Cerebrospinal Fluid Biomarkers Profiling in Cerebral Amyloid Angiopathy and Relationship With Disease Phenotypes.

P 25 CSF biomarkers in CAA compared to AD

There are limited data regarding cerebrospinal fluid (CSF) and plasma biomarkers among patients with Cerebral Amyloid Angiopathy (CAA). We sought to investigate the levels of four biomarkers [β-amyloids (Aβ42 and Aβ40), total tau (tau) and phosphorylated tau (p-tau)] in CAA patients compared to healthy controls (HC) and patients with Alzheimer Disease (AD). A systematic review and meta-analysis of published studies, including also a 5 year single-center cohort study, with available data on CSF and plasma biomarkers in symptomatic sporadic CAA versus HC and AD was conducted. Biomarkers' comparisons were investigated using random-effects models based on the ratio of mean (RoM) biomarker concentrations. RoM < 1 and RoM > 1 indicate lower and higher biomarker concentration in CAA compared to another population, respectively. We identified nine cohorts, comprising 327 CAA patients (mean age: 71 ± 5 years; women: 45%) versus 336 HC (mean age: 65 ± 5 years; women: 45%) and 384 AD patients (mean age: 68 ± 3 years; women: 53%) with available data on CSF biomarkers. CSF Aβ42 levels [RoM: 0.47; 95% CI: 0.36-0.62; p < 0.0001], Aβ40 levels [RoM: 0.70; 95% CI: 0.63-0.79; p < 0.0001] and the ratio Aβ42/Aβ40 [RoM: 0.62; 95% CI: 0.39-0.98; p = 0.0438] differentiated CAA from HC. CSF Aβ40 levels [RoM: 0.73; 95% CI: 0.64-0.83; p = 0.0003] differentiated CAA from AD. CSF tau and p-tau levels differentiated CAA from HC [RoM: 1.71; 95% CI: 1.41-2.09; p = 0.0002 and RoM: 1.44; 95% CI: 1.20-1.73; p = 0.0014, respectively] and from AD [RoM: 0.65; 95% CI: 0.58-0.72; p < 0.0001 and RoM: 0.64; 95% CI: 0.57-0.71; p < 0.0001, respectively]. Plasma Aβ42 [RoM: 1.14; 95% CI: 0.89-1.45; p = 0.2079] and Aβ40 [RoM: 1.07; 95% CI: 0.91-1.25; p = 0.3306] levels were comparable between CAA and HC. CAA is characterized by a distinct CSF biomarker pattern compared to HC and AD. CSF Aβ40 levels are lower in CAA compared to HC and AD, while tau and p-tau levels are higher in CAA compared to HC, but lower in comparison to AD patients.

Elderly and forgetful with transient neurological spells: A story of two amyloids?

BackgroundCerebral amyloid angiopathy (CAA) typically presents as spontaneous lobar intracerebral hemorrhage (ICH) or cognitive impairment. While the Boston criteria 2.0 aid CAA diagnosis in ICH, detecting nonhemorrhagic cases remains challenging. Cerebrospinal fluid (CSF) biomarkers may offer valuable diagnostic support. This study aimed to evaluate CSF Aβ40, Aβ42, total‐τ, phosphorylated‐τ, Aβ42/Aβ40, and phosphorylated‐τ/Aβ42 in patients with CAA with and without symptomatic ICH.MethodsThis prospective observational study recruited patients with CAA from the cerebrovascular clinic of Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan, Italy) from January 2021 to June 2024. Patients underwent T2*‐weighted magnetic resonance imaging and lumbar puncture, with CSF biomarkers measured via Lumipulse. Participants were grouped into CAA−ICH+ (prior symptomatic lobar ICH) and CAA−ICH−.ResultsFifty‐four patients were included: 35 CAA−ICH+ (37.1% women) and 19 CAA−ICH− (52.4% men). Groups were similar in mean age at lumbar puncture (63.8 versus 67.9 years) and cognitive impairment prevalence (57.1% versus 47.4%). Median CSF Aβ40 level was significantly lower in CAA−ICH+ than in CAA−ICH− (4355 versus 6507 pg/mL, P<0.001). Median CSF Aβ42 level, although reduced in the entire CAA population analyzed, did not differ significantly between the 2 groups (245 versus 303 pg/mL, P=0.09). Other CSF biomarkers levels were comparable between CAA−ICH+ and CAA−ICH−: total‐τ (P=0.28), phosphorylated‐τ (P=0.16), Aβ42/Aβ40 (P=0.14), and phosphorylated‐τ/Aβ42 (P=0.93).ConclusionsCSF Aβ40 is significantly lower in patients with CAA with prior ICH. Amyloid dysregulation in CAA may follow distinct pathological trajectories depending on previous ICH. CSF Aβ40 shows promise as a biomarker for CAA and merits further studies to explore its prognostic value in disease progression.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT04204642.

There is no consensus regarding the diagnostic value of cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in cerebral amyloid angiopathy (CAA). To describe the CSF levels of Aβ42, Aβ40, total protein Tau, and phosphorylated-Tau (p-Tau) in a large series of probable CAA patients and to compare with AD patients in order to identify a specific pattern in CAA but also to look for correlations with the neuroimaging profile. We retrospectively included from 2 French centers probable CAA patients according to modified Boston criteria who underwent lumbar puncture (LP) with CSF AD biomarker quantifications. Two neurologists independently analyzed all MRI sequences. A logistic regression and Spearman's correlation coefficient were used to identify correlation between MRI and CSF biomarkers in CAA. We included 63 probable CAA and 27 AD patients. Among CAA 50.8% presented with decreased Aβ42 level associated with elevated p-Tau and/or Tau, 34.9% with isolated decreased Aβ42 level and 14.3% patients with normal Aβ42 level. Compared to AD, CAA showed lower levels of Tau (p = 0.008), p-Tau (p = 0.004), and Aβ40 (p = 0.001) but similar Aβ42 level (p = 0.07). No correlation between Aβ42 or Aβ40 levels and neuroimaging was found. CSF biomarkers may improve the accuracy of the modified Boston criteria with altered profile in 85% of the patients fulfilling revised Boston criteria for probable CAA. Aβ40 appears as an interesting selective biomarker in differential diagnosis.

BackgroundTo evaluate the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers in patients with probable cerebral amyloid angiopathy (CAA) according to the modified Boston criteria in a retrospective multicentric cohort.MethodsBeta-amyloid 1-40 (Aβ40), beta-amyloid 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau 181 (p-tau181) were measured in 31 patients with probable CAA, 28 patients with Alzheimer’s disease (AD), and 30 controls. Receiver-operating characteristics (ROC) analyses were performed for the measured parameters as well as the Aβ42/40 ratio to estimate diagnostic parameters. A meta-analysis of all amenable published studies was conducted.ResultsIn our data Aβ42/40 (AUC 0.88) discriminated best between CAA and controls while Aβ40 did not perform well (AUC 0.63). Differentiating between CAA and AD, p-tau181 (AUC 0.75) discriminated best in this study while Aβ40 (AUC 0.58) and Aβ42 (AUC 0.54) provided no discrimination. In the meta-analysis, Aβ42/40 (AUC 0.90) showed the best discrimination between CAA and controls followed by t-tau (AUC 0.79), Aβ40 (AUC 0.76), and p-tau181 (AUC 0.71). P-tau181 (AUC 0.76), Aβ40 (AUC 0.73), and t-tau (AUC 0.71) differentiated comparably between AD and CAA while Aβ42 (AUC 0.54) did not. In agreement with studies examining AD biomarkers, Aβ42/40 discriminated excellently between AD and controls (AUC 0.92–0.96) in this study as well as the meta-analysis.ConclusionThe analyzed parameters differentiate between controls and CAA with clinically useful accuracy (AUC > ∼0.85) but not between CAA and AD. Since there is a neuropathological, clinical and diagnostic continuum between CAA and AD, other diagnostic markers, e.g., novel CSF biomarkers or other parameters might be more successful.

Inflammation Complicates an ‘Age-Related’ Cerebral Microangiopathy

Background/Objectives: Cognitive impairment represents a core and prodromal clinical feature of cerebral amyloid angiopathy (CAA). We sought to assess specific cognitive domains which are mainly affected among patients with CAA and to investigate probable associations with neuroimaging markers and Cerebrospinal Fluid (CSF) biomarkers. Methods: Thirty-five patients fulfilling the Boston Criteria v1.5 or v2.0 for the diagnosis of probable/possible CAA were enrolled in this prospective cohort study. Brain Magnetic Resonance Imaging and CSF biomarker data were collected. Every eligible participant underwent a comprehensive neurocognitive assessment. Spearman's rank correlation tests were used to identify possible relationships between the Addenbrooke's Cognitive Examination-Revised (ACE-R) sub-scores and other neurocognitive test scores and the CSF biomarker and neuroimaging parameters among CAA patients. Moreover, linear regression analyses were used to investigate the effects of CSF biomarkers on the ACE-R total score and Mini-Mental State Examination (MMSE) score, based on the outcomes of univariate analyses. Results: Cognitive impairment was detected in 80% of patients, and 60% had a coexistent Alzheimer's disease (AD) pathology based on CSF biomarker profiles. Notable correlations were identified between increased levels of total tau (t-tau) and phosphorylated tau (p-tau) and diminished performance in terms of overall cognitive function, especially memory. In contrast, neuroimaging indicators, including lobar cerebral microbleeds and superficial siderosis, had no significant associations with cognitive scores. Among the CAA patients, those without AD had superior neurocognitive test performance, with significant differences observed in their ACE-R total scores and memory sub-scores. Conclusions: The significance of tauopathy in cognitive impairment associated with CAA may be greater than previously imagined, underscoring the necessity for additional exploration of the non-hemorrhagic facets of the disease and new neuroimaging markers.

The Boston criteria v2.0 for cerebral amyloid angiopathy (CAA) incorporated non-hemorrhagic imaging markers. Their prevalence and significance in patients with cognitive impairment remain uncertain. We studied 622 memory clinic patients with available magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers. Two raters assessed non-hemorrhagic markers, and we explored their association with clinical characteristics through multivariate analyses. Most patients had mild cognitive impairment; median age was 71 years and 50% were female. Using the v2.0 criteria, possible or probable CAA increased from 75 to 383 patients. Sixty-eight percent of the sample had non-hemorrhagic CAA markers, which were independently associated with age (odds ratio [OR]=1.04, 95% confidence interval [CI]=1.01-1.07), female sex (OR=1.68, 95% CI=1.11-2.54), and hemorrhagic CAA markers (OR=2.11, 95% CI=1.02-4.35). Two-thirds of patients from a memory clinic cohort had non-hemorrhagic CAA markers, increasing the number of patients meeting the v2.0 CAA criteria. Longitudinal approaches should explore the implications of these markers, particularly the hemorrhagic risk in this population. The updated Boston criteria for cerebral amyloid angiopathy (CAA) now include non-hemorrhagic markers. The prevalence of non-hemorrhagic CAA markers in memory clinic patients is unknown. Two-thirds of patients in our memory clinic presented non-hemorrhagic CAA markers. The presence of these markers was associated with age, female sex, and hemorrhagic CAA markers. The hemorrhagic risk of patients presenting these type of markers remains unclear.

Clinical Relevance of Cerebral Small Vessel Diseases.

Cerebral amyloid angiopathy (CAA) is a common cause of lobar and subarachnoid hemorrhages in the elderly. A diagnosis of CAA requires multiple lobar hemorrhagic lesions (intracerebral hemorrhage and/or cerebral microbleeds) and/or cortical superficial siderosis (cSS). In contrast, hemorrhagic lesions located in the deep structures are the hallmark of hypertensive arteriopathy (HTN-A). They are an exclusion criterion for CAA, and when present with lobar hemorrhagic lesions considered a separate entity: mixed location hemorrhages/microbleeds (MLHs). We compared clinical, radiological, and cerebrospinal fluid (CSF) marker data in patients with CAA, MLH, and Alzheimer's disease (AD), and healthy controls (HCs) and used it to position MLH in the disease spectrum. Retrospective cohort study of consecutive patients with CAA (n = 31), MLH (n = 31), AD (n = 28), and HC (n = 30). Analysis of clinical, radiological, CSF biomarker (Aß42, Aß40, t-tau, and p-tau), and histopathological data in patients each group. cSS was significantly more common in CAA than MLH (45% vs 13%, p = 0.011), and cSS in MLH was associated with intracerebral hemorrhage (ICH) (p = 0.037). Aß42 levels and the Aß42/Aß40 ratio, diagnostic groups followed the order HC > MLH > CAA > AD and the opposite order for t-tau and p-tau. No clear order was apparent forAß40. Aß40 and Aß42 levels as well as the Aß42/Aß40 ratio were lower in both CAA and MLH patients with cSS than in patients without cSS. Aß40 and Aß42 levels were higher in CAA and MLH patients with lacunar infarcts than in those without. Our data suggest that MLH and CAA are mutually not exclusive diagnoses, and are part of a spectrum with variable contributions of both CAA and HTN-A.

The Boston criteria are a set of clinical and neuroimaging features that enable accurate diagnosis of cerebral amyloid angiopathy (CAA) without invasive methods such as brain biopsies or autopsy. The last updates to the Boston criteria, named version 2.0, were recently released and incorporated new nonhemorrhagic MRI features. These criteria have been validated in symptomatic samples, with improved diagnostic yield. We set out to investigate the accuracy of the Boston criteria v2.0 for the diagnosis of CAA in a community-based sample. Participants were recruited from longitudinal clinical-pathologic studies of aging conducted at the Rush Alzheimer's Disease Center in Chicago: the Religious Orders Study and the Rush Memory and Aging Project. Deceased participants with in vivo 3T MRI and detailed pathologic data available were included in the analysis. We compared the diagnostic yield of the current and earlier versions of the Boston criteria in our sample. Among those classified as probable CAA according to the Boston criteria v2.0, we investigated the ability of each neuroimaging marker to distinguish between false-positive and true-positive cases. In total, 134 individuals were included in the study (mean age = 82.4 ± 6.0 years; 69.4% F), and 49 of them were considered pathology-proven definite cases with CAA (mean age = 82.9 ± 6.0 years; 63.3% F). The Boston criteria versions 1.0 and 1.5 yielded similar sensitivity (26.5%, both), specificity (90.6% and 89.4%, respectively), and predictive values (negative: 68.1% and 67.9%; positive: 61.9% and 59.1%, respectively). The recently released Boston criteria v2.0 offered higher sensitivity (38.8%) and slightly lower specificity (83.5%). Among those classified as probable CAA (v2.0), pathology-proven true-positive cases had higher numbers of strictly cortical lobar microbleeds compared with false-positive cases (p = 0.004). Similar to findings from symptomatic samples, the inclusion of nonhemorrhagic neuroimaging markers in the updated Boston criteria offered a 12.3% gain in sensitivity among community-dwelling individuals, at the expense of a 5.9% drop in specificity. In cases with probable CAA, the cortical location of microbleeds may represent a promising distinguishing feature between true-positive and false-positive cases. Despite its improved performance, the diagnostic sensitivity of the updated criteria in a community-based sample remains limited. This study provides Class II evidence that the Boston criteria v2.0 accurately distinguishes people with CAA from those without CAA.

The presence of concomitant Alzheimer pathology has been linked to earlier death in cases with dementia with Lewy bodies (DLB). Recently, elevated cerebrospinal fluid (CSF) tau protein levels have been reported to be associated with shorter survival in clinically diagnosed DLB. Correlations between CSF biomarkers and neuropathological findings in DLB are missing. The aim of this study was to investigate correlations between CSF biomarker levels and histopathological findings, with a focus on concomitant Alzheimer pathology, in neuropathologically verified DLB cases. The extent of neurofibrillary pathology (Braak stage), neuritic plaques (CERAD stage), Alzheimer pathology (PPAD9 stage) and cerebral amyloid angiopathy was assessed in 16 cases with DLB in whom total tau (T-tau), hyperphosphorylated tau and amyloid beta 1-42 (Aβ42) protein levels in CSF had been analyzed in vivo. Demographic and clinical data were collected. Both Braak and PPAD9 stages were inversely correlated with Aβ42 levels, whereas CERAD stage showed no significant correlations. Cerebral amyloid angiopathy correlated positively with T-tau and T-tau/Aβ42 ratio, and inversely with Aβ42 levels, but the group showed a very heterogeneous extent of cerebral amyloid angiopathy. The burden of concomitant Alzheimer pathology correlates with CSF Aβ42 but not with T-tau levels in cases with neuropathologically defined DLB.

BackgroundThere is large variation in estimates of the prevalence of cerebral amyloid angiopathy (CAA). CAA is associated with an increased risk of cognitive dysfunction and intracerebral hemorrhages, and it is tightly linked to immunotherapy‐related side‐effects in Alzheimer’s disease (AD). Thus, accurate estimates of the prevalence of CAA are important. CAA can be diagnosed neuropathologically (‘definite CAA’), or during life (‘probable CAA’) using the (modified) Boston criteria based on MRI markers.MethodWe performed a systematic literature search in PubMed and EMBASE for studies on CAA prevalence in cohorts of patients with AD, population‐based individuals, healthy elderly, patients with intracerebral hemorrhage (ICH), and patients with lobar ICH. Study inclusion criteria were: 1) a study population of at least 10 subjects, 2) a mean age of ≥ 55 years, 3) diagnostic criteria included use of neuropathology or MRI (T2* or SWI), 4) outcome measures included CAA prevalence according to neuropathological assessment or the (modified) Boston criteria, or the prevalence of the MRI markers used in the Boston criteria: strictly lobar microbleeds or cortical superficial siderosis.ResultWe included 170 studies including over 73,000 subjects. We found that in patients with AD, the estimated prevalence of CAA based on pathology (48%) is twice the prevalence based on the presence of strictly lobar microbleeds (22%). In the general population, this difference is threefold (23% vs 7%). However, both methods yield the same estimated prevalence of CAA in healthy elderly (5‐7%), in patients with ICH (19‐24%), and in patients with lobar ICH (50‐57%). In addition, we observed large heterogeneity in both neuropathology and MRI study protocols.ConclusionCAA is a very prevalent condition in AD and in the population. Since CAA is associated with the development of amyloid‐related imaging abnormalities in anti‐amyloid β immunotherapy, a faster decline of cognitive function in AD, and a growing spectrum of clinical symptoms, awareness of the high prevalence of CAA is important. In addition, we found that MRI markers seriously underestimate the prevalence of CAA in AD patients and population‐based individuals. Lastly, our results emphasize the need for standardized assessment and reporting of CAA in neuropathology and MRI studies.

Amyloid positron emission tomography in sporadic cerebral amyloid angiopathy: A systematic critical update