Enlarged Centrum Semiovale Perivascular Spaces as a Non- Invasive Imaging Marker of Vascular Amyloid Deposition in Amyloid-Positive Individuals Without CAA-Related Hemorrhages

Enlarged Centrum Semiovale Perivascular Spaces as a Non- Invasive Imaging Marker of Vascular Amyloid Deposition in Amyloid-Positive Individuals Without CAA-Related Hemorrhages | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Enlarged Centrum Semiovale Perivascular Spaces as a Non- Invasive Imaging Marker of Vascular Amyloid Deposition in Amyloid-Positive Individuals Without CAA-Related Hemorrhages Takashi Kasai, Kentaro Akazawa, Fukiko Kitani-Morii, Yuki Naeshiro, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7661793/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract With the increasing use of anti-amyloid therapy, there is a growing need for reliable methods to detect vascular amyloid in patients with early-stage Alzheimer's disease (AD). The reduction in cerebrospinal fluid (CSF) Aβ42 and Aβ40 levels is a well-documented characteristic of fluid biomarkers for cerebral amyloid angiopathy (CAA). However, the invasive nature of CSF collection hinders its feasibility for routine clinical applications. Alternatively, a high degree of MRI-visible perivascular spaces in the centrum semiovale (CSO-PVS), which are typically associated with CAA-related hemorrhages, is emerging as a promising non-invasive imaging biomarker. Nevertheless, the applicability of a high degree of CSO-PVS to reflect vascular amyloid accumulation in amyloid-positive individuals without definitive CAA-related hemorrhages remains unclear. This study retrospectively analyzed 30 participants diagnosed with mild cognitive impairment due to AD or mild AD characterized by reduced CSF Aβ42/40 ratio without CAA-related hemorrhagic manifestations. Participants were categorized into high- and low-degree CSO-PVS groups based on the median value of visually quantified CSO-PVS. CSF Aβ40 levels were significantly lower in the high-degree CSO-PVS group compared with the low-degree group (P = 0.0235), and CSF Aβ42 levels showed a trend toward lower values (P = 0.0502). These findings suggest that dilated CSO-PVS may serve as a potential surrogate marker for vascular amyloid deposition, offering a non-invasive alternative for monitoring patients undergoing anti-amyloid therapy. Alzheimer’s disease CSO-PVS CSF Aβ40 cerebral amyloid angiopathy Figures Figure 1 Figure 2 Figure 3 Introduction Alzheimer's disease (AD), the leading cause of dementia, is initiated by excessive accumulation of amyloid β (Aβ) as senile plaques within the brain parenchyma [ 1 ]. Although Aβ accumulation is observed even in cognitively normal individuals, it is significantly prominent in patients with AD and typically begins 20 to 30 years prior to dementia onset [ 2 ]. Aβ accumulation is not solely confined to senile plaques (plaque amyloid); it also deposits on blood vessels, forming vascular amyloid [ 3 ]. This vascular amyloid deposition, referred to as cerebral amyloid angiopathy of the Aβ type (CAA), is observed in up to 48% of patients with AD [ 4 ]. Patients with CAA frequently develop hemorrhage and edema in the brain due to vascular disruption or increased permeability, which is partly due to an immune response to the deposited vascular amyloid [ 5 ]. Hemorrhagic and edematous imaging abnormalities associated with CAA have been described by terms such as cortical and subcortical microbleeds (MBs), cortical and subcortical superficial siderosis (SS), and CAA-related inflammation (CAAri). These imaging abnormalities have gained attention in dementia research due to their frequent occurrence as complications of anti-amyloid passive immunotherapy (anti-amyloid therapy). Consequently, the term amyloid-related imaging abnormalities (ARIA) was introduced to encompass idiopathic and iatrogenic CAA-related imaging abnormalities [ 6 ]. Among the multiple mechanisms underlying ARIA, particularly ARIA-E, which manifests as vasogenic edema, vascular amyloid deposition may increase the susceptibility to vascular injury following anti-amyloid therapy by impairing clearance mechanisms and enhancing immune-mediated inflammation. It is hypothesized that anti-amyloid antibodies targeting vascular Aβ deposits may provoke local inflammatory responses, leading to increased vascular permeability and resultant edema or microhemorrhage [ 7 ]. Therefore, noninvasive and accurate assessment of vascular amyloid burden is crucial for predicting and reducing the risk of ARIA during anti-amyloid therapy. Histopathological confirmation through brain biopsy represents the gold standard for diagnosing CAA; however, this approach is clinically infeasible [ 8 ]. Hemorrhagic changes, such as microbleeds (MBs) and superficial siderosis (SS) detected via magnetic resonance imaging (MRI), are reliable imaging biomarkers for identifying CAA under the Boston criteria version 2.0 [ 8 ]. Nevertheless, these biomarkers reflect secondary consequences of CAA rather than the presence or the severity of the vascular amyloid itself [ 9 ]. Amyloid PET imaging identifies amyloid accumulation in the brain; however, it does not distinguish between vascular amyloid and plaque amyloid [ 10 ]. Cerebrospinal fluid (CSF) levels of Aβ-related species decline as amyloid accumulates in the brain, and these decline profiles differ between CAA and AD. In AD, CSF Aβ42 levels are reduced compared to controls, while CSF Aβ40 levels remain largely unchanged [ 11 ]. This reduction is often attributed to the adsorption of Aβ42 in the cerebral interstitial fluid onto plaque amyloid, which primarily consists of insoluble, long-chain Aβ molecular species like Aβ42 [ 12 ]. Conversely, vascular amyloid contains higher concentrations of shorter Aβ peptides (e.g., Aβ40), and in brains with abundant vascular amyloid, both Aβ42 and Aβ40 are thought to be sequestered into the vascular deposits. As a result, CAA reduces both CSF Aβ42 and Aβ40 levels [ 9 ]. Decreases in CSF Aβ40 levels are correlated with increased lobar MB count, greater white matter hyperintensity volume, and the presence of cortical SS [ 13 ]. Therefore, in patients with AD or MCI due to AD, the presence of decreased CSF Aβ40 in addition to reduced CSF Aβ42 may suggest a relatively greater burden of vascular amyloid deposition in the brain. However, because collecting CSF is invasive, it is not suitable for regular use as a biomarker or for tracking changes over time during anti-amyloid treatment. MRI-visible perivascular spaces in the centrum semiovale (CSO-PVS), which have been incorporated as a non-hemorrhagic MRI biomarker in the Boston criteria version 2.0, provide a noninvasive method for assessing vascular amyloid[ 8 ]. The diagnostic value of CSO-PVS findings has been demonstrated in patients with CAA-related hemorrhagic abnormalities [ 14 ]. However, patients with AD receiving anti-amyloid therapy, who are the primary subjects for predicting ARIA onset, generally exhibit negligible CAA-related hemorrhagic findings, particularly at the commencement of treatment. Whether CSO-PVS findings can be adapted to reflect vascular amyloid accumulation in amyloid pathology-positive individuals with such minimal CAA-associated hemorrhagic manifestations remains an open question. Establishing a method to evaluate the utility of CSO-PVS findings for detecting vascular amyloid deposition in Alzheimer's disease (AD) patients without overt hemorrhagic manifestations associated with CAA is a challenging task. This difficulty arises from ethical constraints, as it is problematic to compare CSO-PVS findings with brain pathology in relatively healthy individuals. Therefore, this study indirectly addresses the issue by analyzing the relation between CSO-PVS grades and reductions in both CSF Aβ42 and Aβ40 in patients evaluated for anti-amyloid therapy eligibility (Fig. 1). Combining CSF Aβ42 and Aβ40 concentrations into a composite index may provide a more sensitive measure of amyloid pathology, especially in cases where each individual marker exhibits borderline significance. Previous studies have suggested that using ratios or multiplication products can enhance the sensitivity and robustness of CSF biomarkers by accounting for inter-individual variability and assay noise [ 15 ]. Therefore, we also explored the ratio (Aβ42/40 ratio) and the product of Aβ42 and Aβ40 (Aβ40 × Aβ42) as potential surrogate indicators of plaque amyloid and vascular amyloid burden, respectively. The latter approach may better reflect amyloid burden in the presence of vascular involvement by emphasizing the simultaneous reductions of both Aβ species. Material and Methods Study design, ethics statement, and subject recruitment This study was a retrospective analysis conducted on participants who had provided informed consent as described below. Data collection was completed by August 31, 2025, and all data were fully anonymized prior to access. Written informed consent was obtained from patients with mild AD and mild cognitive impairment (MCI) due to AD allowing the use of their medical records, imaging data, and CSF biomarker data for research purposes. The study was conducted in accordance with the Declaration of Helsinki and was approved by the University Ethics Committee of Kyoto Prefectural University of Medicine (KPUM), Kyoto, Japan (ERB-G-12 and RBMR-G-102). We enrolled participants from the KPUM dementia registry between April 2023 and March 2025. Inclusion criteria were a diagnosis of mild AD or MCI due to AD, supported by a reduced CSF Aβ42/40 ratio (< 0.067), as part of the evaluation for anti-amyloid therapy eligibility. Participants also had a Clinical Dementia Rating (CDR) global score of 0.5 or 1 and a Mini-Mental State Examination-J (MMSE-J) score ranging from 20 to 30. Exclusion criteria included the following MRI findings indicative of cerebral amyloid angiopathy (CAA)-related hemorrhage or inflammation, in accordance with the appropriate use recommendations for lecanemab and donanemab [ 16 , 17 ]: More than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter); a single macrohemorrhage > 10 mm at greatest diameter; an area of superficial siderosis; evidence of vasogenic edema; more than 2 lacunar infarcts or stroke involving a major vascular territory; severe subcortical hyperintensities defined as a Fazekas score of 3; evidence of amyloid beta-related angiitis; CAAri, or other major intracranial pathology that may cause cognitive impairment. Additional exclusion criteria included the use of neprilysin inhibitors due to their confounding effects on Aβ metabolism [ 18 ]. MRI findings indicative of asymptomatic ventriculomegaly with features of idiopathic normal pressure hydrocephalus (iNPH)[ 19 ], as well as neurologically suggestive signs of iNPH, were excluded due to potential confounding effects on CSF Aβ and phosphorylated-tau biomarker interpretation [ 20 ]. Patients with parkinsonism, including DLB, progressive supranuclear palsy, and corticobasal syndrome or with frontal lobe signs (e.g., palmomental reflex, forced grasp reflex, and sucking reflex) were excluded, as the impact of these comorbid neurodegenerative pathologies on CSF Aβ metabolism remains poorly understood. Clinical data, CSF and imaging analyses All participants underwent comprehensive evaluations, including medical history interviews and general and neurological examinations conducted by trained neurologists (TK, FKM) to exclude comorbidities such as parkinsonism, including DLB and iNPH. CDR and MMSE-J assessments were performed by certified neuropsychologists [ 21 , 22 ]. The apolipoprotein E (ApoE) haplotype was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method as described previously [ 23 ]. All participants were treated with lecanemab and followed up for a minimum of six months after the initiation of lecanemab treatment. During this period, brain MRI scans were performed as pre-treatment screening, followed by MRI at one month, three months, and six months after treatment initiation to assess the presence or absence of ARIA. CSF samples were obtained through lumbar puncture at the L3/L4 or L4/L5 interspace and collected in polypropylene vials. These samples were promptly transported to SRL Inc. (Tokyo) without freezing, where concentrations of Aβ1–40, Aβ1–42, and tau phosphorylated at threonine 181 (p-tau181) were measured using the LUMIPULSE G600II platform [ 24 , 25 ]. Participants underwent initial pre-treatment screening MRI within one month of CSF collection under standardized conditions. All MRI scans were performed using a 3.0T Philips Elition scanner (Philips Healthcare, Best, The Netherlands) with a 32-channel head coil. The imaging protocol included the following sequences: T2-weighted imaging (T2WI): Acquired in the axial plane using a fast spin-echo sequence with TR/TE = 5678/100 ms, flip angle = 90°, FOV = 396 × 251 mm², matrix = 784 × 784, and slice thickness/gap = 5/1 mm. T2*-weighted imaging (T2*WI): Acquired in the coronal plane using a 2D gradient-echo sequence with TR/TE = 532/16 ms, flip angle = 18°, FOV = 304 × 216 mm², matrix = 512 × 512, and slice thickness/gap = 5/1 mm. Diffusion-weighted imaging (DWI): Acquired in the axial plane using a single-shot spin-echo echo planar imaging sequence with TR/TE = 3362/86 ms, flip angle = 90°, FOV = 92 × 90 mm², matrix = 128 × 128, slice thickness = 2.5 mm, and b-values of 0 and 1000 s/mm² applied in 15 directions. CSO-PVS were evaluated on T2-weighted MRIs obtained at the initial pre-treatment screening, based on the criteria established by Charidimou et al [ 14 ]. Small sharply delineated structures of (or close to) CSF intensity measuring < 3 mm and following the course of perforating or medullary vessels on the slice where the hand knobs of the primary motor cortex were observed were visually counted by two trained observers (TK, KA) independently. An independent adjudicator (KFM) decided on cases where the two examiners' decisions were inconsistent. TK: Neurologist with 26 years of experience in diagnostic imaging for cognitive disorders, KA: board-certified radiologist with 24 years of experience. KFM: Neurologist with 17 years of experience. All observers were blinded to the clinical data. Statistics Data are presented as mean ± standard deviation (SD). Mann-Whitney U test was used for two-group comparisons using GraphPad Prism 10. Fisher’s exact test was used to evaluate the statistical association between two categorical variables using GraphPad Prism 10. Kappa statistics and intraclass correlation coefficient analyses were conducted using SPSS version 23. Statistical significance was set at two-tailed P < 0.05. Results Clinical Characteristics Thirty-five subjects were initially enrolled in the study. Of these, five subjects were excluded for the following reasons: three due to having more than four microhemorrhages and/or presence of superficial siderosis, one due to a diagnosis of DLB, and one due to MRI findings indicative of asymptomatic ventriculomegaly with features of iNPH but without iNPH symptoms. The demographic characteristics of the remaining 30 participants analyzed in this study (mean age ± standard deviation: 74.0 ± 5.94 years; female: male = 18:12) are summarized in Table 1. Grading of CSO-PVS First, we performed a pilot grading of CSO-PVS on axial T2-weighted MRI sequences using a validated two-point visual rating scale (high degree > 20, low degree ≤ 20), as per the Boston criteria version 2.0 [ 8 , 14 ]. Inter- and intra-rater reliability were evaluated using the Kappa statistic by two independent raters. Excellent inter- and intra-rater reliability was observed for dichotomized grading (inter-rater Kappa = 1.000, intra-rater Kappa = 1.000). Among the 30 cases assessed, only one participant had a high degree of CSO-PVS (> 20), whereas the remaining 29 had ≤ 20 CSO-PVS. The limited sample size made statistical comparisons impossible when using the previously reported cutoff of 20 for the CSO-PVS grading. Intraclass correlation coefficients (ICC (2,1)) for the raw CSO-PVS counts demonstrated good reliability (0.811, 95% confidence interval = 0.642–0.950, P = 0.000). While the lower limit of the 95% confidence interval (0.642) is relatively low, the overall interval suggested that the inter-rater agreement is within a practically acceptable range. The raw counts of CSO-PVS from the two raters were consistent. Consequently, we adopted their median value of CSO-PVS as a new criterion for grouping participants. Subjects with raw counts above the median were assigned to the high-degree group, while those with counts at or below the median were assigned to the low-degree group. The inter-rater reliability for this dichotomized classification demonstrated substantial agreement (inter-rater Kappa = 0.798). The final cutoff value for CSO-PVS counts was set at 9. For cases in which the classification results differed between the two independent raters (TK, KA), a final group assignment was determined by an independent adjudicator (KFM), who reviewed the results of both raters. Histograms of CSO-PVS counts and representative images from the high-degree and low-degree groups are presented in Fig. 2. Comparison Between High and Low-Degree Groups of CSO-PVS In accordance with the dichotomization as described above, participants were categorized into low-degree and high-degree CSO-PVS groups. The clinical characteristics of the two groups are presented in Table 2. There were no significant differences between the two groups regarding sex, age, dementia diagnosis (MCI-due to AD or mild AD), history of hypertension, dyslipidemia, diabetes, atrial fibrillation, stroke, or ApoE genotype. MMSE-J scores were significantly lower in the low-degree CSO-PVS group than in the high-degree group. There were four cases with ARIA E/H during 6-months observation period, of which one case was symptomatic. Among the four cases with ARIA E/H, three belonged to the high-degree CSO-PVS group, while one was in the low-degree CSO-PVS group. The case with symptomatic ARIA belonged to the low-degree CSO-PVS group (as reported previously [ 26 ]). There was no significant difference in the incidence of ARIA E/H between the two groups. Figure 3 presents the concentrations of Aβ40, Aβ42, and p-tau181 in CSF. CSF Aβ40 levels were significantly lower in the high-degree CSO-PVS group compared to the low-degree group (P = 0.0235). CSF Aβ42 levels also tended to be lower in the high-degree group, although the difference narrowly missed statistical significance (P = 0.0502). CSF p-tau181 levels were significantly lower in the high-degree group than in the low-degree group (P = 0.0264). The CSF Aβ42/40 ratio did not differ significantly between the high- and low-degree groups (P = 0.5453). However, as hypothesized, the product of Aβ40 and Aβ42 (Aβ40 × Aβ42) was significantly lower in the high-degree group (P = 0.0264). Discussion In this study, participants with high-degree of CSO-PVS exhibited lower CSF Aβ40 levels. Although the difference did not reach statistical significance, Aβ42 levels also tended to be lower in the high-degree CSO-PVS group. Importantly, this study targeted patients with mild AD or MCI due to AD who were eligible for lecanemab treatment, thus including only individuals with minimal CAA-related hemorrhagic findings and few enlarged CSO-PVS. Indeed, only one case exhibited 21 or more enlarged CSO-PVS, the threshold defined by the Boston criteria version 2.0 [ 8 ]. Even though only a few participants exhibited a high degree of CSO-PVS in this cohort, it was noteworthy that further reductions in CSF Aβ42 and Aβ40 levels—biomarkers of vascular amyloid deposition—were still observed in accordance with the relative severity of the CSO-PVS burden. Previous studies have reported significantly reduced Aβ40 and Aβ42 levels in patients with sporadic CAA meeting the modified Boston criteria and hereditary Dutch CAA compared to control groups [ 9 , 13 ] [ 27 ]. Additionally, the severity of CSO-PVS has been shown to correlate with the extent of CAA-related hemorrhages and white matter lesions [ 14 ]. The findings of the current study align with the results predicted from those previous reports. In particular, considering the fact that our subjects exhibited less CAA-related hemorrhages, the current results suggest the implication that CSO-PVS dilation and associated reductions in CSF Aβ42 and Aβ40 might precede the development of CAA-related cerebral hemorrhages. This interpretation is consistent with prior research in hereditary Dutch CAA, which demonstrated that reduction in CSF Aβ42 and Aβ40 as well as dilation of CSO-PVS were evident even in asymptomatic carriers[ 13 , 28 ]. Notably, the product of Aβ42 and Aβ40 concentrations (Aβ42 × Aβ40) was also significantly lower in the high-degree CSO-PVS group. This composite metric may reflect the cumulative loss of both longer (Aβ42) and shorter (Aβ40) amyloid species into vascular deposits and has the advantage of mitigating potential variability from individual peptide measurements. Although not commonly used, such multiplicative indices have been proposed as exploratory biomarkers in previous fluid biomarker studies [ 15 ]. To the best of our knowledge, there are few studies that have conducted a direct comparison between CSO-PVS grading and reductions in Aβ40 and Aβ42 levels. Our findings imply that dilated CSO-PVS may serve as a potential diagnostic marker reflecting vascular amyloid deposition for candidates for anti-amyloid therapy who exhibited minimal or no CAA-related hemorrhages. Interestingly, CSF p-tau181 levels were lower in the high-degree CSO-PVS group. This may reflect impaired glymphatic or perivascular clearance vascular amyloid, which hinders the transport of phosphorylated tau into the CSF [ 29 ]. Furthermore, given that vascular amyloid deposition per se has limited neurotoxicity to the brain parenchyma unless accompanied by hemorrhage[ 7 ], it is conceivable that the increase in p-tau181—a biomarker reflecting both tau phosphorylation and the presence of plaque—was attenuated in the high-degree CSO-PVS group [ 30 ]. This latter hypothesis is in line with our finding that the high-degree CSO-PVS group demonstrated significantly higher MMSE-J scores. Finally, we acknowledge that the small sample size represents a significant limitation of this study, potentially reducing the statistical power to detect associations between CSO-PVS severity and CSF biomarkers. Future research should focus on developing objective, automated methodologies for CSO-PVS grading, minimizing reliance on visual assessments. Moreover, large-scale, multicenter studies are necessary to further elucidate the relationship between CSF biomarkers for amyloids and CSO-PVS findings. Conclusion Among individuals with mild AD or MCI due to AD characterized by reduced CSF Aβ42/40 ratio and minimal or no CAA-related hemorrhages, CSF Aβ40 levels were significantly lower and CSF Aβ42 levels tended to be lower in those with a high degree of CSO-PVS compared with those with a low degree of CSO-PVS. These findings suggest that dilated CSO-PVS may serve as a potential surrogate marker of vascular amyloid deposition in patients undergoing anti-amyloid therapy. Declarations Acknowledgements This study was supported by the grant for Social Welfare Activities of Mitsubishi Foundation to TK. Author Contributions TK and MFK were involved in the conceptualization and design of the study, patient enrollment, data collection, data analysis, interpretation of the data, and review of the manuscript. TK wrote the first manuscript. KA conducted assessment of MRI images and was involved in data interpretation and review of the manuscript. KW was involved in data collection. YN, HS, TS, and MY assisted with patient enrollment and manuscript review. IM conducted analysis of ApoE haplotype. YF, KS, KW, and TO reviewed and revised the manuscript. All the authors reviewed the drafts and approved the final version of the manuscript. Co mpeting interests: The authors declare no competing interests. Data availability statement The data that support the findings of this study are available in Supplementary Table. Ethics declarations Study procedures were designed and performed in accordance with the Declaration of Helsinki. The study was approved by the University Ethics Committee of Kyoto Prefectural University of Medicine (KPUM), Kyoto, Japan (ERB-G-12) Consent to Participate declaration Written informed consent was obtained before participation from the participants. Consent to Publish Not applicable. Clinical Trial Registration Not applicable. Funding declaration TK received Social Welfare Activities of Mitsubishi Foundation, Grants-in-Aid (grant numbers 21K07466) from the Ministry of Education, Culture, Sports, Science, and Grant-in-Aid (grant number 24FC010) from the Ministry of Health Labour and Welfare). FKM received a Japan Heart Foundation Research Grant. The other authors declare no financial disclosures. The funding organizations were not involved in the study design, data collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. References Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science (New York, N.Y.) 297 , 353-356, doi:10.1126/science.1072994 (2002). Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. The New England journal of medicine 367 , 795-804, doi:10.1056/NEJMoa1202753 (2012). Glenner, G. G., Henry, J. 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Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Isolated Supratentorial Cortical Superficial Siderosis. Journal of Alzheimer's disease : JAD 54 , 1291-1295, doi:10.3233/jad-160400 (2016). Martinez-Ramirez, S. et al. Perivascular Spaces Volume in Sporadic and Hereditary (Dutch-Type) Cerebral Amyloid Angiopathy. Stroke 49 , 1913-1919, doi:10.1161/strokeaha.118.021137 (2018). Peng, W. et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease. Neurobiology of disease 93 , 215-225, doi:10.1016/j.nbd.2016.05.015 (2016). Blennow, K. & Zetterberg, H. Biomarkers for Alzheimer's disease: current status and prospects for the future. Journal of internal medicine 284 , 643-663, doi:10.1111/joim.12816 (2018). Tables Tables 1 and 2 are available in the Supplementary Files section Additional Declarations No competing interests reported. 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23:12:35","extension":"html","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":91949,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7661793/v1/c9259877ca41b71ef22a42ca.html"},{"id":94048180,"identity":"01f53f87-b0bd-4d59-9214-5b7f4444358c","added_by":"auto","created_at":"2025-10-21 23:20:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":9225271,"visible":true,"origin":"","legend":"\u003cp\u003eHypothetical Framework of the Study\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-7661793/v1/514a3f488d48db72414f453b.png"},{"id":94047057,"identity":"c29ce4d2-cf07-46b5-929e-a275f5ec558b","added_by":"auto","created_at":"2025-10-21 23:12:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":9381465,"visible":true,"origin":"","legend":"\u003cp\u003e(a) The histograms of raw CSO-PVS counts were shown. The Y-axis represented the number of cases. The upper and lower panels were assessed by TK and KA, respectively. The solid line indicated the cut-off used in this study (≥9). The dashed line represented the cut-off conventionally used in previous studies (\u0026gt;20).\u003c/p\u003e\n\u003cp\u003e(b) (c) Representative axial T2-weighted MRI images of the brain are presented for both the low-degree (b) and high-degree (c) groups.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-7661793/v1/d748976c8bcd8fc8b214454b.png"},{"id":94048182,"identity":"8e0f3fef-1512-40ed-ae46-7c6e6a81a365","added_by":"auto","created_at":"2025-10-21 23:20:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":5201343,"visible":true,"origin":"","legend":"\u003cp\u003eThe CSF biomarkers, including Aβ42 (a), Aβ40 (b), p-tau181 (c), the Aβ42/40 ratio (d), and the product of Aβ40 and Aβ42 concentrations (Aβ40 × Aβ42) (e), were compared between the low-degree and high-degree groups of CSO-PVS. Statistically significant differences between the two groups are indicated by asterisks. Bars indicate median values.\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-7661793/v1/e11c5f6b65136439036ddbb3.png"},{"id":94047053,"identity":"874ddde3-6001-42ae-b9c9-605452e23628","added_by":"auto","created_at":"2025-10-21 23:12:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":681337,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7661793/v1/aa9b592a-cef7-4dcb-bf61-edd8fc4dd2c0.pdf"},{"id":94047054,"identity":"f0226a14-5b84-4e21-a1d0-5ce0050262f5","added_by":"auto","created_at":"2025-10-21 23:12:34","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":10022,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7661793/v1/06d35d9eff16a3d61d24acf2.xlsx"},{"id":94047058,"identity":"c9d8dea3-b933-4bdb-91f4-90b7dce42cc1","added_by":"auto","created_at":"2025-10-21 23:12:34","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10748,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7661793/v1/caee106b883b2e6d86cc33e8.xlsx"},{"id":94048181,"identity":"2ca50e20-0550-460e-a5a8-73d964548472","added_by":"auto","created_at":"2025-10-21 23:20:34","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20113,"visible":true,"origin":"","legend":"","description":"","filename":"SupplmentayTable.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7661793/v1/090ae4768adecf198fec99f0.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Enlarged Centrum Semiovale Perivascular Spaces as a Non- Invasive Imaging Marker of Vascular Amyloid Deposition in Amyloid-Positive Individuals Without CAA-Related Hemorrhages","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAlzheimer's disease (AD), the leading cause of dementia, is initiated by excessive accumulation of amyloid β (Aβ) as senile plaques within the brain parenchyma [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although Aβ accumulation is observed even in cognitively normal individuals, it is significantly prominent in patients with AD and typically begins 20 to 30 years prior to dementia onset [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Aβ accumulation is not solely confined to senile plaques (plaque amyloid); it also deposits on blood vessels, forming vascular amyloid [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This vascular amyloid deposition, referred to as cerebral amyloid angiopathy of the Aβ type (CAA), is observed in up to 48% of patients with AD [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Patients with CAA frequently develop hemorrhage and edema in the brain due to vascular disruption or increased permeability, which is partly due to an immune response to the deposited vascular amyloid [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Hemorrhagic and edematous imaging abnormalities associated with CAA have been described by terms such as cortical and subcortical microbleeds (MBs), cortical and subcortical superficial siderosis (SS), and CAA-related inflammation (CAAri). These imaging abnormalities have gained attention in dementia research due to their frequent occurrence as complications of anti-amyloid passive immunotherapy (anti-amyloid therapy). Consequently, the term amyloid-related imaging abnormalities (ARIA) was introduced to encompass idiopathic and iatrogenic CAA-related imaging abnormalities [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Among the multiple mechanisms underlying ARIA, particularly ARIA-E, which manifests as vasogenic edema, vascular amyloid deposition may increase the susceptibility to vascular injury following anti-amyloid therapy by impairing clearance mechanisms and enhancing immune-mediated inflammation. It is hypothesized that anti-amyloid antibodies targeting vascular Aβ deposits may provoke local inflammatory responses, leading to increased vascular permeability and resultant edema or microhemorrhage [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Therefore, noninvasive and accurate assessment of vascular amyloid burden is crucial for predicting and reducing the risk of ARIA during anti-amyloid therapy.\u003c/p\u003e\u003cp\u003eHistopathological confirmation through brain biopsy represents the gold standard for diagnosing CAA; however, this approach is clinically infeasible [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Hemorrhagic changes, such as microbleeds (MBs) and superficial siderosis (SS) detected via magnetic resonance imaging (MRI), are reliable imaging biomarkers for identifying CAA under the Boston criteria version 2.0 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Nevertheless, these biomarkers reflect secondary consequences of CAA rather than the presence or the severity of the vascular amyloid itself [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Amyloid PET imaging identifies amyloid accumulation in the brain; however, it does not distinguish between vascular amyloid and plaque amyloid [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Cerebrospinal fluid (CSF) levels of Aβ-related species decline as amyloid accumulates in the brain, and these decline profiles differ between CAA and AD. In AD, CSF Aβ42 levels are reduced compared to controls, while CSF Aβ40 levels remain largely unchanged [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This reduction is often attributed to the adsorption of Aβ42 in the cerebral interstitial fluid onto plaque amyloid, which primarily consists of insoluble, long-chain Aβ molecular species like Aβ42 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Conversely, vascular amyloid contains higher concentrations of shorter Aβ peptides (e.g., Aβ40), and in brains with abundant vascular amyloid, both Aβ42 and Aβ40 are thought to be sequestered into the vascular deposits. As a result, CAA reduces both CSF Aβ42 and Aβ40 levels [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Decreases in CSF Aβ40 levels are correlated with increased lobar MB count, greater white matter hyperintensity volume, and the presence of cortical SS [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Therefore, in patients with AD or MCI due to AD, the presence of decreased CSF Aβ40 in addition to reduced CSF Aβ42 may suggest a relatively greater burden of vascular amyloid deposition in the brain. However, because collecting CSF is invasive, it is not suitable for regular use as a biomarker or for tracking changes over time during anti-amyloid treatment.\u003c/p\u003e\u003cp\u003eMRI-visible perivascular spaces in the centrum semiovale (CSO-PVS), which have been incorporated as a non-hemorrhagic MRI biomarker in the Boston criteria version 2.0, provide a noninvasive method for assessing vascular amyloid[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The diagnostic value of CSO-PVS findings has been demonstrated in patients with CAA-related hemorrhagic abnormalities [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, patients with AD receiving anti-amyloid therapy, who are the primary subjects for predicting ARIA onset, generally exhibit negligible CAA-related hemorrhagic findings, particularly at the commencement of treatment. Whether CSO-PVS findings can be adapted to reflect vascular amyloid accumulation in amyloid pathology-positive individuals with such minimal CAA-associated hemorrhagic manifestations remains an open question. Establishing a method to evaluate the utility of CSO-PVS findings for detecting vascular amyloid deposition in Alzheimer's disease (AD) patients without overt hemorrhagic manifestations associated with CAA is a challenging task. This difficulty arises from ethical constraints, as it is problematic to compare CSO-PVS findings with brain pathology in relatively healthy individuals. Therefore, this study indirectly addresses the issue by analyzing the relation between CSO-PVS grades and reductions in both CSF Aβ42 and Aβ40 in patients evaluated for anti-amyloid therapy eligibility (Fig.\u0026nbsp;1). Combining CSF Aβ42 and Aβ40 concentrations into a composite index may provide a more sensitive measure of amyloid pathology, especially in cases where each individual marker exhibits borderline significance. Previous studies have suggested that using ratios or multiplication products can enhance the sensitivity and robustness of CSF biomarkers by accounting for inter-individual variability and assay noise [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, we also explored the ratio (Aβ42/40 ratio) and the product of Aβ42 and Aβ40 (Aβ40 \u0026times; Aβ42) as potential surrogate indicators of plaque amyloid and vascular amyloid burden, respectively. The latter approach may better reflect amyloid burden in the presence of vascular involvement by emphasizing the simultaneous reductions of both Aβ species.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design, ethics statement, and subject recruitment\u003c/h2\u003e\u003cp\u003eThis study was a retrospective analysis conducted on participants who had provided informed consent as described below. Data collection was completed by August 31, 2025, and all data were fully anonymized prior to access. Written informed consent was obtained from patients with mild AD and mild cognitive impairment (MCI) due to AD allowing the use of their medical records, imaging data, and CSF biomarker data for research purposes. The study was conducted in accordance with the Declaration of Helsinki and was approved by the University Ethics Committee of Kyoto Prefectural University of Medicine (KPUM), Kyoto, Japan (ERB-G-12 and RBMR-G-102).\u003c/p\u003e\u003cp\u003eWe enrolled participants from the KPUM dementia registry between April 2023 and March 2025. Inclusion criteria were a diagnosis of mild AD or MCI due to AD, supported by a reduced CSF Aβ42/40 ratio (\u0026lt;\u0026thinsp;0.067), as part of the evaluation for anti-amyloid therapy eligibility. Participants also had a Clinical Dementia Rating (CDR) global score of 0.5 or 1 and a Mini-Mental State Examination-J (MMSE-J) score ranging from 20 to 30.\u003c/p\u003e\u003cp\u003eExclusion criteria included the following MRI findings indicative of cerebral amyloid angiopathy (CAA)-related hemorrhage or inflammation, in accordance with the appropriate use recommendations for lecanemab and donanemab [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]: More than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter); a single macrohemorrhage\u0026thinsp;\u0026gt;\u0026thinsp;10 mm at greatest diameter; an area of superficial siderosis; evidence of vasogenic edema; more than 2 lacunar infarcts or stroke involving a major vascular territory; severe subcortical hyperintensities defined as a Fazekas score of 3; evidence of amyloid beta-related angiitis; CAAri, or other major intracranial pathology that may cause cognitive impairment. Additional exclusion criteria included the use of neprilysin inhibitors due to their confounding effects on Aβ metabolism [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. MRI findings indicative of asymptomatic ventriculomegaly with features of idiopathic normal pressure hydrocephalus (iNPH)[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], as well as neurologically suggestive signs of iNPH, were excluded due to potential confounding effects on CSF Aβ and phosphorylated-tau biomarker interpretation [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Patients with parkinsonism, including DLB, progressive supranuclear palsy, and corticobasal syndrome or with frontal lobe signs (e.g., palmomental reflex, forced grasp reflex, and sucking reflex) were excluded, as the impact of these comorbid neurodegenerative pathologies on CSF Aβ metabolism remains poorly understood.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinical data, CSF and imaging analyses\u003c/h3\u003e\n\u003cp\u003eAll participants underwent comprehensive evaluations, including medical history interviews and general and neurological examinations conducted by trained neurologists (TK, FKM) to exclude comorbidities such as parkinsonism, including DLB and iNPH. CDR and MMSE-J assessments were performed by certified neuropsychologists [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The apolipoprotein E (ApoE) haplotype was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method as described previously [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. All participants were treated with lecanemab and followed up for a minimum of six months after the initiation of lecanemab treatment. During this period, brain MRI scans were performed as pre-treatment screening, followed by MRI at one month, three months, and six months after treatment initiation to assess the presence or absence of ARIA.\u003c/p\u003e\u003cp\u003eCSF samples were obtained through lumbar puncture at the L3/L4 or L4/L5 interspace and collected in polypropylene vials. These samples were promptly transported to SRL Inc. (Tokyo) without freezing, where concentrations of Aβ1\u0026ndash;40, Aβ1\u0026ndash;42, and tau phosphorylated at threonine 181 (p-tau181) were measured using the LUMIPULSE G600II platform [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eParticipants underwent initial pre-treatment screening MRI within one month of CSF collection under standardized conditions.\u003c/p\u003e\u003cp\u003eAll MRI scans were performed using a 3.0T Philips Elition scanner (Philips Healthcare, Best, The Netherlands) with a 32-channel head coil. The imaging protocol included the following sequences:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eT2-weighted imaging (T2WI): Acquired in the axial plane using a fast spin-echo sequence with TR/TE\u0026thinsp;=\u0026thinsp;5678/100 ms, flip angle\u0026thinsp;=\u0026thinsp;90\u0026deg;, FOV\u0026thinsp;=\u0026thinsp;396 \u0026times; 251 mm\u0026sup2;, matrix\u0026thinsp;=\u0026thinsp;784 \u0026times; 784, and slice thickness/gap\u0026thinsp;=\u0026thinsp;5/1 mm.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eT2*-weighted imaging (T2*WI): Acquired in the coronal plane using a 2D gradient-echo sequence with TR/TE\u0026thinsp;=\u0026thinsp;532/16 ms, flip angle\u0026thinsp;=\u0026thinsp;18\u0026deg;, FOV\u0026thinsp;=\u0026thinsp;304 \u0026times; 216 mm\u0026sup2;, matrix\u0026thinsp;=\u0026thinsp;512 \u0026times; 512, and slice thickness/gap\u0026thinsp;=\u0026thinsp;5/1 mm.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDiffusion-weighted imaging (DWI): Acquired in the axial plane using a single-shot spin-echo echo planar imaging sequence with TR/TE\u0026thinsp;=\u0026thinsp;3362/86 ms, flip angle\u0026thinsp;=\u0026thinsp;90\u0026deg;, FOV\u0026thinsp;=\u0026thinsp;92 \u0026times; 90 mm\u0026sup2;, matrix\u0026thinsp;=\u0026thinsp;128 \u0026times; 128, slice thickness\u0026thinsp;=\u0026thinsp;2.5 mm, and b-values of 0 and 1000 s/mm\u0026sup2; applied in 15 directions.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eCSO-PVS were evaluated on T2-weighted MRIs obtained at the initial pre-treatment screening, based on the criteria established by Charidimou et al [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Small sharply delineated structures of (or close to) CSF intensity measuring\u0026thinsp;\u0026lt;\u0026thinsp;3 mm and following the course of perforating or medullary vessels on the slice where the hand knobs of the primary motor cortex were observed were visually counted by two trained observers (TK, KA) independently. An independent adjudicator (KFM) decided on cases where the two examiners' decisions were inconsistent. TK: Neurologist with 26 years of experience in diagnostic imaging for cognitive disorders, KA: board-certified radiologist with 24 years of experience. KFM: Neurologist with 17 years of experience. All observers were blinded to the clinical data.\u003c/p\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Mann-Whitney U test was used for two-group comparisons using GraphPad Prism 10. Fisher\u0026rsquo;s exact test was used to evaluate the statistical association between two categorical variables using GraphPad Prism 10. Kappa statistics and intraclass correlation coefficient analyses were conducted using SPSS version 23. Statistical significance was set at two-tailed P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eClinical Characteristics\u003c/h2\u003e\u003cp\u003eThirty-five subjects were initially enrolled in the study. Of these, five subjects were excluded for the following reasons: three due to having more than four microhemorrhages and/or presence of superficial siderosis, one due to a diagnosis of DLB, and one due to MRI findings indicative of asymptomatic ventriculomegaly with features of iNPH but without iNPH symptoms. The demographic characteristics of the remaining 30 participants analyzed in this study (mean age\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation: 74.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.94 years; female: male\u0026thinsp;=\u0026thinsp;18:12) are summarized in Table\u0026nbsp;1.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eGrading of CSO-PVS\u003c/h2\u003e\u003cp\u003eFirst, we performed a pilot grading of CSO-PVS on axial T2-weighted MRI sequences using a validated two-point visual rating scale (high degree\u0026thinsp;\u0026gt;\u0026thinsp;20, low degree\u0026thinsp;\u0026le;\u0026thinsp;20), as per the Boston criteria version 2.0 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Inter- and intra-rater reliability were evaluated using the Kappa statistic by two independent raters. Excellent inter- and intra-rater reliability was observed for dichotomized grading (inter-rater Kappa\u0026thinsp;=\u0026thinsp;1.000, intra-rater Kappa\u0026thinsp;=\u0026thinsp;1.000). Among the 30 cases assessed, only one participant had a high degree of CSO-PVS (\u0026gt;\u0026thinsp;20), whereas the remaining 29 had\u0026thinsp;\u0026le;\u0026thinsp;20 CSO-PVS. The limited sample size made statistical comparisons impossible when using the previously reported cutoff of 20 for the CSO-PVS grading. Intraclass correlation coefficients (ICC (2,1)) for the raw CSO-PVS counts demonstrated good reliability (0.811, 95% confidence interval\u0026thinsp;=\u0026thinsp;0.642\u0026ndash;0.950, P\u0026thinsp;=\u0026thinsp;0.000). While the lower limit of the 95% confidence interval (0.642) is relatively low, the overall interval suggested that the inter-rater agreement is within a practically acceptable range. The raw counts of CSO-PVS from the two raters were consistent. Consequently, we adopted their median value of CSO-PVS as a new criterion for grouping participants. Subjects with raw counts above the median were assigned to the high-degree group, while those with counts at or below the median were assigned to the low-degree group. The inter-rater reliability for this dichotomized classification demonstrated substantial agreement (inter-rater Kappa\u0026thinsp;=\u0026thinsp;0.798). The final cutoff value for CSO-PVS counts was set at 9. For cases in which the classification results differed between the two independent raters (TK, KA), a final group assignment was determined by an independent adjudicator (KFM), who reviewed the results of both raters. Histograms of CSO-PVS counts and representative images from the high-degree and low-degree groups are presented in Fig.\u0026nbsp;2.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eComparison Between High and Low-Degree Groups of CSO-PVS\u003c/h3\u003e\n\u003cp\u003eIn accordance with the dichotomization as described above, participants were categorized into low-degree and high-degree CSO-PVS groups. The clinical characteristics of the two groups are presented in Table\u0026nbsp;2. There were no significant differences between the two groups regarding sex, age, dementia diagnosis (MCI-due to AD or mild AD), history of hypertension, dyslipidemia, diabetes, atrial fibrillation, stroke, or ApoE genotype. MMSE-J scores were significantly lower in the low-degree CSO-PVS group than in the high-degree group. There were four cases with ARIA E/H during 6-months observation period, of which one case was symptomatic. Among the four cases with ARIA E/H, three belonged to the high-degree CSO-PVS group, while one was in the low-degree CSO-PVS group. The case with symptomatic ARIA belonged to the low-degree CSO-PVS group (as reported previously [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]). There was no significant difference in the incidence of ARIA E/H between the two groups.\u003c/p\u003e\u003cp\u003eFigure\u0026nbsp;3 presents the concentrations of Aβ40, Aβ42, and p-tau181 in CSF. CSF Aβ40 levels were significantly lower in the high-degree CSO-PVS group compared to the low-degree group (P\u0026thinsp;=\u0026thinsp;0.0235). CSF Aβ42 levels also tended to be lower in the high-degree group, although the difference narrowly missed statistical significance (P\u0026thinsp;=\u0026thinsp;0.0502). CSF p-tau181 levels were significantly lower in the high-degree group than in the low-degree group (P\u0026thinsp;=\u0026thinsp;0.0264). The CSF Aβ42/40 ratio did not differ significantly between the high- and low-degree groups (P\u0026thinsp;=\u0026thinsp;0.5453). However, as hypothesized, the product of Aβ40 and Aβ42 (Aβ40 \u0026times; Aβ42) was significantly lower in the high-degree group (P\u0026thinsp;=\u0026thinsp;0.0264).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, participants with high-degree of CSO-PVS exhibited lower CSF Aβ40 levels. Although the difference did not reach statistical significance, Aβ42 levels also tended to be lower in the high-degree CSO-PVS group. Importantly, this study targeted patients with mild AD or MCI due to AD who were eligible for lecanemab treatment, thus including only individuals with minimal CAA-related hemorrhagic findings and few enlarged CSO-PVS. Indeed, only one case exhibited 21 or more enlarged CSO-PVS, the threshold defined by the Boston criteria version 2.0 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Even though only a few participants exhibited a high degree of CSO-PVS in this cohort, it was noteworthy that further reductions in CSF Aβ42 and Aβ40 levels\u0026mdash;biomarkers of vascular amyloid deposition\u0026mdash;were still observed in accordance with the relative severity of the CSO-PVS burden. Previous studies have reported significantly reduced Aβ40 and Aβ42 levels in patients with sporadic CAA meeting the modified Boston criteria and hereditary Dutch CAA compared to control groups [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Additionally, the severity of CSO-PVS has been shown to correlate with the extent of CAA-related hemorrhages and white matter lesions [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The findings of the current study align with the results predicted from those previous reports. In particular, considering the fact that our subjects exhibited less CAA-related hemorrhages, the current results suggest the implication that CSO-PVS dilation and associated reductions in CSF Aβ42 and Aβ40 might precede the development of CAA-related cerebral hemorrhages. This interpretation is consistent with prior research in hereditary Dutch CAA, which demonstrated that reduction in CSF Aβ42 and Aβ40 as well as dilation of CSO-PVS were evident even in asymptomatic carriers[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Notably, the product of Aβ42 and Aβ40 concentrations (Aβ42 \u0026times; Aβ40) was also significantly lower in the high-degree CSO-PVS group. This composite metric may reflect the cumulative loss of both longer (Aβ42) and shorter (Aβ40) amyloid species into vascular deposits and has the advantage of mitigating potential variability from individual peptide measurements. Although not commonly used, such multiplicative indices have been proposed as exploratory biomarkers in previous fluid biomarker studies [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. To the best of our knowledge, there are few studies that have conducted a direct comparison between CSO-PVS grading and reductions in Aβ40 and Aβ42 levels. Our findings imply that dilated CSO-PVS may serve as a potential diagnostic marker reflecting vascular amyloid deposition for candidates for anti-amyloid therapy who exhibited minimal or no CAA-related hemorrhages.\u003c/p\u003e\u003cp\u003eInterestingly, CSF p-tau181 levels were lower in the high-degree CSO-PVS group. This may reflect impaired glymphatic or perivascular clearance vascular amyloid, which hinders the transport of phosphorylated tau into the CSF [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Furthermore, given that vascular amyloid deposition per se has limited neurotoxicity to the brain parenchyma unless accompanied by hemorrhage[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], it is conceivable that the increase in p-tau181\u0026mdash;a biomarker reflecting both tau phosphorylation and the presence of plaque\u0026mdash;was attenuated in the high-degree CSO-PVS group [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. This latter hypothesis is in line with our finding that the high-degree CSO-PVS group demonstrated significantly higher MMSE-J scores.\u003c/p\u003e\u003cp\u003eFinally, we acknowledge that the small sample size represents a significant limitation of this study, potentially reducing the statistical power to detect associations between CSO-PVS severity and CSF biomarkers. Future research should focus on developing objective, automated methodologies for CSO-PVS grading, minimizing reliance on visual assessments. Moreover, large-scale, multicenter studies are necessary to further elucidate the relationship between CSF biomarkers for amyloids and CSO-PVS findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAmong individuals with mild AD or MCI due to AD characterized by reduced CSF Aβ42/40 ratio and minimal or no CAA-related hemorrhages, CSF Aβ40 levels were significantly lower and CSF Aβ42 levels tended to be lower in those with a high degree of CSO-PVS compared with those with a low degree of CSO-PVS. These findings suggest that dilated CSO-PVS may serve as a potential surrogate marker of vascular amyloid deposition in patients undergoing anti-amyloid therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the grant for Social Welfare Activities of Mitsubishi Foundation to TK.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTK and MFK were involved in the conceptualization and design of the study, patient enrollment, data collection, data analysis, interpretation of the data, and review of the manuscript. TK wrote the first manuscript. KA conducted assessment of MRI images and was involved in data interpretation and review of the manuscript. KW was involved in data collection. \u0026nbsp;YN, HS, TS, and MY assisted with patient enrollment and manuscript review. IM conducted analysis of ApoE haplotype. YF, KS, KW, and TO reviewed and revised the manuscript. All the authors reviewed the drafts and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCo\u003c/strong\u003e\u003cstrong\u003empeting\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available in Supplementary Table.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy procedures were designed and performed in accordance with the Declaration of Helsinki. The study was approved by the University Ethics Committee of Kyoto Prefectural University of Medicine (KPUM), Kyoto, Japan (ERB-G-12)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e \u003cstrong\u003edeclaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained before participation from the participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTK received Social Welfare Activities of Mitsubishi Foundation, Grants-in-Aid (grant numbers 21K07466) from the Ministry of Education, Culture, Sports, Science, and Grant-in-Aid (grant number 24FC010) from the Ministry of Health Labour and Welfare). FKM received a Japan Heart Foundation Research Grant. The other authors declare no financial disclosures. The funding organizations were not involved in the study design, data collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eHardy, J. \u0026amp; Selkoe, D. J. The amyloid hypothesis of Alzheimer\u0026apos;s disease: progress and problems on the road to therapeutics. \u003cem\u003eScience (New York, N.Y.)\u003c/em\u003e \u003cstrong\u003e297\u003c/strong\u003e, 353-356, doi:10.1126/science.1072994 (2002).\u003c/li\u003e\n \u003cli\u003eBateman, R. 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Biomarkers for Alzheimer\u0026apos;s disease: current status and prospects for the future. \u003cem\u003eJournal of internal medicine\u003c/em\u003e \u003cstrong\u003e284\u003c/strong\u003e, 643-663, doi:10.1111/joim.12816 (2018).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer’s disease, CSO-PVS, CSF Aβ40, cerebral amyloid angiopathy","lastPublishedDoi":"10.21203/rs.3.rs-7661793/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7661793/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWith the increasing use of anti-amyloid therapy, there is a growing need for reliable methods to detect vascular amyloid in patients with early-stage Alzheimer's disease (AD). The reduction in cerebrospinal fluid (CSF) Aβ42 and Aβ40 levels is a well-documented characteristic of fluid biomarkers for cerebral amyloid angiopathy (CAA). However, the invasive nature of CSF collection hinders its feasibility for routine clinical applications. Alternatively, a high degree of MRI-visible perivascular spaces in the centrum semiovale (CSO-PVS), which are typically associated with CAA-related hemorrhages, is emerging as a promising non-invasive imaging biomarker. Nevertheless, the applicability of a high degree of CSO-PVS to reflect vascular amyloid accumulation in amyloid-positive individuals without definitive CAA-related hemorrhages remains unclear.\u003c/p\u003e\u003cp\u003eThis study retrospectively analyzed 30 participants diagnosed with mild cognitive impairment due to AD or mild AD characterized by reduced CSF Aβ42/40 ratio without CAA-related hemorrhagic manifestations. Participants were categorized into high- and low-degree CSO-PVS groups based on the median value of visually quantified CSO-PVS. CSF Aβ40 levels were significantly lower in the high-degree CSO-PVS group compared with the low-degree group (P\u0026thinsp;=\u0026thinsp;0.0235), and CSF Aβ42 levels showed a trend toward lower values (P\u0026thinsp;=\u0026thinsp;0.0502). These findings suggest that dilated CSO-PVS may serve as a potential surrogate marker for vascular amyloid deposition, offering a non-invasive alternative for monitoring patients undergoing anti-amyloid therapy.\u003c/p\u003e","manuscriptTitle":"Enlarged Centrum Semiovale Perivascular Spaces as a Non- Invasive Imaging Marker of Vascular Amyloid Deposition in Amyloid-Positive Individuals Without CAA-Related Hemorrhages","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-21 23:12:29","doi":"10.21203/rs.3.rs-7661793/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d9b639c3-6a5c-4559-93ce-3ce3a5aa90de","owner":[],"postedDate":"October 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-02T15:38:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-21 23:12:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7661793","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7661793","identity":"rs-7661793","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}