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Abstract

Background

Carotid occlusive disease is a risk factor for cognitive decline. A possible underlying etiology is that hemodynamic impairment results in decreased cerebral perfusion, exacerbated amyloid-β accumulation (Aβ) and poorer cognitive performance.

Objective

We aimed to determine whether patients with unilateral internal carotid artery (ICA) occlusion have less cerebral perfusion and more Aβ in the ipsilateral than in the contralateral hemisphere, and whether perfusion and Aβ are associated with cognitive functioning.

Methods

We included 20 patients (age 67.2 ± 7.0 years, 8 females, MMSE 29 [27–29]) with unilateral ICA occlusion, which underwent neuropsychological assessment and dynamic ¹⁸F-Florbetaben positron emission tomography (PET). Global and regional relative perfusion (R₁) and binding potential (BP_ND) were obtained from the PET-images using a simplified reference tissue model. We performed Wilcoxon signed-rank tests to examine differences between hemispheres within subjects and linear regression to investigate associations with cognitive functioning.

Results

Median global R₁ was 0.911 (0.883–0.950) and global BP_ND was 0.172 (0.129–0.187). R₁ was lower in the hemisphere ipsilateral to the ICA occlusion than in the contralateral hemisphere (0.899 [0.876–0.921] versus 0.935 [0.889–0.970]). BP_ND did not differ significantly between hemispheres (ipsilateral 0.172 [0.124–0.181] versus contralateral 0.168 [0.137–0.191]). Neither cerebral perfusion nor Aβ burden were associated with cognitive functioning.

Conclusions

Patients with unilateral ICA occlusion did not have more Aβ in the ipsilateral hemisphere than in the contralateral hemisphere despite ipsilateral hypoperfusion. Perfusion and Aβ were unrelated to cognitive functioning. This indicates that cognitive impairment in patients with ICA occlusion is not due to exacerbated Aβ accumulation.

Keywords

Alzheimer's disease amyloid-β carotid artery diseases cerebral perfusion dementia positron emission tomography

Introduction

Carotid occlusive disease (COD) is a risk factor for cognitive decline.¹ One potential etiology is impaired cerebral hemodynamics. In patients with COD, reduction in cerebral perfusion is initially countered by vasodilation.^2,3 With increasing hemodynamic compromise, when this compensation mechanism is exhausted, actual cerebral perfusion drops and oxygen extraction fraction increases.^2,3 Patients with a unilateral internal carotid artery (ICA) occlusion provide the rare opportunity to study hemodynamic impairment in vivo within patients, in which the hemisphere ipsilateral to the ICA occlusion is expected to be more severely impacted than the contralateral hemisphere. Some previous studies have indeed found a lower cerebral perfusion in the ipsilateral hemisphere.^4–7

An important outstanding question is whether the reduced cerebral perfusion results in exacerbated deposition of amyloid-β (Aβ), as this could provide a potential treatment target for cognitive impairment in COD.⁸ Earlier studies in patients with unilateral ICA stenosis or occlusion did not report a higher cerebral Aβ burden in the ipsilateral hemisphere than the contralateral hemisphere.^7,9–13 However, patient numbers in these studies were small, and only one small study investigated both cerebral perfusion and Aβ burden in the same cohort.⁷ Furthermore, the positron emission tomography (PET) scans were mostly static, which might underestimate the Aβ burden.

Using dynamic PET instead of static PET could overcome those issues. Dynamic PET can be used for quantitative assessment of both cerebral perfusion and cerebral Aβ burden, allowing to estimate both brain pathologies at the same time. Moreover, dynamic PET enables full quantification of the Aβ load by correcting for individual differences in cerebral perfusion.¹⁴ These individual differences in cerebral perfusion may result in differences in radiotracer delivery to and clearance from the brain, which can result in spurious results for estimation of Aβ binding, when using semi-quantitative measures like the standardized uptake value ratio.¹⁴ This correction is especially relevant in patients with ICA occlusion with a potentially reduced cerebral perfusion.

In this study, we intended to investigate the effects of hemodynamic impairment in a specifically selected group of patients with a unilateral, complete occlusion of the ICA. We aimed to determine with dynamic PET if these patients have less perfusion, accompanied by more Aβ, in the hemisphere ipsilateral to the occlusion than in the contralateral hemisphere. Additionally, we examined whether the global cerebral perfusion and Aβ burden are associated with cognitive functioning.

Methods

Study population

We conducted a prospective observational study in the University Medical Center Utrecht, The Netherlands, between 2021 and 2023, as a part of the Heart-Brain Connection Study.¹⁵ For the current study, new data was acquired. The main inclusion criterion of this new study was a unilateral occlusion of the ICA visible on magnetic resonance angiography (N = 8), computed tomography angiography (N = 10) or digital subtraction angiography (N = 2). Additionally, patients had to be 55 years or older and be able to undergo the PET-scan procedures. They had to have a Mini-Mental State Examination (MMSE) score of 18 or higher, thereby allowing participants with cognitive impairment to enter the study, but excluding participants that are too cognitively impaired to give informed consent or to adequately follow instructions during the dynamic PET-scan. We strived for as little stenosis as possible in the contralateral ICA and middle cerebral artery (MCA; contralateral ICA or MCA stenosis of less than 50% in all patients). Patients were also excluded if they had a history of vascular reconstructive surgery in the neck or brain, had structural abnormalities on brain magnetic resonance imaging (MRI) that were likely to interfere with the clinical presentation or interpretation of the PET-scan, participated in an experimental study with an Aβ targeting agent or had a history of another neurological or major psychiatric disorder.

We included 21 patients and scheduled them for a structured interview, brain MRI-scan and dynamic Aβ PET-scan within a period of two months. One patient dropped out of the study prematurely, because the PET-scan had to be rescheduled last-minute due to a failed production of the radiotracer. This patient was excluded from the present analyses, leaving us with the intended sample size of 20 patients. Based on the repeated measures design comparing the ipsilateral to the contralateral hemisphere, a presumed alpha of 0.05 and a power of 0.80, an effect size of dz 0.58 can be demonstrated in this sample of 20 participants.

Ethics statement

The study has been approved by the institutional review board of the University Medical Center Utrecht, The Netherlands, and was conducted in accordance with the Declaration of Helsinki. All subjects signed an informed consent form.

Clinical information

Demographic information, medical history and medication use were recorded during a structured interview. Hyperlipidemia was defined as a self-reported history of hyperlipidemia. Diabetes mellitus was defined as a self-reported history of diabetes mellitus or the use of anti-diabetic medication. History of transient ischemic attack or ischemic stroke was based on a self-reported history of those events in the hemisphere ipsilateral to the occlusion. Known duration of the occlusion was defined as the time from the first detection of the occlusion on any imaging method until the participation in the study. We measured height, weight and resting blood pressure.

Neuropsychological assessment

Participants underwent a standardized neuropsychological assessment with tests for global cognitive functioning and four major cognitive domains, namely memory, language, attention and psychomotor speed and executive functioning.¹⁵ We calculated z-scores from the raw test scores of the individual tests with the healthy, control participants from the Heart-Brain Connection Study as the reference group.¹⁵ The z-score for each cognitive domain (secondary outcome) was then calculated as the average z-scores in that domain. Global cognitive functioning (main outcome) was calculated as an average z-score across the four cognitive domains. A cognitive domain was rated as impaired if the z-score was ≤ −1.5.

We used the MMSE and Montreal Cognitive Assessment (MoCA) as cognitive screening tests.

Magnetic resonance imaging scan acquisition and processing

We acquired a 3 T brain MRI on a Philips Ingenia scanner (Philips, Best, The Netherlands), which encompassed T1-weighted images (resolution 1 × 1 × 1 mm³, magnetization-prepared rapid acquisition gradient echo, repetition time 8.2 ms, echo time 4.5 ms, shot interval 3000 ms, flip angle 8°, inversion delay 990 ms) and fluid-attenuated inversion recovery images (FLAIR; resolution 1.11 × 1.11 × 1.11 mm³, repetition time 4800 ms, echo time 313 ms, inversion time 1650 ms, turbo spin-echo factor 182).¹⁵

We applied a brain tissue and white matter hyperintensity (WMH) segmentation method to the T1-weighted images and FLAIR images (Quantib BV, Rotterdam, The Netherlands).¹⁶ First, the intracranial volume was determined. We then manually segmented infarcts and measured the total brain volume and WMH volume excluding these infarcts regions. We calculated the whole brain parenchymal fraction as the total brain volume divided by the intracranial volume. We expressed WMH volume as the percentage of the intracranial volume.

Positron emission tomography scan acquisition and processing

Patients underwent a dynamic positron emission tomography-computed tomography (PET-CT) scan on a clinical PET-CT scanner (Siemens Biograph 40 mCT, Siemens, Munich, Germany) with ¹⁸F-Florbetaben as the radiotracer (NeuraCeq^®; Curium, Paris, France), which has highly selective binding for Aβ. We used a 60-min dual-time-window acquisition protocol.¹⁷ A low dose CT-scan (effective 120 kV, 30 mAs) was first acquired for attenuation correction. Patients then received an intravenous bolus of 273 ± 61 MBq ¹⁸F-Florbetaben, after which the first PET-scanning session of 30 min (6 × 5, 3 × 10, 4 × 60, 2 × 150, 2 × 300 and 1 × 600 s) was immediately initiated. This was followed by a 60-min break, a second low dose CT-scan (effective 120 kV, 30 mAs) for attenuation correction and finally the second PET-scanning session of 20 min (4 × 5 min). PET-images were reconstructed with the TrueX algorithm, an iterative reconstruction with 4 iterations and 21 subsets, including time-of-flight, point spread function modeling and a 5 mm Gaussian filter.

PET-scans were analyzed in PMOD 4.205 with the PNEURO add-on (PMOD Technologies Ltd, Zürich, Switzerland). Both PET-scans were combined into a single multi-frame PET-image, with all time-frames co-registered. T1-weighted images were then also co-registered to the combined PET-image. We measured the cortical relative perfusion (R₁) and binding potential relative to the non-displaceable compartment (BP_ND) using a simplified reference tissue model with the entire cerebellar gray matter as the reference region.^18–20 The transformation from MNI atlas space to the T1-weighted images was automatically calculated in PMOD, after which the Hammers N30R83.^21,22 and watershed atlases^23,24 were deformed to match the image. The infarct regions assessed at the MRI-scans were re-used for the PET-scans. For the PET-analyses only, we mirrored the infarct regions onto the contralateral hemisphere, as comparing a hemisphere with an infarct to a hemisphere without an infarct would provide unreliable results. There is namely no Aβ accumulation in the infarct regions, but it is possible for Aβ to accumulate in the contralateral cortex without infarct. By excluding the infarct regions on both sides, the volume of tissue at risk for Aβ accumulation is equal again, thereby reducing the risk of false differences in Aβ burden between the hemispheres. Both the mean R₁ and the mean BP_ND for the Hammers N30R83 atlas regions and watershed areas were determined excluding these infarcts regions on both sides.

Global R₁ and BP_ND covered the entire cerebral cortex and were measured for characterization of our cohort and for assessing associations with cognitive functioning. We checked for crossed cerebellar diaschisis by comparing the R₁ of the ipsilateral cerebellar cortex to the R₁ of the contralateral cerebellar cortex. Since the entire cerebellar gray matter is selected as reference region, any interhemispheric differences in the cerebellum are preserved. We examined the R₁ and BP_ND in the entire hemisphere as main outcome for the within patient analyses. In addition to the hemispheric R₁ and BP_ND, we assessed 1) the individual lobes (i.e., frontal, temporal, parietal and occipital lobe), 2) the regions that are the first to become amyloid-positive in Alzheimer's disease (i.e., anterior cingulate, posterior cingulate, paracentral gyrus, lateral orbitofrontal cortex, medial orbitofrontal cortex, precuneus and insula)²⁵ and 3) the regions that are most at risk for cerebral hypoperfusion (i.e., the watershed areas between the flow territory of the anterior cerebral artery and MCA as well as between the MCA and posterior cerebral artery)^23,24 as secondary outcomes for the within patient analyses. Next, a R₁-delta and BP_ND-delta were calculated as, respectively, the R₁ or BP_ND of the ipsilateral hemisphere minus the R₁ or BP_ND of the contralateral hemisphere. Patients with a R₁-delta of less than 0 were classified as having ipsilateral hypoperfusion. Patients with a BP_ND-delta of more than 0 were defined to have an increased ipsilateral cerebral Aβ burden.

Apart from the quantitative analyses, an experienced nuclear medicine physician visually (NT) rated the PET-images according to the manufacturer's instructions to determine amyloid positivity.

Statistical analyses

Data distribution was assessed by visual inspection of histograms and Q-Q plots. WMH volumes were log transformed to achieve a normal data distribution. No other variables were transformed.

We first evaluated the differences in R₁ between the cerebellum, hemispheres, lobes, early Alzheimer's regions and watershed areas ipsilateral and contralateral to the ICA occlusion with Wilcoxon signed-rank tests. We then determined the differences in BP_ND in the same regions, except for the cerebellum. As sensitivity analyses, we repeated the analyses for BP_ND restricting the analyses to patients with ipsilateral hypoperfusion.

Next, we assessed the association between cerebral perfusion and cerebral Aβ burden, both within hemispheres and between hemispheres with the R₁-delta and BP_ND-delta. We calculated both crude coefficients and coefficients adjusted for age and sex with multiple linear regression. Additional adjustment for covariates such as vascular risk factors and COD characteristics was not possible given the limited sample size of our cohort. We also assessed whether age, sex, known duration of the occlusion, WMH volume and global R₁ would affect the interhemispheric differences in R₁ by assessing their association with the R₁-delta, again calculating crude coefficients as well as age- and sex-adjusted coefficients. We then determined similar associations for the BP_ND-delta.

Finally, we determined the associations between global R₁ or BP_ND, global cognitive functioning and the specific cognitive domains. For these analyses specifically, global R₁ or BP_ND were standardized to facilitate comparison. We used multiple linear regression to calculate both crude coefficients and coefficients adjusted for age, sex and years of education. Additional adjustment for other potentially relevant covariates was not possible due to the limited sample size. We performed several sensitivity analyses: 1) repeating the analyses for BP_ND without the only visually amyloid-positive participant, 2) determining associations with lobar instead of global R₁ or BP_ND and 3) testing for possible interactions between age, sex, R₁ and BP_ND by adding an interaction term to the models.

We applied false discovery rate (FDR) correction to correct for multiple testing. Statistical significance was defined as a p-value < 0.05 after FDR-correction. Analyses were performed in R version 4.0.3.

Results

Patients had a mean age of 67.2 ± 7.0 years and 8 (40%) were female (Table 1). Eight patients had an occlusion of the left ICA and 12 of the right ICA. The median known duration of the occlusion was 7.1 years (interquartile range (IQR) 0.9–12.4). Median scores for MMSE and MoCA were 29 and 26, respectively.

Table 1.

Demographics of the patients.

Characteristics	Entire cohort N = 20
Female	8 (40)
Age, y	67.2 ± 7.0
Education level of Verhage ≥ 5*	16 (80)
Vascular risk factors
Current smoking	5 (25)
Systolic blood pressure, mmHg	147.5 ± 20.9
Diastolic blood pressure, mmHg	79.1 ± 15.1
Hyperlipidemia	13 (65)
Diabetes mellitus	5 (25)
Body mass index, kg/m²	28.5 ± 3.2
History of TIA or ischemic stroke ipsilateral to ICA occlusion	18 (90)
Medication
Anti-hypertensive medication	16 (80)
Lipid lowering medication	16 (80)
COD characteristics
Left sided occlusion	8 (40)
Known duration of the occlusion, y	7.1 (0.9–12.4)
Contralateral ICA stenosis
- 0–30%	16 (80)
- 31–50%	4 (20)
Cognitive functioning
MMSE, score	29 (27–29)
MoCA, score	26 (23–27)
Global cognitive functioning, z-score	−0.29 (−0.99 – −0.11)
Memory domain, z-score	−0.07 (−0.91–0.48)
Language domain, z-score	−0.53 (−0.86 – −0.28)
Attention-psychomotor speed domain, z-score	−0.73 (−1.98 – −0.23)
Executive functioning domain, z-score	−0.24 (−0.62–0.13)
Amyloid-β burden
Global BP_ND	0.172 (0.129–0.187)
Atrophy and cerebral vascular disease burden
Brain parenchymal fraction, ratio	0.78 ± 0.03
Global cerebral perfusion, R₁	0.911 (0.883–0.950)
WMH volume, % of intracranial volume	0.09 (0.04–0.26)

Data are presented as number (percentage) for categorical variables and mean ± standard deviation or median (interquartile range) for continuous variables.

BP_ND: binding potential; COD: carotid occlusive disease; ICA: internal carotid artery; MMSE: Mini-Mental State Examination; MoCA: Montreal Cognitive Assessment, R₁: relative perfusion; TIA: transient ischemic attack; WMH: white matter hyperintensities.

Cerebral perfusion

The median global R₁ was 0.911 (IQR 0.883–0.950). Cerebellar R₁ was similar on the ipsilateral and contralateral side (R₁ ipsilateral 1.004 [IQR 0.996–1.012] versus contralateral 0.997 [IQR 0.988–1.005], p = 0.430). Seventeen of 20 patients had a R₁-delta of less than 0, i.e., ipsilateral hypoperfusion (median R₁-delta of −0.024 [IQR −0.045 – −0.009]). The remaining three patients had a R₁-delta of 0.007, 0.009 and 0.150.

When comparing hemispheres within patients, R₁ was lower in the hemisphere ipsilateral to the ICA occlusion than in the contralateral hemisphere (Table 2; R₁ ipsilateral 0.899 [IQR 0.876–0.921] versus contralateral 0.935 [IQR 0.889–0.970]). In the regional analyses, R₁ was lower on the side ipsilateral to the occlusion than on the contralateral side in the frontal lobe, the parietal lobe, the paracentral gyrus, the precuneus and the insula (Table 2). There were no significant differences between hemispheres in the remaining regions.

Table 2.

Hemispheric differences in cerebral perfusion and cerebral amyloid-β burden.

	Side ipsilateral to the ICA occlusion N = 20	Side contralateral to the ICA occlusion N = 20	p
Cerebral perfusion, R₁
Entire hemisphere	0.899 (0.876–0.921)	0.935 (0.889–0.970)	0.002*
Lobe
Frontal lobe	0.924 (0.885–0.975)	0.955 (0.920–1.002)	0.002*
Temporal lobe	0.830 (0.806–0.853)	0.853 (0.825–0.890)	0.070
Parietal lobe	0.896 (0.854–0.933)	0.938 (0.875–0.971)	0.002*
Occipital lobe	0.964 (0.928–1.014)	0.975 (0.934–1.023)	0.033
Alzheimer's region
Anterior cingulate	0.902 (0.858–0.955)	0.942 (0.887–0.968)	0.076
Posterior cingulate	1.094 (1.043–1.155)	1.102 (1.025–1.162)	0.388
Paracentral gyrus	0.866 (0.798–0.915)	0.907 (0.868–0.947)	0.001*
Lateral orbitofrontal cortex	0.985 (0.953–1.019)	0.995 (0.955–1.033)	0.648
Medial orbitofrontal cortex	0.935 (0.897–0.959)	0.939 (0.902–0.980)	0.452
Precuneus	0.907 (0.869–0.968)	0.958 (0.884–1.003)	0.011*
Insula	0.872 (0.841–0.895)	0.914 (0.878–0.951)	0.002*
Watershed areas	0.806 (0.738–0.847)	0.764 (0.710–0.844)	0.165
Cerebral amyloid-β burden, BP_ND
Entire hemisphere	0.172 (0.124–0.181)	0.168 (0.137–0.191)	0.083
Lobe
Frontal lobe	0.188 (0.146–0.203)	0.185 (0.154–0.202)	0.368
Temporal lobe	0.152 (0.103–0.168)	0.149 (0.124–0.171)	0.571
Parietal lobe	0.157 (0.120–0.181)	0.158 (0.133–0.178)	0.105
Occipital lobe	0.175 (0.122–0.184)	0.178 (0.141–0.190)	0.246
Alzheimer's region
Anterior cingulate	0.131 (0.109–0.185)	0.154 (0.117–0.188)	0.870
Posterior cingulate	0.158 (0.118–0.181)	0.141 (0.104–0.164)	0.202
Paracentral gyrus	0.171 (0.140–0.189)	0.175 (0.149–0.191)	0.027
Lateral orbitofrontal cortex	0.178 (0.153–0.259)	0.192 (0.153–0.216)	0.165
Medial orbitofrontal cortex	0.180 (0.141–0.198)	0.178 (0.135–0.205)	0.349
Precuneus	0.158 (0.129–0.182)	0.159 (0.132–0.187)	0.076
Insula	0.164 (0.140–0.185)	0.172 (0.146–0.206)	0.409
Watershed areas	0.163 (0.142–0.195)	0.167 (0.138–0.198)	0.246

Data are presented as median (interquartile range).

BP_ND: binding potential; ICA: internal carotid artery; R₁: relative perfusion.

*p < 0.05 after false discovery rate correction.

Cerebral amyloid-β burden

Only one patient was amyloid-positive based on visual reading of the PET-scan. The median global BP_ND for all patients was 0.172 (IQR 0.129–0.187). Nine of 20 patients had a BP_ND-delta of more than 0, i.e., higher ipsilateral cerebral Aβ burden (median BP_ND-delta of −0.010 [IQR −0.015–0.006]).

BP_ND did not differ significantly between hemispheres (Table 2; BP_ND ipsilateral 0.172 [IQR 0.124–0.181] versus contralateral 0.168 [IQR 0.137–0.191]). Furthermore, there were no significant differences in BP_ND in the individual lobes, early Alzheimer's regions or watershed areas. Repeating the analyses in 17 patients with ipsilateral hypoperfusion, provided similar results (Supplemental Table 1).

Association between cerebral perfusion and cerebral amyloid-β burden

There were no statistically significant associations between R₁ and BP_ND within hemispheres, nor between the R₁-delta and BP_ND-delta (Figure 1, Supplemental Table 2).

Figure 1.

Associations between cerebral perfusion and cerebral amyloid-β burden. This figure shows the crude associations between R₁ and BP_ND (A) within the hemisphere ipsilateral to the internal carotid artery occlusion, (B) within the hemisphere contralateral to the internal carotid artery occlusion and (C) between hemispheres. BP_ND: binding potential; R₁: relative perfusion.

Potential determinants of R₁-delta and BP_ND-delta

Age, sex, known duration of the occlusion, WMH volume and global R₁ were not associated with the R₁-delta (Supplemental Figure 1, Supplemental Table 3). Age, known duration of the occlusion, WMH volume and global BP_ND were not associated with the BP_ND-delta (Figure 2, Supplemental Table 3). Female sex was associated with a significantly higher BP_ND-delta than male sex after adjustment for confounders. Males tended to have more amyloid binding in the contralateral hemisphere, resulting in a negative BP_ND-delta, whereas there was almost no interhemispheric difference in amyloid binding in females, resulting in a BP_ND-delta of nearly zero.

Figure 2.

Associations between potential effect modifiers and the BP_ND-delta. This figure shows the crude associations between the BP_ND-delta and (A) age, (B) sex, (C) known duration of the ICA occlusion, (D) WMH volume, and (E) global BP_ND. BP_ND: binding potential; ICA: internal carotid artery; ICV: intracranial volume; IQR: interquartile range; WMH: white matter hyperintensity.

Cognitive functioning

Two participants had minor cognitive impairment (1 domain impaired) and 5 participants had major cognitive impairment (2 or more domains impaired). The domains attention-psychomotor speed (35%) and memory (20%) were most commonly affected, followed by executive functioning (10%) and language (5%).

Global R₁ was not associated with global cognitive functioning (adjusted β 0.10, 95% CI −0.28–0.49), nor was global BP_ND (adjusted β −0.14, 95% CI −0.52–0.24) (Table 3). There were also no significant associations between global R₁ or BP_ND and any of the specific cognitive domains.

Table 3.

Associations between cerebral perfusion, cerebral amyloid-β burden and cognitive functioning.

	Unadjusted β (95% CI)	p	Adjusted β (95% CI)^a	p
Cerebral perfusion
Global cognitive functioning	0.29 (−0.06–0.64)	0.098	0.10 (−0.28–0.49)	0.568
Memory	0.33 (−0.21–0.87)	0.218	0.11 (−0.52–0.74)	0.718
Language	0.28 (−0.08–0.63)	0.116	0.16 (−0.26–0.59)	0.423
Attention-psychomotor speed	0.24 (−0.36–0.85)	0.412	−0.04 (−0.71–0.64)	0.907
Executive functioning	0.30 (0.04–0.57)	0.027	0.18 (−0.08–0.44)	0.153
Cerebral amyloid-β burden
Global cognitive functioning	−0.11 (−0.48–0.26)	0.547	−0.14 (−0.52–0.24)	0.437
Memory	0.20 (−0.36–0.76)	0.459	0.08 (−0.55–0.71)	0.779
Language	−0.08 (−0.46–0.30)	0.667	−0.11 (−0.54–0.32)	0.600
Attention-psychomotor speed	−0.32 (−0.91–0.28)	0.279	−0.35 (−1.00–0.31)	0.275
Executive functioning	−0.24 (−0.52–0.04)	0.088	−0.20 (−0.45–0.06)	0.123

Cerebral perfusion is modeled per 1 standard deviation increase in relative perfusion (R₁). Cerebral amyloid-β burden is modeled per 1 standard deviation increase in binding potential (BP_ND). None of the associations remained statistically significant after false discovery rate correction.

Adjusted for age, sex, and years of education.

After exclusion of the visually amyloid-positive patient, findings remained essentially unchanged (Supplemental Table 4). For executive functioning specifically, the association attenuated towards zero. Assessing lobar R₁ in relation to cognitive functioning, revealed that higher R₁ in the temporal lobe and occipital lobe related to a better global cognitive function, driven by differences in memory and language for temporal lobe R₁ and by differences in language and executive functioning for occipital lobe R₁ (Supplemental Table 5). These associations attenuated after adjustment for confounders and became not statistically significant. Lobar BP_ND was not associated with cognitive functioning (Supplemental Table 6). There was no significant interaction between age or sex and R₁ or BP_ND in relation to cognitive functioning, nor was there an interaction between R₁ and BP_ND (FDR-corrected p-interaction all > 0.05).

Discussion

We found lower cerebral perfusion in the hemisphere ipsilateral to the occlusion than in the contralateral hemisphere in our specifically selected patients with a unilateral, complete ICA occlusion. However, this did not result in an asymmetrical cerebral Aβ burden. Furthermore, neither cerebral perfusion nor Aβ burden were associated with cognitive functioning.

We reasoned that the first step towards cognitive impairment in patients with a unilateral ICA occlusion could be reduced ipsilateral cerebral perfusion. While it is generally accepted that patients with a unilateral ICA occlusion are hemodynamically impaired, it has been questioned repeatedly whether this hemodynamic impairment is severe enough to result in ipsilateral cerebral hypoperfusion. Indeed, a lower cerebral perfusion in the ipsilateral hemisphere has been found in some studies,^4–6 but not in other previous studies.^26–28 Regional differences in cerebral perfusion have been described with larger asymmetries in regions that are primarily dependent on flow from the ICA and MCA, namely the frontal and parietal regions.^5,6 In the current study, we have shown that the hemodynamic impairment due to the ICA occlusion resulted in cerebral perfusion asymmetry between hemispheres, predominantly in the frontal and parietal lobes, thereby proving that our model of unilateral hypoperfusion is valid.

After establishing ipsilateral cerebral hypoperfusion, we then investigated whether this might be accompanied by a higher burden of Aβ in the ipsilateral hemisphere. With the exception of one patient, we did not find substantial Aβ binding at all. There were no differences in Aβ binding between hemispheres, with notably also no differences between hemispheres in the subgroup of patients with unilateral hypoperfusion. Previous studies examining cerebral Aβ burden in participants with or without a stenosis of the ICA also did not find a significant difference in cerebral Aβ burden on PET²⁹ or postmortem neuropathological examination between patients and controls.³⁰ Similarly, none of the studies, although few and with a small sample size, assessing differences within patients with a unilateral stenosis or occlusion of the ICA or MCA, found a significant difference in Aβ between the ipsilateral and contralateral hemisphere.^7,9–12 However, only two of those studies used dynamic PET, as we did, to ensure that limited radiotracer uptake was not caused by impaired radiotracer delivery because of the COD, thereby accurately quantifying the Aβ load.¹⁴

We did not find evidence that cerebral hypoperfusion was associated with increased cerebral Aβ burden in patients with a unilateral ICA occlusion. Yet, given that our study population overall had low levels of Aβ, it might be more difficult to find an association between cerebral hypoperfusion and Aβ. However, we had expected to already find some Aβ pathology, even in the absence of clear clinical manifestation of cognitive decline, in line with the slow accumulation of Alzheimer pathology and long preclinical stage.³¹

Although 35% of the patients had at least one impaired cognitive domain, which is comparable in both frequency and cognitive profile to a previous cohort of patients with COD who underwent a similar neuropsychological assessment,^32,33 variation in cognitive performance remained limited in this sample of 20 patients. This probably reduced our sensitivity to detect significant associations with cognitive functioning. Previous studies were able to link decreased cerebral perfusion to a reduced cognitive functioning in COD patients,^34,35 though these findings were not confirmed in other studies.^33,36 Moreover, preclinical animal studies reported that animals with both carotid occlusion and Aβ performed worse on a spatial memory task than animals with carotid occlusion only.^37–40 Although the association between Aβ and cognitive functioning has not been examined in patients with carotid occlusion specifically, the association between Aβ and cognitive functioning in community-based cohorts is well established.^41,42 Alternatively, cerebral perfusion or Aβ accumulation may not fully explain the frequently observed cognitive impairment in patients with COD. Instead, the hemodynamic vulnerability of COD patients may need to result in structural vascular brain injury, such as WMH or ischemic stroke, in order to affect cognitive functioning. Indeed, chronic white matter damage, particularly in several strategic white matter tracts, relates to worse cognitive performance in COD patients.⁴³ COD is a known risk factor for cognitive impairment after stroke.⁴⁴ Non-vascular mechanisms, such as inflammation, may also form the link between atherosclerosis and Alzheimer's disease.⁴⁵

The main strength of our study is the detailed phenotyping using a standardized neuropsychological assessment in combination with the dynamic PET-scanning. This enabled us to measure and verify unilateral cerebral hypoperfusion and correct for that in the quantification of the Aβ load. Our cohort of patients with longstanding, complete unilateral ICA occlusions is relatively large compared to previous studies that have made within patient comparisons of Aβ burden in patients with COD. Although the still limited size of the cohort renders our study susceptible to type II errors and may also give a single outlier a substantial influence on the results. The specific characteristics of our cohort make them suitable to examine our hypothesis, but those characteristics also bring limitations regarding the generalizability. As by design, we excluded patients with a contralateral stenosis or history of vascular reconstructive surgery, which are frequent characteristics of patients with a ICA occlusion. Moreover, the fact that the patients performed well in daily living despite their ICA occlusion, may have limited our chances of finding higher levels of cerebral Aβ. Arguments can be made that the overall Aβ burden was too low to detect any differences between hemispheres or any associations with cerebral perfusion or cognitive functioning (i.e., floor effect). Similar reasoning can be applied to the limited amount of variation in cognitive functioning, which also hampered our ability to find significant associations with either cerebral perfusion or cerebral Aβ. Furthermore, R₁ is not a direct measure of cerebral blood flow, but rather the influx (i.e., flow multiplied by extraction) into the target region relative to the influx into the reference region, in our case the cerebellar gray matter. Yet it is generally assumed that the extraction of various amyloid tracers is constant in different brain regions, which makes R₁ a marker for relative cerebral blood flow.⁴⁶ Finally, performing multiple analyses increases the risk of type I errors, which we tried to mitigate by applying FDR-correction.

The complex pathway leading to cognitive impairment in patients with COD remains to be fully elucidated. This study unfortunately did not find a target for treatment in cerebral perfusion or Aβ burden, leaving current treatment options limited to managing traditional vascular risk factors, such as hypertension. Cerebral Aβ in particular, could have made a promising target, in light of the recent developments in anti-amyloid treatment. Future research may instead focus on studying inflammation as a potential contributor to cognitive decline.

In conclusion, patients with a unilateral ICA occlusion have a lower cerebral perfusion in the hemisphere ipsilateral to the occlusion than in the contralateral hemisphere. However, this was not accompanied by an asymmetrical cerebral Aβ burden. Furthermore, neither cerebral perfusion nor Aβ burden were associated with cognitive functioning. Our findings indicate that cognitive impairment in patients with ICA occlusion is not due to exacerbated accumulation of Aβ in the brain.

Supplemental Material

sj-docx-1-alz-10.1177_13872877251329593 - Supplemental material for Dynamic PET imaging in patients with unilateral carotid occlusion shows lateralized cerebral hypoperfusion, but no amyloid binding

Supplemental material, sj-docx-1-alz-10.1177_13872877251329593 for Dynamic PET imaging in patients with unilateral carotid occlusion shows lateralized cerebral hypoperfusion, but no amyloid binding by Naomi LP Starmans, Anna E Leeuwis, Edwin Bennink, Sebastiaan L Meyer Viol, Sandeep SV Golla, Jan Willem Dankbaar, Esther E Bron, Geert Jan Biessels, L Jaap Kappelle, Wiesje M van der Flier, Nelleke Tolboom and in Journal of Alzheimer's Disease

Footnotes

Acknowledgments

We acknowledge Alexander Harms for his assistance in the analyses of the MRI-images.

ORCID iDs

Naomi LP Starmans

Edwin Bennink

Sandeep SV Golla

Jan Willem Dankbaar

Esther E Bron

Geert Jan Biessels

L Jaap Kappelle

Wiesje M van der Flier

Nelleke Tolboom

Ethical considerations

The study has been approved by the institutional review board of the University Medical Center Utrecht, The Netherlands (approval number: 20-492/D), and was conducted in accordance with the Declaration of Helsinki.

Consent to participate

All participants provided written informed consent prior to participation in the study.

Consent for publication

Not applicable.

Author contributions

Naomi LP Starmans, MD (Conceptualization; Data curation; Formal analysis; Investigation; Writing – original draft; Writing – review & editing); Anna E Leeuwis (Conceptualization; Investigation; Writing – review & editing); Edwin Bennink (Data curation; Writing – review & editing); Sebastiaan L Meyer Viol (Data curation; Writing – review & editing); Sandeep SV Golla (Data curation; Writing – review & editing); Jan Willem Dankbaar (Investigation; Writing – review & editing); Esther E Bron (Data curation; Writing – review & editing); Geert Jan Biessels (Conceptualization; Writing – review & editing); L Jaap Kappelle (Conceptualization; Investigation; Supervision; Writing – review & editing); Wiesje M van der Flier (Conceptualization; Methodology; Supervision; Writing – original draft; Writing – review & editing); Nelleke Tolboom (Conceptualization; Data curation; Supervision; Writing – review & editing).

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Heart-Brain Connection Consortium has received funding from the Dutch Heart Foundation under grant agreements 2018–28 and CVON 2012-06. In kind co-financing for tracer production of amyloid PET-scans was provided by Life-MI.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability

The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Supplemental material

Supplemental material for this article is available online.

References

Oudeman

Kappelle

Van den Berg-Vos

, et al. Cognitive functioning in patients with carotid artery occlusion; a systematic review. J Neurol Sci 2018; 394: 132–137.

Derdeyn

. Hemodynamics and oxygen extraction in chronic large artery steno-occlusive disease: clinical applications for predicting stroke risk. J Cereb Blood Flow Metab 2018; 38: 1584–1597.

Derdeyn

Videen

Yundt

, et al. Variability of cerebral blood volume and oxygen extraction: stages of cerebral haemodynamic impairment revisited. Brain 2002; 125: 595–607.

Van Osch

MJP

Rutgers

Vonken

EPA

, et al. Quantitative cerebral perfusion MRI and CO₂ reactivity measurements in patients with symptomatic internal carotid artery occlusion. Neuroimage 2002; 17: 469–478.

Bokkers

RPH

Bremmer

Van Berckel

BNM

, et al. Arterial spin labeling perfusion MRI at multiple delay times: a correlative study with H₂¹⁵O positron emission tomography in patients with symptomatic carotid artery occlusion. J Cereb Blood Flow Metab 2010; 30: 222–229.

De Boorder

Van der Grond

Van Dongen

, et al. Spect measurements of regional cerebral perfusion and carbondioxide reactivity: correlation with cerebral collaterals in internal carotid artery occlusive disease. J Neurol 2006; 253: 1285–1291.

Yamauchi

Kagawa

Takahashi

, et al. Misery perfusion and amyloid deposition in atherosclerotic major cerebral artery disease. Neuroimage Clin 2019; 22: 101762.

Gupta

Iadecola

. Impaired aβ clearance: a potential link between atherosclerosis and Alzheimer’s disease. Front Aging Neurosci 2015; 7: 15.

Hansson

Palmqvist

Ljung

, et al. Cerebral hypoperfusion is not associated with an increase in amyloid β pathology in middle-aged or elderly people. Alzheimers Dement 2018; 14: 54–61.

10.

Huang

Lin

, et al. Amyloid deposition after cerebral hypoperfusion: evidenced on [¹⁸F]AV-45 positron emission tomography. J Neurol Sci 2012; 319: 124–129.

11.

Ogasawara

Fujiwara

Chida

, et al. Reduction in amyloid β deposition on ¹⁸F-florbetapir positron emission tomography with correction of cerebral hypoperfusion after endarterectomy for carotid stenosis. Am J Nucl Med Mol Imaging 2019; 9: 316–320.

12.

Fan

Chen

, et al. Chronic hypoperfusion due to intracranial large artery stenosis is not associated with cerebral β-amyloid deposition and brain atrophy. Chin Med J 2022; 135: 591–597.

13.

Starmans

NLP

Leeuwis

Biessels

, et al. Cerebral amyloid-β deposition in patients with heart disease or carotid occlusive disease: a systematic review and meta-analysis. J Neurol Sci 2023; 445: 120551.

14.

Van Berckel

BNM

Ossenkoppele

Tolboom

, et al. Longitudinal amyloid imaging using ¹¹C-PiB: methodological considerations. J Nucl Med 2013; 54: 1570–1576.

15.

Hooghiemstra

Bertens

Leeuwis

, et al. The missing link in the pathophysiology of vascular cognitive impairment: design of the Heart-Brain Study. Cerebrovasc Dis Extra 2018; 7: 140–152.

16.

De Boer

Vrooman

Van der Lijn

, et al. White matter lesion extension to automatic brain tissue segmentation on MRI. Neuroimage 2009; 45: 1151–1161.

17.

Heeman

Yaqub

Lopes Alves

, et al. Optimized dual-time-window protocols for quantitative [¹⁸F]flutemetamol and [¹⁸F]florbetaben PET studies. EJNMMI Res 2019; 9: 32.

18.

Gunn

Lammertsma

Hume

, et al. Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. Neuroimage 1997; 6: 279–287.

19.

Carson

. Noise reduction in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab 2002; 22: 1440–1452.

20.

Boellaard

Yaqub

Lubberink

, et al. PPET: a software tool for kinetic and parametric analyses of dynamic PET studies. Neuroimage 2006; 31: T62.

21.

Hammers

Allom

Koepp

, et al. Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp 2003; 19: 224–247.

22.

Gousias

Rueckert

Heckemann

, et al. Automatic segmentation of brain MRIs of 2-year-olds into 83 regions of interest. Neuroimage 2008; 40: 672–684.

23.

Hartkamp

Petersen

Chappell

, et al. Relationship between haemodynamic impairment and collateral blood flow in carotid artery disease. J Cereb Blood Flow Metab 2018; 38: 2021–2032.

24.

Ferro

Mutsaerts

HJJM

Hilal

, et al. Cortical microinfarcts in memory clinic patients are associated with reduced cerebral perfusion. J Cereb Blood Flow Metab 2020; 40: 1869–1878.

25.

Collij

Heeman

Salvadó

, et al. Multitracer model for staging cortical amyloid deposition using PET imaging. Neurology 2020; 95: e1538–e1553.

26.

Apruzzese

Silvestrini

Floris

, et al. Cerebral hemodynamics in asymptomatic patients with internal carotid artery occlusion: a dynamic susceptibility contrast MR and transcranial Doppler study. AJNR Am J Neuroradiol 2001; 22: 1062–1067.

27.

Cheng

Tian

Zuo

, et al. Quantitative perfusion computed tomography measurements of cerebral hemodynamics: correlation with digital subtraction angiography identified primary and secondary cerebral collaterals in internal carotid artery occlusive disease. Eur J Radiol 2012; 81: 1224–1230.

28.

De Vis

Petersen

Bhogal

, et al. Calibrated MRI to evaluate cerebral hemodynamics in patients with an internal carotid artery occlusion. J Cereb Blood Flow Metab 2015; 35: 1015–1023.

29.

Kang

Byun

Lee

, et al. Association of carotid and intracranial stenosis with Alzheimer’s disease biomarkers. Alzheimers Res Ther 2020; 12: 106.

30.

Arias

Edwards

Vitali

, et al. Extracranial carotid atherosclerosis is associated with increased neurofibrillary tangle accumulation. J Vasc Surg 2022; 75: 223–228.

31.

Aisen

Cummings

Jack

Jr , et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimers Res Ther 2017; 9: 60.

32.

Hooghiemstra

Leeuwis

Bertens

, et al. Frequent cognitive impairment in patients with disorders along the Heart-Brain Axis. Stroke 2019; 50: 3369–3375.

33.

Leeuwis

Hooghiemstra

Bron

, et al. Cerebral blood flow and cognitive functioning in patients with disorders along the heart-brain axis: cerebral blood flow and the heart-brain axis. Alzheimers Dement 2020; 6: e12034.

34.

Marshall

Pavol

Cheung

, et al. Cognitive impairment correlates linearly with mean flow velocity by transcranial Doppler below a definable threshold. Cerebrovasc Dis Extra 2020; 10: 21–27.

35.

Marshall

Festa

Cheung

, et al. Cerebral hemodynamics and cognitive impairment: baseline data from the RECON trial. Neurology 2012; 78: 250–255.

36.

Ishikawa

Saito

Yamaguro

, et al. Cognitive impairment and neurovascular function in patients with severe steno-occlusive disease of a main cerebral artery. J Neurol Sci 2016; 361: 43–48.

37.

Choi

Lee

Han

, et al. Synergistic memory impairment through the interaction of chronic cerebral hypoperfusion and amyloid toxicity in a rat model. Stroke 2011; 42: 2595–2604.

38.

Pimentel-Coelho

Michaud

Rivest

. Effects of mild chronic cerebral hypoperfusion and early amyloid pathology on spatial learning and the cellular innate immune response in mice. Neurobiol Aging 2013; 34: 679–693.

39.

Sun

Alkon

. Cerebral hypoperfusion and amyloid-induced synergistic impairment of hippocampal CA1 synaptic efficacy and spatial memory in young adult rats. J Alzheimers Dis 2004; 6: 355–366.

40.

Dai

Zhang

Bao

, et al. Intracerebroventricular injection of Aβ₁₋₄₂ combined with two-vessel occlusion accelerate Alzheimer’s disease development in rats. Pathol Res Pract 2018; 214: 1583–1595.

41.

Jack

Jr Therneau

Lundt

, et al. Long-term associations between amyloid positron emission tomography, sex, apolipoprotein E and incident dementia and mortality among individuals without dementia: hazard ratios and absolute risk. Brain Commun 2022; 4: fcac017.

42.

Donohue

Sperling

Petersen

, et al. Association between elevated brain amyloid and subsequent cognitive decline among cognitively normal persons. JAMA 2017; 317: 2305–2316.

43.

Meng

Hosseini

Simpson

, et al. Lesion topography and microscopic white matter tract damage contribute to cognitive impairment in symptomatic carotid artery disease. Radiology 2017; 282: 502–515.

44.

Yue

Wang

Zhu

, et al. Association between carotid artery stenosis and cognitive impairment in stroke patients: a cross-sectional study. PLoS One 2016; 11: e0146890.

45.

Stahr

Galkina

. Immune response at the crossroads of atherosclerosis and Alzheimer’s disease. Front Cardiovasc Med 2022; 9: 870144.

46.

Heeman

Visser

Yaqub

, et al. Precision estimates of relative and absolute cerebral blood flow in Alzheimer’s disease and cognitively normal individuals. J Cereb Blood Flow Metab 2023; 43: 369–378.

Supplementary Material

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Dynamic PET imaging in patients with unilateral carotid occlusion shows lateralized cerebral hypoperfusion,but no amyloid binding

Abstract

Background

Objective

Methods

Results

Conclusions

Keywords

Introduction

Methods

Study population

Ethics statement

Clinical information

Neuropsychological assessment

Magnetic resonance imaging scan acquisition and processing

Positron emission tomography scan acquisition and processing

Statistical analyses

Results

Cerebral perfusion

Cerebral amyloid-β burden

Association between cerebral perfusion and cerebral amyloid-β burden

Potential determinants of R1-delta and BPND-delta

Cognitive functioning

Discussion

Supplemental Material

sj-docx-1-alz-10.1177_13872877251329593 - Supplemental material for Dynamic PET imaging in patients with unilateral carotid occlusion shows lateralized cerebral hypoperfusion, but no amyloid binding

Footnotes

Acknowledgments

ORCID iDs

Ethical considerations

Consent to participate

Consent for publication

Author contributions

Funding

Declaration of conflicting interests

Data availability

Supplemental material

References

Supplementary Material

Potential determinants of R₁-delta and BP_ND-delta