Background: Cerebral amyloid angiopathy (CAA) is a heterogeneous small vessel disease that can occur independently or alongside Alzheimer disease (AD). CAA is diagnosed using the Boston Criteria 2.0, integrating clinical and neuroimaging features, whereas the Cerebrospinal Fluid (CSF) role in clinical practice remains under investigation. This study explores whether CSF biomarkers can identify distinct disease phenotypes, supporting hemorrhagic risk stratification. Methods: We enrolled probable patients with CAA retrospectively (Boston Criteria 2.0) from 2 institutions, collecting clinical, neuroimaging, and follow‐up data alongside core CSF biomarkers (Aβ40 [amyloid β 1–40], Aβ42 [amyloid β 1–42], p‐Tau181 [phosphorylated Tau], total‐Tau). Patients with CAA were stratified applying the Amyloid Tau Neurodegeneration (ATN) research framework, according to the presence of CSF amyloidosis (A ⁺ CAA versus A ⁻ CAA) and tauopathy (A ⁺ T ⁺ CAA versus A ⁺ T ⁻ CAA), and using unsupervised clustering, which defined CAA subgroups based on CSF biomarker levels only. Kaplan‐Meier and Cox regression analyses assessed the predictive value of CSF‐based subgroups for symptomatic hemorrhages during follow‐up. Results: Seventy‐one probable CAA patients (aged 71.77±8.45 years, 66% men, median follow‐up 1.15 years [0.50–2.44]) were enrolled. A ⁺ CAA showed a higher prevalence of cortical superficial siderosis than A ⁻ CAA (67% versus 25%, P =0.016). A ⁺ T ⁻ CAA had a greater hemorrhagic risk than A ⁺ T ⁺ CAA during follow‐up (29 versus 7 events per 100 patient‐years, P =0.010; log‐rank test: P =0.013). Unsupervised clustering identified 2 subgroups, which we defined as pure CAA and CAA‐ADA, with pure CAA presenting more symptomatic hemorrhages during follow‐up (22 versus 0 events per 100 patient‐years, P =0.017; log‐rank test, P =0.011). Conclusions: CSF‐based profiling effectively stratifies CAA phenotypes, offering a promising prognostic tool alongside neuroimaging markers. Further validation is needed to confirm its role in identifying patients with CAA with different natural histories.

Background: Amyloid-related imaging abnormalities (ARIA) have gained significance in the context of anti-amyloid therapies (AATs), exhibiting clinical and radiological manifestations that overlap with Cerebral Amyloid Angiopathy-related inflammation (CAA-ri). This review aims to elucidate the similarities and differences between spontaneous (sARIA) and drug-induced ARIA (dARIA). Methods: We conducted a narrative review comparing sARIA and dARIA, focusing on their underlying mechanisms, clinical presentations, and implications for diagnosis and treatment. Results: Both sARIA and dARIA are characterized by similar pathophysiological mechanisms involving amyloid deposits and neuroinflammation. Notably, ARIA can manifest as ARIA-E (edema) or ARIA-H (hemorrhage), with varying incidence rates in clinical trials. The review highlights that while sARIA occurs independently from treatment, dARIA is associated with AAT and can lead to significant symptomatic presentations. Conclusions: Understanding the continuum between sARIA and dARIA is crucial for improving diagnostic criteria, risk stratification, and therapeutic approaches. The proposed unified framework emphasizes the need for consensus in managing these conditions and advancing future research in amyloid-related diseases.

Dementia with Lewy bodies (DLB) and Parkinson disease (PD), especially when associated with REM sleep behavior disorder (RBD), represent partially overlapping phenotypes of overt α-synucleinopathies. We aimed to investigate overlapping and discrepant features between DLB with RBD (DLBRBD), PD with RBD (PDRBD), and PD without RBD (PD) patients. This was a cross-sectional study where consecutive patients with de novo PD, de novo PDRBD, and de novo DLBRBD underwent a full neuropsychological battery to study cognitive impairment, brain [¹⁸F]FDG PET as a marker of brain glucose metabolism, and [¹²³I]FP-CIT SPECT as a marker of nigrostriatal dopaminergic functioning. Diagnosis was performed following current criteria, confirmed by evidence of dopaminergic deficit on [¹²³I]FP-CIT SPECT and by at least 2 years of clinical follow-up. We recruited 31 de novo PD (mean age 71.8 ± 6.2; 38.7% females), 32 de novo PDRBD (mean age 72.6 ± 6, 28% females), and 30 de novo DLBRBD (mean age 78 ± 5.4; 40% females). Compared with de novo PD and de novo PDRBD, de novo DLBRBD patients were older, and had a lower education and significantly poorer cognitive performance (p < 0.001), especially involving attention, executive, and visuospatial functions. De novo DLBRBD patients showed significant reduced glucose metabolism involving the bilateral precuneus, bilateral cuneus, right angular gyrus, right posterior cingulate cortex, and right fusiform gyrus. Dopaminergic function was significantly worst in de novo PD, with a significantly lower [¹²³I]FP-CIT binding in the least affected hemisphere (LAH) putamen (p = 0.042), LAH caudate (p = 0.027), and most affected hemisphere (MAH) putamen (p = 0.046) compared with de novo PDRBD patients, which was significantly lower also compared with de novo DLBRBD patients (p = 0.03). De novo DLBRBD had a lower binding compared with de novo PDRBD patients (p = 0.021) in the LAH caudate. The putamen/caudate ratio in the MAH was significantly lower in de novo PD compared with de novo PDRBD patients (p < 0.001) and in de novo PDRBD compared with de novo DLBRBD patients (p = 0.002). This study emphasizes how DLB with RBD and PD without RBD represent opposite ends of the neuronal α-synucleinopathy spectrum. The study highlights both overlapping and divergent clinical and neuroimaging features, with PD with RBD patients displaying an intermediate profile.

Background: Anti-amyloid therapies (AAT) are reshaping the therapeutic landscape of Alzheimer’s disease (AD), yet their implementation remains constrained by the risk of amyloid-related imaging abnormalities (ARIA). Although the ARIA phenomenon is well recognized, most available evidence stems from clinical trial safety reports framed predominantly from a dementia-oriented perspective, with relatively limited integration of vascular neurology principles. Methods: In this narrative review, we examine drug-induced ARIA through a neurovascular lens, highlighting how cerebrovascular comorbidity, particularly cerebral amyloid angiopathy (CAA), influences the risk and severity of ARIA. Results: We critically evaluated how CAA comorbidity has been assessed in randomized controlled trials, focusing on exclusion criteria, imaging thresholds, and the resulting implications for external validity. Finally, we evaluated current approaches to ARIA risk stratification and proposed a more integrative framework that combines vascular imaging markers, APOE ε4 genotype, and key clinical comorbidities. Conclusions: A more tailored patient selection and monitoring strategies may ultimately improve real-world outcomes and optimize resources in the era of AAT.

Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by hemorrhagic and nonhemorrhagic brain injuries. While cortical cerebral microinfarcts (CMI) have been associated with cortical superficial siderosis (cSS), the mechanisms linking these lesions remain unknown. This study aims to determine the spatiotemporal relationship between cortical CMI and cSS in CAA, with the hypothesis that cSS can promote local ischemic injury. Patients with probable CAA (Boston Criteria v2.0) without previous symptomatic intracerebral hemorrhage or CAA-related inflammation were recruited from a prospective memory clinic-based cohort at Massachusetts General Hospital. CAA-related radiologic manifestations-including cortical CMI and cSS-were quantified at baseline and at the 24-month follow-up on 3-Tesla MRI. Multivariable logistic regression and generalized linear models were applied to assess associations between baseline radiologic features and radiologic progression. We also compared the local density of cortical CMIs in regions with and without overlaid cSS. Among 74 patients with probable CAA (age: 73.0 [67.9-78.2] years; 38% female), 26 (35%) had cortical CMIs (n = 135, 39% underlying cSS). Compared with CMI-negative CAA, those with CMI had a higher cSS prevalence (73% vs 40%; p = 0.006), cSS volume (1.3 [0.1-8.3] vs 0 [0-0.5] mL; p < 0.001), and lobar lacunes count (50% vs 19%; p = 0.005). At baseline, cortical CMI count demonstrated a nonlinear association with cSS volume (Exp(B) = 1.12 [95% CI 1.07-1.18]; p < 0.001) and with lobar lacunes count (Exp(B) = 1.65 [95% CI 1.52-1.80]; p < 0.001). The CMI density was markedly higher in cSS-covered vs non-cSS regions (median: 20.84 [0.00-56.95] vs 0.49 [0.11-0.89]n° cortical CMI/1,000 cm2; p = 0.010). Follow-up scans (n = 36) revealed 23 incident cortical CMIs (43% underlying cSS). Baseline cSS volume was independently associated with incident CMI (OR:1.41 [95% CI 1.02-1.95]; p = 0.036), whereas baseline CMI burden was not associated with cSS progression. Our findings demonstrate a close interplay between cortical CMI and cSS, with the spatiotemporal relationship supporting the hypothesis that convexity subarachnoid hemorrhage, and potentially resultant cSS, may trigger local ischemic injury. Given the sample size of the longitudinal cohort, we consider these data hypothesis-generating. Further studies should confirm this association and identify the driving pathophysiology, which may represent a new therapeutic target for preventing cSS-associated cortical injury.