional amyloid uptake in CAA-CI and CAA-ICH versus AD</caption><thead><tr><th></th><th>AD (n=18)</th><th>CAA-CI (n=18)</th><th>P</th><th>CAA-ICH (n=24)</th><th>P</th></tr></thead><tbody><tr><td colspan="6"><strong>Absolute uptake (SUVR)</strong></td></tr><tr><td>Occipital cortex</td><td>1.07 (0.81-1.19)</td><td>0.80 (0.67-0.90)</td><td>0.004*</td><td>0.75 (0.65-1.03)</td><td>0.010*</td></tr><tr><td>Whole cortex</td><td>1.15 (0.98-1.26)</td><td>0.77 (0.67-0.92)</td><td>&lt;0.001*</td><td>0.87 (0.63-1.06)</td><td>0.002*</td></tr><tr><td>Frontal cortex</td><td>1.16 (0.97-1.30)</td><td>0.74 (0.65-0.99)</td><td>&lt;0.001*</td><td>0.85 (0.63-1.12)</td><td>0.002*</td></tr><tr><td>Posterior cingulate</td><td>1.35 (1.11-1.49)</td><td>0.89 (0.79-1.14)</td><td>&lt;0.001*</td><td>1.01 (0.69-1.31)</td><td>0.006*</td></tr><tr><td colspan="6"><strong>ROI-to-whole cortex amyloid PET ratio</strong></td></tr><tr><td>Occipital cortex</td><td>0.95 (0.87-1.01)</td><td>1.03 (0.98-1.07)</td><td>0.002*</td><td>1.02 (0.96-1.05)</td><td>0.010*</td></tr><tr><td>Frontal cortex</td><td>1.01 (0.97-1.10)</td><td>0.98 (0.95-1.00)</td><td>0.076</td><td>0.99 (0.97-1.03)</td><td>0.204</td></tr><tr><td>Posterior cingulate</td><td>1.18 (1.10-1.24)</td><td>1.15 (1.09-1.27)</td><td>0.924</td><td>1.17 (1.10-1.27)</td><td>0.980</td></tr></tbody></table>

Values are median (interquartile range).

CAA-CI, cerebral amyloid angiopathy-cognitive impairment; CAA-ICH, cerebral amyloid angiopathy intracerebral hemorrhage; AD, Alzheimer's disease; SUVR, standardized uptake value ratio; ROI, region of interest; PET, positron emission tomography.

\*P<0.05.

<table><caption>**Table 4.** Diagnostic performance of occipital/WC ratio on amyloid PET for CAA versus AD</caption><thead><tr><th></th><th>Pure CAA (n=42) vs. pure AD (n=18)</th></tr><tr><th></th><th>Occipital/WC ratio</th></tr></thead><tbody><tr><td>Cutoff</td><td>&gt;0.98</td></tr><tr><td>Sensitivity (%)</td><td>73.8 (58.0-86.1)</td></tr><tr><td>Specificity (%)</td><td>72.2 (46.5-90.3)</td></tr><tr><td>AUC</td><td>0.762 (0.635-0.889)</td></tr><tr><td>PPV (%)</td><td>86.1 (74.2-93.0)</td></tr><tr><td>NPV (%)</td><td>54.2 (39.8-67.9)</td></tr></tbody></table>

WC, whole cortex; PET, positron emission tomography; CAA, cerebral amyloid angiopathy; AD, Alzheimer's disease; AUC, area under curve; PPV, positive predictive value; NPV, negative predictive value.

60-year-old symptomatic patients with hereditary CAA, where almost pure vascular Aβ accumulation is expected.38,39 Using strict selection criteria to reduce CAA and AD overlap as far as possible, our study has demonstrated that the occipital predominant uptake pattern on amyloid PET has value as a specific marker in CAA and may have clinical utility to differentiate CAA from AD. In addition to ¹¹C-PiB PET, fluorine-18-labeled amyloid PET

<table><caption>**Table 5.** Diagnostic performance of SUVR cutoffs on amyloid PET for AD versus CAA</caption><thead><tr><th></th><th colspan="3">Pure AD (n=18) vs. pure CAA (n=42)</th></tr><tr><th></th><th>Frontal SUVR</th><th>PCC SUVR</th><th>Whole cortex SUVR</th></tr></thead><tbody><tr><td>Cutoff</td><td>&gt;1.07</td><td>&gt;1.20</td><td>&gt;1.00</td></tr><tr><td>Sensitivity (%)</td><td>72.2 (46.5-90.3)</td><td>72.2 (46.5-90.3)</td><td>77.8 (52.4-93.6)</td></tr><tr><td>Specificity (%)</td><td>83.3 (68.6-93.0)</td><td>78.6 (63.2-89.7)</td><td>78.6 (63.2-89.7)</td></tr><tr><td>AUC</td><td>0.816<br>(0.692-0.941)</td><td>0.803<br>(0.683-0.923)</td><td>0.823<br>(0.706-0.939)</td></tr><tr><td>PPV (%)</td><td>65.0 (47.1-79.5)</td><td>69.1 (43.1-73.4)</td><td>60.9 (45.3-74.5)</td></tr><tr><td>NPV (%)</td><td>87.5 (76.7-93.7)</td><td>86.8 (75.5-93.4)</td><td>89.2 (77.4-95.2)</td></tr></tbody></table>

SUVR, standardized uptake value ratio; PET, positron emission tomography; AD, Alzheimer's disease; CAA, cerebral amyloid angiopathy; PCC, posterior cingulate cortex; AUC, area under curve; PPV, positive predictive value; NPV, negative predictive value.

ligands such as ¹⁸F-florbetaben and ¹⁸F-flutemetamol have been shown to have similar global and regional signal retention characteristics as ¹¹C-PiB in both healthy controls and patients with AD.40,41 Therefore, we can safely assume that our results have di-
rect applicability to these commercially available PET ligands us-
ing the AAL atlas.

The significantly higher amyloid uptake in AD as compared to CAA in the current study is in line with previous reports both in sporadic³ and Dutch-type CAA³⁹ and indicates a globally higher Aβ load in AD. It might also partly reflect a lower tracer binding affinity for vascular Aβ in CAA,⁴² and PET tracers that specifically target vascular Aβ plaque are being investigated.⁴³⁻⁴⁵ On a clinical standpoint, our data suggest that, over and above the occipital/WC ratio, global amyloid uptake might help in the differentiation of AD from CAA as a two-pronged approach. For instance, in a patient with a cognitive presentation, a high occipital/WC ratio would help rule in CAA, while a concomitantly low amyloid SUVR would help rule out AD. Thus, in our cognitive phenotype cohort, *post hoc* calculations using both markers together showed PPV (rule-in) and NPV (rule-out) of 85.8% and 73%, respectively, for CAA.

Regarding the investigation of a regional uptake pattern spe-
cific to AD, and to avoid the issue of multiple statistical compari-
sons, we assessed two brain regions known to have the highest
amyloid uptake in AD, namely, the PCC and frontal lobe. The re-
sults showed that these two regions have a similar diagnostic
utility for WC uptake. As the precuneus is reported to show ear-
ly involvement and high amyloid uptake in AD,⁴⁶ we conducted
a *post hoc* analysis, which revealed SUVR values very similar to
those of the PCC and frontal lobe (pure CAA vs. pure AD: 0.87
[0.65–1.16] vs. 1.27 [1.01–1.48], respectively).

Potentially "hidden" biases are present in the samples. First, our "pure CAA" sample included patients with probable CAA with either lobar ICH or cognitive presentation, and the latter may have consisted of early AD pathology mixed with CAA,⁴⁷ despite tau PET negativity. However, the results of our secondary pre-specified analysis assessing these two phenotypes separately suggest that amyloid PET could achieve good accuracy for differentiating CAA from AD in patients with cognitive presentation, pointing to a potential role of amyloid PET in the memory clinic setting. Second, as already mentioned, the "pure AD" sample may have included patients with mixed AD/CAA. Third, the population studied was 100% Asian, more precisely of Chinese descent; thus far, no study has specifically investigated amyloid PET in CAA versus AD in this population. However, further studies are required to address this issue.

Our study has several limitations. First, it lacked pathological
data, and our probabilistic categorization of CAA and AD was
based on clinical symptoms and neuroimaging. A prospective
study that includes patients with post-mortem histopathology
is needed to validate our findings, although such a study would
represent a major challenge. Second, our participants represent-

ed a selected population, as only patients who agreed to and
successfully received amyloid and tau PET and 3D MRI were el-
igible, potentially affecting the generalizability of our results.
Third, our sample size was relatively small. However, our study is
the first to combine dual PET modalities for precise phenotyping
of sporadic CAA, with a final sample size comparable to or even
larger than that of most previous similar studies, yet without
tau PET selection.⁴,⁹,¹⁰,¹²,⁴⁸ Lastly, we did not include age-matched
healthy controls in the current study. However, as the primary
focus was to investigate the specificity of amyloid PET for CAA
versus AD rather than its already established sensitivity in de-
tecting CAA, we believe that the lack of normal controls did not
directly impact our findings.

Conclusions

The present study firmly established that higher relative occipital amyloid uptake in CAA than in AD is a robust feature. Accordingly, the occipital/WC ratio provides good specificity for differentiating CAA from AD, even among patients with cognitive dysfunction. We also underline the presence of markedly lower absolute amyloid uptake in CAA than in AD, which might also provide clinical utility over and above or on top of relative occipital uptake. Overall, although based on a highly selected population, our study suggests the potential diagnostic utility of amyloid PET for differentiating CAA from AD, which may have clinical and therapeutic implications.

Supplementary materials

Supplementary materials related to this article can be found
online at https://doi.org/10.5853/jos.2024.02376.

Funding statement

This work was supported by grants from the Taiwan National Science and Technology Council (Tsai HH, 112-2923-B-002-001-MY3 and 113-2628-B-002-013-MY3) and the National Taiwan University Hospital (Liu CJ, 113-N0075 and 113-X0018).

Conflicts of interest

The authors have no financial conflicts of interest.

Author contribution

Study design: HHT, MP, AC, JCB. Methodology: HHT, MP, AC, JCB. Data collection: HHT, CJL, YCT, JSJ, LKT. Investigation: HHT,
CJL, LKT. Statistical analysis: HHT. Writing—original draft: HHT. Writing—review & editing: MP, AC, JCB. Funding acquisition: HHT, CJL. Approval of final manuscript: all authors.

## Acknowledgments

We thank the staff of the Fifth Core Lab, Department of Medical Research, National Taiwan University Hospital for their technical support during the study.

## References

1. Charidimou A, Boulouis G, Gurol ME, Ayata C, Bacskai BJ, Frosch MP, et al. Emerging concepts in sporadic cerebral amyloid angiopathy. *Brain* 2017;140:1829-1850.

2. Farid K, Charidimou A, Baron JC. Amyloid positron emission tomography in sporadic cerebral amyloid angiopathy: a systematic critical update. *Neuroimage Clin* 2017;15:247-263.

3. Charidimou A, Farid K, Tsai HH, Tsai LK, Yen RF, Baron JC. Amyloid-PET burden and regional distribution in cerebral amyloid angiopathy: a systematic review and meta-analysis of biomarker performance. *J Neurol Neurosurg Psychiatry* 2018;89:410-417.

4. Baron JC, Farid K, Dolan E, Turc G, Marrapu ST, O'Brien E, et al. Diagnostic utility of amyloid PET in cerebral amyloid angiopathy-related symptomatic intracerebral hemorrhage. *J Cereb Blood Flow Metab* 2014;34:753-758.

5. Roberts RO, Aakre JA, Kremers WK, Vassilaki M, Knopman DS, Mielke MM, et al. Prevalence and outcomes of amyloid positivity among persons without dementia in a longitudinal, population-based setting. *JAMA Neurol* 2018;75:970-979.

6. Charidimou A, Farid K, Baron JC. Amyloid-PET in sporadic cerebral amyloid angiopathy: a diagnostic accuracy meta-analysis. *Neurology* 2017;89:1490-1498.

7. Greenberg SM, Bacskai BJ, Hernandez-Guillamon M, Pruzin J, Sperling R, van Veluw SJ. Cerebral amyloid angiopathy and Alzheimer disease - one peptide, two pathways. *Nat Rev Neurol* 2020;16:30-42.

8. van Veluw SJ, Arfanakis K, Schneider JA. Neuropathology of vascular brain health: insights from ex vivo magnetic resonance imaging-histopathology studies in cerebral small vessel disease. *Stroke* 2022;53:404-415.

9. Johnson KA, Gregas M, Becker JA, Kinnecom C, Salat DH, Moran EK, et al. Imaging of amyloid burden and distribution in cerebral amyloid angiopathy. *Ann Neurol* 2007;62:229-234.

10. Chang Y, Liu J, Wang L, Li X, Wang Z, Lin M, et al. Diagnostic utility of integrated 11C-Pittsburgh compound B positron emission tomography/magnetic resonance for cerebral amyloid angiopathy: a pilot study. *Front Aging Neurosci* 2021;13:721780.

11. Jang H, Jang YK, Kim HJ, Werring DJ, Lee JS, Choe YS, et al. Clinical significance of amyloid β positivity in patients with probable cerebral amyloid angiopathy markers. *Eur J Nucl Med Mol Imaging* 2019;46:1287-1298.

12. Planton M, Saint-Aubert L, Raposo N, Payoux P, Salabert AS, Albucher JF, et al. Florbetapir regional distribution in cerebral amyloid angiopathy and Alzheimer's disease: a PET study. *J Alzheimers Dis* 2020;73:1607-1614.

13. Chapleau M, Iaccarino L, Soleimani-Meigooni D, Rabinovici GD. The role of amyloid PET in imaging neurodegenerative disorders: a review. *J Nucl Med* 2022;63(Suppl 1):13S-19S.

14. Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D, et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. *Ann Neurol* 2016;79:110-119.

15. Medeiros R, Baglietto-Vargas D, LaFerla FM. The role of tau in Alzheimer's disease and related disorders. *CNS Neurosci Ther* 2011;17:514-524.

16. Ossenkoppele R, Rabinovici GD, Smith R, Cho H, Schöll M, Strandberg O, et al. Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. *JAMA* 2018;320:1151-1162.

17. Linn J, Halpin A, Demaerel P, Ruhland J, Giese AD, Dichgans M, et al. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. *Neurology* 2010;74:1346-1350.

18. Charidimou A, Boulouis G, Frosch MP, Baron JC, Pasi M, Albucher JF, et al. The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI-neuropathology diagnostic accuracy study. *Lancet Neurol* 2022;21:714-725.

19. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. *Alzheimers Dement* 2011;7:263-269.

20. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. *Br J Psychiatry* 1982;140:566-572.

21. Dauphinot V, Calvi S, Moutet C, Xie J, Dautricourt S, Batsavanis A, et al. Reliability of the assessment of the clinical dementia rating scale from the analysis of medical records in comparison with the reference method. *Alzheimers Res Ther* 2024;16:198.

22. Tsai HH, Chen YF, Yen RF, Lo YL, Yang KC, Jeng JS, et al. Plasma soluble TREM2 is associated with white matter lesions in
dependent of amyloid and tau. *Brain* 2021;144:3371-3380.

23. Duering M, Biessels GJ, Brodtmann A, Chen C, Cordonnier C, de Leeuw FE, et al. Neuroimaging standards for research into small vessel disease-advances since 2013. *Lancet Neurol* 2023; 22:602-618.

24. Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, et al. Cerebral microbleeds: a guide to detection and interpretation. *Lancet Neurol* 2009;8: 165-174.

25. Charidimou A, Boulouis G, Roongpiboonsopit D, Auriel E, Pasi M, Haley K, et al. Cortical superficial siderosis multifocality in cerebral amyloid angiopathy: a prospective study. *Neurol- ogy* 2017;89:2128-2135.

26. Tsai HH, Pasi M, Tsai LK, Huang CC, Chen YF, Lee BC, et al. Centrum semiovale perivascular space and amyloid deposi- tion in spontaneous intracerebral hemorrhage. *Stroke* 2021;52: 2356-2362.

27. Charidimou A, Boulouis G, Pasi M, Auriel E, van Etten ES, Hal- ey K, et al. MRI-visible perivascular spaces in cerebral amyloid angiopathy and hypertensive arteriopathy. *Neurology* 2017; 88:1157-1164.

28. Ng S, Villemagne VL, Berlangieri S, Lee ST, Cherk M, Gong SJ, et al. Visual assessment versus quantitative assessment of 11C-PIB PET and 18F-FDG PET for detection of Alzheimer's disease. *J Nucl Med* 2007;48:547-552.

29. Pasi M, Pongpitakmetha T, Charidimou A, Singh SD, Tsai HH, Xiong L, et al. Cerebellar microbleed distribution patterns and cerebral amyloid angiopathy. *Stroke* 2019;50:1727-1733.

30. Tsai HH, Pasi M, Tsai LK, Chen YF, Chen YW, Tang SC, et al. Superficial cerebellar microbleeds and cerebral amyloid an- giopathy: a magnetic resonance imaging/positron emission tomography study. *Stroke* 2020;51:202-208.

31. Klunk WE, Koeppe RA, Price JC, Benzinger TL, Devous MD Sr, Jagust WJ, et al. The centiloid project: standardizing quanti- tative amyloid plaque estimation by PET. *Alzheimers Dement* 2015;11:1-15.e4.

32. Strikwerda-Brown C, Hobbs DA, Gonneaud J, St-Onge F, Bi- nette AP, Ozlen H, et al. Association of elevated amyloid and tau positron emission tomography signal with near-term de- velopment of Alzheimer disease symptoms in older adults without cognitive impairment. *JAMA Neurol* 2022;79:975-985.

33. Groot C, Villeneuve S, Smith R, Hansson O, Ossenkoppele R. Tau PET imaging in neurodegenerative disorders. *J Nucl Med* 2022;63(Suppl 1):20S-26S.

34. Switzer AR, Charidimou A, McCarter S, Vemuri P, Nguyen AT, Przybelski SA, et al. Boston criteria v2.0 for cerebral amyloid angiopathy without hemorrhage: an MRI-neuropathologic validation study. *Neurology* 2024;102:e209386.

35. Tsai HH, Liu CJ, Lee BC, Chen YF, Yen RF, Jeng JS, et al. Cerebral tau pathology in cerebral amyloid angiopathy. *Brain Commun* 2024;6:fcae086.

36. Thal DR, Ronisz A, Tousseyn T, Rijal Upadhaya A, Balakrishnan K, Vandenberghe R, et al. Different aspects of Alzheimer's disease-related amyloid β-peptide pathology and their rela- tionship to amyloid positron emission tomography imaging and dementia. *Acta Neuropathol Commun* 2019;7:178.

37. McCarter SJ, Lesnick TG, Lowe V, Mielke MM, Constantopoulos E, Rabinstein AA, et al. Cerebral amyloid angiopathy pa- thology and its association with amyloid-β PET signal. *Neurology* 2021;97:e1799-e1808.

38. Greenberg SM, Grabowski T, Gurol ME, Skehan ME, Nandigam RN, Becker JA, et al. Detection of isolated cerebrovascular be- ta-amyloid with Pittsburgh compound B. *Ann Neurol* 2008; 64:587-591.

39. Schultz AP, Kloet RW, Sohrabi HR, van der Weerd L, van Rooden S, Wermer MJH, et al. Amyloid imaging of dutch-type hered- itary cerebral amyloid angiopathy carriers. *Ann Neurol* 2019; 86:616-625.

40. Mountz JM, Laymon CM, Cohen AD, Zhang Z, Price JC, Boud- har S, et al. Comparison of qualitative and quantitative imag- ing characteristics of [11C]PiB and [18F]flutemetamol in nor- mal control and Alzheimer's subjects. *Neuroimage Clin* 2015; 9:592-598.

41. Villemagne VL, Mulligan RS, Pejoska S, Ong K, Jones G, O'Keefe G, et al. Comparison of 11C-PiB and 18F-florbetaben for Aβ imaging in ageing and Alzheimer's disease. *Eur J Nucl Med Mol Imaging* 2012;39:983-989.

42. Lockhart A, Lamb JR, Osredkar T, Sue LI, Joyce JN, Ye L, et al. PIB is a non-specific imaging marker of amyloid-beta (Aβ) peptide-related cerebral amyloidosis. *Brain* 2007;130(Pt 10): 2607-2615.

43. Abrahamson EE, Stehouwer JS, Vazquez AL, Huang GF, Mason NS, Lopresti BJ, et al. Development of a PET radioligand selec- tive for cerebral amyloid angiopathy. *Nucl Med Biol* 2021;92: 85-96.

44. Zha Z, Song J, Choi SR, Wu Z, Ploessl K, Smith M, et al. (68) Ga-bivalent polypegylated styrylpyridine conjugates for im- aging Aβ plaques in cerebral amyloid angiopathy. *Bioconjug Chem* 2016;27:1314-1323.

45. Zhang Q, Zhao X, Lei P, Kung HF, Yang Z, Zhu L, et al. Evalu- ating [68Ga]Ga-p14-032 as a novel PET tracer for diagnosis cerebral amyloid angiopathy. *Front Neurol* 2021;12:702185.

46. Villeneuve S, Rabinovici GD, Cohn-Sheehy BI, Madison C, Ayakta N, Ghosh PM, et al. Existing Pittsburgh compound-B positron emission tomography thresholds are too high: sta- tistical and pathological evaluation. *Brain* 2015;138(Pt 7):
2020-2033.

47. Schoemaker D, Charidimou A, Zanon Zotin MC, Raposo N, Johnson KA, Sanchez JS, et al. Association of memory impairment with concomitant tau pathology in patients with cerebral amyloid angiopathy. *Neurology* 2021;96:e1975-e1986.

48. Ly JV, Donnan GA, Villemagne VL, Zavala JA, Ma H, O'Keefe G, et al. 11C-PIB binding is increased in patients with cerebral amyloid angiopathy-related hemorrhage. *Neurology* 2010;74: 487-493.
<table><caption>**Supplementary Table 1.** Diagnostic performance of amyloid PET for CAA subgroups versus AD</caption><thead><tr><th rowspan="2"></th><th>Pure CAA-Cl (n=18) vs. pure AD (n=18)</th><th>Pure CAA-ICH (n=24) vs. pure AD (n=18)</th></tr><tr><th>Occipital/WC ratio</th><th>Occipital/WC ratio</th></tr></thead><tbody><tr><td>Cutoff SUVR</td><td>&gt;1.01</td><td>&gt;1.00</td></tr><tr><td>Sensitivity (%)</td><td>66.7 (41.0–86.7)</td><td>62.5 (40.6–81.2)</td></tr><tr><td>Specificity (%)</td><td>83.3 (58.6–96.4)</td><td>83.3 (58.6–96.4)</td></tr><tr><td>AUC</td><td>0.762 (0.635–0.889)</td><td>0.736 (0.584–0.888)</td></tr><tr><td>PPV (%)</td><td>80.0 (57.5–92.2)</td><td>75.0 (57.2–87.1)</td></tr><tr><td>NPV (%)</td><td>71.4 (55.8–87.9)</td><td>59.1 (44.5–72.3)</td></tr></tbody></table>

PET, positron emission tomography; CAA, cerebral amyloid angiopathy; AD, Alzheimer's disease; CAA-Cl, cerebral amyloid angiopathy-cognitive impairment; CAA-ICH, cerebral amyloid angiopathy intracerebral hemorrhage; WC, whole cortex; SUVR, standardized uptake value ratio; AUC, area under curve; PPV, positive predictive value; NPV, negative predictive value.

<figure><img src="image_4.png" /><figcaption>**Supplementary Figure 1.** Flowchart of patient enrolment. AD, Alzheimer's disease; CAA, cerebral amyloid angiopathy; CMBs, cerebral microbleeds.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**Supplementary Figure 2.** Comparisons of amyloid PET uptake in the frontal cortex and PCC. Box plots showing absolute amyloid burden in (A) frontal cortex, (B) PCC, and relative amyloid burden (ROI/whole cortex ratio) in (C) frontal cortex, (D) PCC. SUV/R, standardized uptake value ratio; AD, Alzheimer's disease; CAA, cerebral amyloid angiopathy; PCC, posterior cingulate cortex; PET, positron emission tomography; ROI, region of interest. \*P<0.05.</figcaption></figure>