ABSTRACT
Cerebral amyloid angiopathy (CAA) is a highly prevalent and progressive pathology, involving amyloid-ß (Aß) deposition in the cerebral blood vessel walls. CAA is associated with an increased risk for intracerebral hemorrhages (ICH). Insight into the molecular mechanisms associated with CAA pathology is urgently needed, to develop additional diagnostic tools to allow for reliable and early diagnosis of CAA and to obtain novel leads for the development of targeted therapies. Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) is associated with cardiovascular functioning and disease and has been linked to vascular dementia. Using immunohistochemistry, we studied occipital brain tissue samples of 57 patients with CAA (39 without ICH and 18 with ICH) and 42 controls, and semi-quantitatively assessed expression levels of TIMP4. Patients with CAA had increased vascular expression of TIMP4 compared to controls (p < 0.001), and in these patients, TIMP4 expression correlated with CAA severity (τb = 0.38; p = 0.001). Moreover, TIMP4 expression was higher in CAA-ICH compared to CAA-non-ICH cases (p = 0.024). In a prospective cross-sectional study of 38 patients with CAA and 37 age- and sex-matched controls, we measured TIMP4 levels in cerebrospinal fluid (CSF) and serum using ELISA. Mean CSF levels of TIMP4 were decreased in patients with CAA compared to controls (3.36 ± 0.20 vs. 3.96 ± 0.22 ng/ml, p = 0.033), whereas median serum levels were increased in patients with CAA (4.51 ng/ml [IQR 3.75-5.29] vs 3.60 ng/ml [IQR 3.11-4.85], p-9.013). Moreover, mean CSF TIMP4 levels were lower in CAA patients who had experienced a symptomatic hemorrhage compared to CAA patients who did not (2.13 ± 0.24 vs. 3.57 ± 0.24 ng/ml, p = 0.007). CSF TIMP4 levels were associated with CSF levels of Aß40 (spearman r (rs) = 0.321, p = 0.009). In summary, we show that TIMP4 is highly associated with CAA and CAA-related ICH, which is reflected by higher levels in the cerebral vasculature and lower levels in CSF. With these findings we provide novel insights into the pathophysiology of CAA, and more specifically in CAA-associated ICH.
Subject(s)
Brain , Cerebral Amyloid Angiopathy , Tissue Inhibitor of Metalloproteinase-4 , Tissue Inhibitor of Metalloproteinases , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Peptides/metabolism , Brain/metabolism , Brain/pathology , Cerebral Amyloid Angiopathy/cerebrospinal fluid , Cerebral Amyloid Angiopathy/pathology , Cerebral Hemorrhage/cerebrospinal fluid , Cerebral Hemorrhage/metabolism , Tissue Inhibitor of Metalloproteinases/cerebrospinal fluid , Tissue Inhibitor of Metalloproteinases/metabolismABSTRACT
BACKGROUND AND PURPOSE: Possible differences in the prevalence of cerebral amyloid angiopathy (CAA) in East-Asian compared to Western populations have received little attention, and results so far have been ambiguous. Our aim is to compare the prevalence of CAA neuropathology and magnetic resonance imaging markers of CAA in East-Asian and Western cohorts reflecting the general population, cognitively normal elderly, patients with Alzheimer's disease (AD), and patients with (lobar) intracerebral hemorrhage (ICH). METHODS: We performed a systematic literature search in PubMed and Embase for original research papers on the prevalence of CAA and imaging markers of CAA published up until February 17th 2022. Records were screened by two independent reviewers. Pooled estimates were determined using random-effects models. We compared studies from Japan, China, Taiwan, South Korea (East-Asian cohorts) to studies from Europe or North America (Western cohorts) by meta-regression models. RESULTS: We identified 12,257 unique records, and we included 143 studies on Western study populations and 53 studies on East-Asian study populations. Prevalence of CAA neuropathology did not differ between East-Asian and Western cohorts in any of the investigated patient domains. The prevalence of strictly lobar microbleeds was lower in East-Asian cohorts of population-based individuals (5.6% vs. 11.4%, P=0.020), cognitively normal elderly (2.6% vs. 11.4%, P=0.001), and patients with ICH (10.2% vs. 24.6%, P<0.0001). However, age was in general lower in the East-Asian cohorts. CONCLUSION: The prevalence of CAA neuropathology in the general population, cognitively normal elderly, patients with AD, and patients with (lobar) ICH is similar in East-Asian and Western countries. In East-Asian cohorts reflecting the general population, cognitively normal elderly, and patients with ICH, strictly lobar microbleeds were less prevalent, likely due to their younger age. Consideration of potential presence of CAA is warranted in decisions regarding antithrombotic treatment and potential new anti-amyloid-ß immunotherapy as treatment for AD in East-Asian and Western countries alike.
ABSTRACT
BACKGROUND: Patients with sporadic cerebral amyloid angiopathy (sCAA) frequently report cognitive or neuropsychiatric symptoms. The aim of this study is to investigate whether in patients with sCAA, cognitive impairment and neuropsychiatric symptoms are associated with a cerebrospinal fluid (CSF) biomarker profile associated with Alzheimer's disease (AD). METHODS: In this cross-sectional study, we included participants with sCAA and dementia- and stroke-free, age- and sex-matched controls, who underwent a lumbar puncture, brain MRI, cognitive assessments, and self-administered and informant-based-questionnaires on neuropsychiatric symptoms. CSF phosphorylated tau, total tau and Aß42 levels were used to divide sCAA patients in two groups: CAA with (CAA-AD+) or without a CSF biomarker profile associated with AD (CAA-AD-). Performance on global cognition, specific cognitive domains (episodic memory, working memory, processing speed, verbal fluency, visuoconstruction, and executive functioning), presence and severity of neuropsychiatric symptoms, were compared between groups. RESULTS: sCAA-AD+ (n=31; mean age: 72 ± 6; 42%, 61% female) and sCAA-AD- (n=23; 70 ± 5; 42% female) participants did not differ with respect to global cognition or type of affected cognitive domain(s). The number or severity of neuropsychiatric symptoms also did not differ between sCAA-AD+ and sCAA-AD- participants. These results did not change after exclusion of patients without prior ICH. CONCLUSIONS: In participants with sCAA, a CSF biomarker profile associated with AD does not impact global cognition or specific cognitive domains, or the presence of neuropsychiatric symptoms.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Biomarkers , Cerebral Amyloid Angiopathy , Neuropsychological Tests , tau Proteins , Humans , Female , Male , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/complications , Alzheimer Disease/diagnostic imaging , Aged , Cross-Sectional Studies , Cerebral Amyloid Angiopathy/cerebrospinal fluid , Cerebral Amyloid Angiopathy/complications , Cerebral Amyloid Angiopathy/diagnostic imaging , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Cognitive Dysfunction/cerebrospinal fluid , Cognitive Dysfunction/etiology , Peptide Fragments/cerebrospinal fluid , Cognition/physiology , Middle Aged , Magnetic Resonance ImagingABSTRACT
BACKGROUND: Sporadic cerebral amyloid angiopathy (sCAA) is a disease characterised by the progressive deposition of the amyloid beta (Aß) in the cerebral vasculature, capable of causing a variety of symptoms, from (mild) cognitive impairment, to micro- and major haemorrhagic lesions. Modern diagnosis of sCAA relies on radiological detection of late-stage hallmarks of disease, complicating early diagnosis and potential interventions in disease progression. Our goal in this study was to identify and validate novel biomarkers for sCAA. METHODS: We performed a proximity extension assay (PEA) on cerebrospinal fluid (CSF) samples of sCAA/control participants (n = 34/51). Additionally, we attempted to validate the top candidate biomarker in CSF and serum samples (n = 38/26) in a largely overlapping validation cohort, through analysis with a targeted immunoassay. RESULTS: Thirteen proteins were differentially expressed through PEA, with top candidate NFL significantly increased in CSF of sCAA patients (p < 0.0001). Validation analyses using immunoassays revealed increased CSF and serum NFL levels in sCAA patients (both p < 0.0001) with good discrimination between sCAA and controls (AUC: 0.85; AUC: 0.79 respectively). Additionally, the CSF: serum NFL ratio was significantly elevated in sCAA (p = 0.002). DISCUSSION: Large-scale targeted proteomics screening of CSF of sCAA patients and controls identified thirteen biomarker candidates for sCAA. Orthogonal validation of NFL identified NFL in CSF and serum as biomarker, capable of differentiating between sCAA patients and controls.
Subject(s)
Biomarkers , Cerebral Amyloid Angiopathy , Neurofilament Proteins , Humans , Female , Biomarkers/cerebrospinal fluid , Biomarkers/blood , Cerebral Amyloid Angiopathy/cerebrospinal fluid , Cerebral Amyloid Angiopathy/diagnosis , Male , Neurofilament Proteins/cerebrospinal fluid , Neurofilament Proteins/blood , Aged , Middle Aged , Immunoassay/methodsABSTRACT
Decreased microvascular levels of claudin-5 in the occipital and temporal lobe of patients with cerebral amyloid angiopathy are associated with intracerebral haemorrhage.
ABSTRACT
BACKGROUND: Neuropsychiatric symptoms (NPS) may affect cognition, but their burden in cerebral amyloid angiopathy (CAA), one of the main causes of intracerebral hemorrhage (ICH) and dementia in the elderly, remains unclear. We investigated NPS, with emphasis on apathy and irritability in sporadic (sCAA) and Dutch-type hereditary (D-)CAA. METHODS: We included patients with sCAA and (pre)symptomatic D-CAA, and controls from four prospective cohort studies. We assessed NPS per group, stratified for history of ICH, using the informant-based Neuropsychiatric Inventory (NPI-Q), Starkstein Apathy scale (SAS), and Irritability Scale. We modeled the association of NPS with disease status, executive function, processing speed, and CAA-burden score on MRI and investigated sex-differences. RESULTS: We included 181 participants: 82 with sCAA (mean[SD] age 72[6] years, 44% women, 28% previous ICH), 56 with D-CAA (52[11] years, 54% women, n = 31[55%] presymptomatic), and 43 controls (69[9] years, 44% women). The NPI-Q NPS-count differed between patients and controls (sCAA-ICH+:adj.ß = 1.4[95%CI:0.6-2.3]; sCAA-ICH-:1.3[0.6-2.0]; symptomatic D-CAA:2.0[1.1-2.9]; presymptomatic D-CAA:1.2[0.1-2.2], control median:0[IQR:0-3]), but not between the different CAA-subgroups. Apathy and irritability were reported most frequently: n = 12[31%] sCAA, 19[37%] D-CAA had a high SAS-score; n = 12[29%] sCAA, 14[27%] D-CAA had a high Irritability Scale score. NPS-count was associated with decreased processing speed (adj.ß=-0.6[95%CI:-0.8;-0.4]) and executive function (adj.ß=-0.4[95%CI:-0.6;-0.1]), but not with radiological CAA-burden. Men had NPS more often than women. DISCUSSION: According to informants, one third to half of patients with CAA have NPS, mostly apathy, even in presymptomatic D-CAA and possibly with increased susceptibility in men. Neurologists should inform patients and caregivers of these disease consequences and treat or refer patients with NPS appropriately.
Subject(s)
Apathy , Cerebral Amyloid Angiopathy, Familial , Cerebral Amyloid Angiopathy , Male , Humans , Female , Aged , Child , Cerebral Amyloid Angiopathy, Familial/complications , Prospective Studies , Cerebral Amyloid Angiopathy/complications , Cerebral Amyloid Angiopathy/diagnostic imaging , Cerebral Hemorrhage/complications , Magnetic Resonance ImagingABSTRACT
BACKGROUND: Neurofilament light chain (NFL) is a biomarker for neuroaxonal damage and glial fibrillary acidic protein (GFAP) for reactive astrocytosis. Both processes occur in cerebral amyloid angiopathy (CAA), but studies investigating the potential of NFL and GFAP as markers for CAA are lacking. We aimed to investigate NFL and GFAP as biomarkers for neuroaxonal damage and astrocytosis in CAA. METHODS: For this cross-sectional study serum and cerebrospinal fluid (CSF) samples were collected between 2010 and 2020 from controls, (pre)symptomatic Dutch-type hereditary (D-CAA) mutation-carriers and participants with sporadic CAA (sCAA) from two prospective CAA studies at two University hospitals in the Netherlands. NFL and GFAP levels were measured with Simoa-assays. The association between NFL and GFAP levels and age, cognitive performance (MoCA), CAA-related MRI markers (CAA-CSVD-burden) and Aß40 and Aß42 levels in CSF were assessed with linear regression adjusted for confounders. The control group was divided in age < 55 and ≥55 years to match the specific groups. RESULTS: We included 187 participants: 28 presymptomatic D-CAA mutation-carriers (mean age 40 years), 29 symptomatic D-CAA participants (mean age 58 years), 59 sCAA participants (mean age 72 years), 33 controls < 55 years (mean age 42 years) and 38 controls ≥ 55 years (mean age 65 years). In presymptomatic D-CAA, only GFAP in CSF (7.7*103pg/mL vs. 4.4*103pg/mL in controls; P<.001) was increased compared to controls. In symptomatic D-CAA, both serum (NFL:26.2pg/mL vs. 12.5pg/mL; P=0.008, GFAP:130.8pg/mL vs. 123.4pg/mL; P=0.027) and CSF (NFL:16.8*102pg/mL vs. 7.8*102pg/mL; P=0.01 and GFAP:11.4*103pg/mL vs. 7.5*103pg/mL; P<.001) levels were higher than in controls and serum levels (NFL:26.2pg/mL vs. 6.7pg/mL; P=0.05 and GFAP:130.8pg/mL vs. 66.0pg/mL; P=0.004) were higher than in pre-symptomatic D-CAA. In sCAA, only NFL levels were increased compared to controls in both serum (25.6pg/mL vs. 12.5pg/mL; P=0.005) and CSF (20.0*102pg/mL vs 7.8*102pg/mL; P=0.008). All levels correlated with age. Serum NFL correlated with MoCA (P=0.008) and CAA-CSVD score (P<.001). NFL and GFAP in CSF correlated with Aß42 levels (P=0.01/0.02). CONCLUSIONS: GFAP level in CSF is an early biomarker for CAA and is increased years before symptom onset. NFL and GFAP levels in serum and CSF are biomarkers for advanced CAA.
Subject(s)
Biomarkers , Cerebral Amyloid Angiopathy , Glial Fibrillary Acidic Protein , Neurofilament Proteins , Humans , Neurofilament Proteins/cerebrospinal fluid , Neurofilament Proteins/blood , Glial Fibrillary Acidic Protein/cerebrospinal fluid , Glial Fibrillary Acidic Protein/blood , Female , Male , Middle Aged , Cross-Sectional Studies , Biomarkers/cerebrospinal fluid , Biomarkers/blood , Aged , Cerebral Amyloid Angiopathy/cerebrospinal fluid , Cerebral Amyloid Angiopathy/blood , Cerebral Amyloid Angiopathy/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Peptides/blood , Adult , Prospective Studies , Magnetic Resonance ImagingABSTRACT
Brain amyloid-ß (Aß) deposits are key pathological hallmarks of both cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Microvascular deposits in CAA mainly consist of the Aß40 peptide, whereas Aß42 is the predominant variant in parenchymal plaques in AD. The relevance in pathogenesis and diagnostic accuracy of various other Aß isoforms in CAA remain understudied. We aimed to investigate the biomarker potential of various Aß isoforms in cerebrospinal fluid (CSF) to differentiate CAA from AD pathology. We included 25 patients with probable CAA, 50 subjects with a CSF profile indicative of AD pathology (AD-like), and 23 age- and sex-matched controls. CSF levels of Aß1-34, Aß1-37, Aß1-38, Aß1-39, Aß1-40, and Aß1-42 were quantified by liquid chromatography mass spectrometry. Lower CSF levels of all six Aß peptides were observed in CAA patients compared with controls (p = 0.0005-0.03). Except for Aß1-42 (p = 1.0), all peptides were decreased in CAA compared with AD-like subjects (p = 0.007-0.03). Besides Aß1-42, none of the Aß peptides were decreased in AD-like subjects compared with controls. All Aß peptides combined differentiated CAA from AD-like subjects better (area under the curve [AUC] 0.84) than individual peptide levels (AUC 0.51-0.75). Without Aß1-42 in the model (since decreased Aß1-42 served as AD-like selection criterion), the AUC was 0.78 for distinguishing CAA from AD-like subjects. CAA patients and AD-like subjects showed distinct disease-specific CSF Aß profiles. Peptides shorter than Aß1-42 were decreased in CAA patients, but not AD-like subjects, which could suggest different pathological mechanisms between vascular and parenchymal Aß accumulation. This study supports the potential use of this panel of CSF Aß peptides to indicate presence of CAA pathology with high accuracy.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Biomarkers , Cerebral Amyloid Angiopathy , Humans , Cerebral Amyloid Angiopathy/cerebrospinal fluid , Cerebral Amyloid Angiopathy/diagnosis , Amyloid beta-Peptides/cerebrospinal fluid , Female , Male , Aged , Biomarkers/cerebrospinal fluid , Middle Aged , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnosis , Alzheimer Disease/pathology , Peptide Fragments/cerebrospinal fluid , Aged, 80 and overABSTRACT
Cerebral amyloid angiopathy (CAA) is a form of small vessel disease characterised by the progressive deposition of amyloid ß protein in the cerebral vasculature, inducing symptoms including cognitive impairment and cerebral haemorrhages. Due to their accessibility and homogeneous disease phenotypes, animal models are advantageous platforms to study diseases like CAA. Untargeted proteomics studies of CAA rat models (e.g. rTg-DI) and CAA patients provide opportunities for the identification of novel biomarkers of CAA. We performed untargeted, data-independent acquisition proteomic shotgun analyses on the cerebrospinal fluid of rTg-DI rats and wild-type (WT) littermates. Rodents were analysed at 3 months (n = 6/10), 6 months (n = 8/8), and 12 months (n = 10/10) for rTg-DI and WT respectively. For humans, proteomic analyses were performed on CSF of sporadic CAA patients (sCAA) and control participants (n = 39/28). We show recurring patterns of differentially expressed (mostly increased) proteins in the rTg-DI rats compared to wild type rats, especially of proteases of the cathepsin protein family (CTSB, CTSD, CTSS), and their main inhibitor (CST3). In sCAA patients, decreased levels of synaptic proteins (e.g. including VGF, NPTX1, NRXN2) and several members of the granin family (SCG1, SCG2, SCG3, SCG5) compared to controls were discovered. Additionally, several serine protease inhibitors of the SERPIN protein family (including SERPINA3, SERPINC1 and SERPING1) were differentially expressed compared to controls. Fifteen proteins were significantly altered in both rTg-DI rats and sCAA patients, including (amongst others) SCG5 and SERPING1. These results identify specific groups of proteins likely involved in, or affected by, pathophysiological processes involved in CAA pathology such as protease and synapse function of rTg-DI rat models and sCAA patients, and may serve as candidate biomarkers for sCAA.
Subject(s)
Cerebral Amyloid Angiopathy , Rodentia , Humans , Rats , Animals , Complement C1 Inhibitor Protein , Amyloid beta-Peptides , Proteomics , Endopeptidases , BiomarkersABSTRACT
BACKGROUND: The diagnosis of probable cerebral amyloid angiopathy (CAA) is currently mostly based on characteristics of brain MRI. Blood biomarkers would be a cost-effective, easily accessible diagnostic method that may complement diagnosis by MRI and aid in monitoring disease progression. We studied the diagnostic potential of plasma Aß38, Aß40, and Aß42 in patients with hereditary Dutch-type CAA (D-CAA) and sporadic CAA (sCAA). METHODS: All Aß peptides were quantified in the plasma by immunoassays in a discovery cohort (11 patients with presymptomatic D-CAA and 24 patients with symptomatic D-CAA, and 16 and 24 matched controls, respectively) and an independent validation cohort (54 patients with D-CAA, 26 presymptomatic and 28 symptomatic, and 39 and 46 matched controls, respectively). In addition, peptides were quantified in the plasma in a group of 61 patients with sCAA and 42 matched controls. We compared Aß peptide levels between patients and controls using linear regression adjusting for age and sex. RESULTS: In the discovery cohort, we found significantly decreased levels of all Aß peptides in patients with presymptomatic D-CAA (Aß38: p < 0.001; Aß40: p = 0.009; Aß42: p < 0.001) and patients with symptomatic D-CAA (Aß38: p < 0.001; Aß40: p = 0.01; Aß42: p < 0.001) compared with controls. In contrast, in the validation cohort, plasma Aß38, Aß40, and Aß42 were similar in patients with presymptomatic D-CAA and controls (Aß38: p = 0.18; Aß40: p = 0.28; Aß42: p = 0.63). In patients with symptomatic D-CAA and controls, plasma Aß38 and Aß40 were similar (Aß38: p = 0.14; Aß40: p = 0.38), whereas plasma Aß42 was significantly decreased in patients with symptomatic D-CAA (p = 0.033). Plasma Aß38, Aß40, and Aß42 levels were similar in patients with sCAA and controls (Aß38: p = 0.092; Aß40: p = 0.64. Aß42: p = 0.68). CONCLUSIONS: Plasma Aß42 levels, but not plasma Aß38 and Aß40, may be used as a biomarker for patients with symptomatic D-CAA. In contrast, plasma Aß38, Aß40, and Aß42 levels do not appear to be applicable as a biomarker in patients with sCAA.
Subject(s)
Alzheimer Disease , Cerebral Amyloid Angiopathy , Humans , Amyloid beta-Peptides , Cerebral Amyloid Angiopathy/diagnostic imaging , Peptide Fragments , Biomarkers , Alzheimer Disease/diagnosisABSTRACT
BACKGROUND: Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) share pathogenic pathways related to amyloid-ß deposition. Whereas AD is known to affect synaptic function, such an association for CAA remains yet unknown. OBJECTIVE: We therefore aimed to investigate synaptic dysfunction in CAA. METHODS: Multiple reaction monitoring mass spectrometry was used to quantify cerebrospinal fluid (CSF) concentrations of 15 synaptic proteins in CAA and AD patients, and age- and sex-matched cognitively unimpaired controls. RESULTS: We included 25 patients with CAA, 49 patients with AD, and 25 controls. Only neuronal pentraxin-2 levels were decreased in the CSF of CAA patients compared with controls (pâ=â0.04). CSF concentrations of 12 other synaptic proteins were all increased in AD compared with CAA or controls (all p≤0.01) and were unchanged between CAA and controls. Synaptic protein concentrations in the subgroup of CAA patients positive for AD biomarkers (CAA/ATN+; nâ=â6) were similar to AD patients, while levels in CAA/ATN- (nâ=â19) were comparable with those in controls. A regression model including all synaptic proteins differentiated CAA from AD at high accuracy levels (area under the curve 0.987). CONCLUSION: In contrast to AD, synaptic CSF biomarkers were found to be largely unchanged in CAA. Moreover, concomitant AD pathology in CAA is associated with abnormal synaptic protein levels. Impaired synaptic function in AD was confirmed in this independent cohort. Our findings support an apparent differential involvement of synaptic dysfunction in CAA and AD and may reflect distinct pathological mechanisms.
Subject(s)
Alzheimer Disease , Cerebral Amyloid Angiopathy , Humans , Alzheimer Disease/pathology , Cerebral Amyloid Angiopathy/pathology , Amyloid beta-Peptides/metabolism , Biomarkers/cerebrospinal fluidABSTRACT
BACKGROUND: To evaluate the potential of cerebrospinal fluid (CSF) levels of matrix metalloproteinases and tissue-type inhibitors (MMP; TIMP), and ratios of MMPs to TIMPs, to function as biomarkers for sporadic or hereditary cerebral amyloid angiopathy (CAA). METHODS: CSF concentrations of the matrix metalloproteinases MMP-2, MMP-9 and MMP-14, as well as the tissue inhibitors of metalloproteinases TIMP-1, TIMP-2 and TIMP-3, were determined using immunoassays. These assays were applied to two, independent study groups of sporadic CAA (sCAA) (n = 28/43) and control subjects (n = 40/40), as well as to groups of pre-symptomatic (n = 11) and symptomatic hereditary Dutch-CAA (D-CAA) patients (n = 12), and age-matched controls (n = 22/28, respectively). RESULTS: In the sCAA/control cohorts, inconsistent differences were found for individual MMPs and TIMPs, but MMP-2/TIMP-2 (discovery/validation: p = 0.004; p = 0.02) and MMP-14/TIMP-2 ratios (discovery/validation: p < 0.001; p = 0.04) were consistently decreased in sCAA, compared to controls. Moreover, MMP-14 was decreased in symptomatic D-CAA (p = 0.03), compared to controls. The MMP-14/TIMP-1 (p = 0.03) and MMP-14/TIMP-2 (p = 0.04) ratios were decreased in symptomatic D-CAA compared to controls and also compared to pre-symptomatic D-CAA (p = 0.004; p = 0.005, respectively). CONCLUSION: CSF MMP-2/TIMP-2 and MMP-14/TIMP-2 were consistently decreased in sCAA, compared to controls. Additionally, MMP-14/TIMP-2 levels were also decreased in symptomatic D-CAA, compared to both pre-symptomatic D-CAA and controls, and can therefore be considered a biomarker for sporadic and late-stage hereditary forms of CAA.
Subject(s)
Cerebral Amyloid Angiopathy, Familial , Tissue Inhibitor of Metalloproteinase-2 , Humans , Tissue Inhibitor of Metalloproteinase-1 , Matrix Metalloproteinase 14 , Matrix Metalloproteinase 2ABSTRACT
OBJECTIVE: Vascular amyloid ß (Aß) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides Aß38, Aß40, Aß42, and Aß43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimer disease (AD). METHODS: Aß peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD, and 37 controls), and a group of 22 patients with D-CAA and 54 controls. To determine the diagnostic accuracy, the area under the curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI). RESULTS: We found decreased levels of all Aß peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for Aß42 (AUC of sCAA vs controls for discovery: 0.90, 95% CI = 0.82-0.99; for validation: 0.94, 95% CI = 0.89-0.99) and Aß43 (AUC of sCAA vs controls for discovery: 0.95, 95% CI = 0.88-1.00; for validation: 0.91, 95% CI = 0.83-1.0). All Aß peptides except Aß43 were also decreased in sCAA compared to AD (CSF Aß38: AUC = 0.82, 95% CI = 0.71-0.93; CSF Aß40: AUC = 0.88, 95% CI = 0.80-0.96; CSF Aß42: AUC = 0.79, 95% CI = 0.66-0.92). INTERPRETATION: A combined biomarker panel of CSF Aß38, Aß40, Aß42, and Aß43 has potential to differentiate sCAA from AD and controls, and D-CAA from controls. ANN NEUROL 2023;93:1173-1186.
Subject(s)
Alzheimer Disease , Cerebral Amyloid Angiopathy, Familial , Cerebral Amyloid Angiopathy , Humans , Amyloid beta-Peptides/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Alzheimer Disease/diagnosis , Alzheimer Disease/cerebrospinal fluid , Biomarkers/cerebrospinal fluidABSTRACT
AIMS: The aim of this work is to study the association of urokinase plasminogen activator (uPA) with development and progression of cerebral amyloid angiopathy (CAA). MATERIALS AND METHODS: We studied the expression of uPA mRNA by quantitative polymerase chain reaction (qPCR) and co-localisation of uPA with amyloid-ß (Aß) using immunohistochemistry in the cerebral vasculature of rTg-DI rats compared with wild-type (WT) rats and in a sporadic CAA (sCAA) patient and control subject using immunohistochemistry. Cerebrospinal fluid (CSF) uPA levels were measured in rTg-DI and WT rats and in two separate cohorts of sCAA and Dutch-type hereditary CAA (D-CAA) patients and controls, using enzyme-linked immunosorbent assays (ELISA). RESULTS: The presence of uPA was clearly detected in the cerebral vasculature of rTg-DI rats and an sCAA patient but not in WT rats or a non-CAA human control. uPA expression was highly co-localised with microvascular Aß deposits. In rTg-DI rats, uPA mRNA expression was highly elevated at 3 months of age (coinciding with the emergence of microvascular Aß deposition) and sustained up to 12 months of age (with severe microvascular CAA deposition) compared with WT rats. CSF uPA levels were elevated in rTg-DI rats compared with WT rats (p = 0.03), and in sCAA patients compared with controls (after adjustment for age of subjects, p = 0.05 and p = 0.03). No differences in CSF uPA levels were found between asymptomatic and symptomatic D-CAA patients and their respective controls (after age-adjustment, p = 0.09 and p = 0.44). Increased cerebrovascular expression of uPA in CAA correlates with increased quantities of CSF uPA in rTg-DI rats and human CAA patients, suggesting that uPA could serve as a biomarker for CAA.
Subject(s)
Cerebral Amyloid Angiopathy , Urokinase-Type Plasminogen Activator , Amyloid beta-Peptides/metabolism , Animals , Brain/metabolism , Cerebral Amyloid Angiopathy/metabolism , Humans , RNA, Messenger/metabolism , Rats , Rodentia/genetics , Rodentia/metabolism , Urokinase-Type Plasminogen Activator/genetics , Urokinase-Type Plasminogen Activator/metabolismABSTRACT
Reported prevalence estimates of sporadic cerebral amyloid angiopathy (CAA) vary widely. CAA is associated with cognitive dysfunction and intracerebral hemorrhage, and linked to immunotherapy-related side-effects in Alzheimer's disease (AD). Given ongoing efforts to develop AD immunotherapy, accurate estimates of CAA prevalence are important. CAA can be diagnosed neuropathologically or during life using MRI markers including strictly lobar microbleeds. In this meta-analysis of 170 studies including over 73,000 subjects, we show that in patients with AD, CAA prevalence based on pathology (48%) is twice that based on presence of strictly lobar cerebral microbleeds (22%); in the general population this difference is three-fold (23% vs 7%). Both methods yield similar estimated prevalences of CAA in cognitively normal elderly (5% to 7%), in patients with intracerebral hemorrhage (19% to 24%), and in patients with lobar intracerebral hemorrhage (50% to 57%). However, we observed large heterogeneity among neuropathology and MRI protocols, which calls for standardized assessment and reporting of CAA.
Subject(s)
Cerebral Amyloid Angiopathy/epidemiology , Cerebral Hemorrhage/epidemiology , Immunotherapy/adverse effects , Neuropathology , Alzheimer Disease/drug therapy , Cerebral Amyloid Angiopathy/pathology , Cognitive Dysfunction/drug therapy , Humans , Magnetic Resonance Imaging/standards , PrevalenceABSTRACT
BACKGROUND: Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-ß (PDGFRß) has been proposed as a biomarker of blood-brain barrier (BBB) breakdown. We studied PDGFRß levels as a biomarker for cerebral amyloid angiopathy (CAA), amnestic mild cognitive impairment (aMCI), or Alzheimer's disease (AD). METHODS: CSF PDGFRß levels were quantified by enzyme-linked immunosorbent assay in patients with CAA, patients with aMCI/AD, and in matched controls. In aMCI/AD we evaluated CSF PDGFRß both by clinical phenotype and by using the AT(N) biomarker classification system defined by CSF amyloid (A), tau (T), and neurodegeneration (N) biomarkers. RESULTS: PDGFRß levels were similar in CAA patients and controls (P = .78) and in aMCI/AD clinical phenotype and controls (P = .91). aMCI/AD patients with an AD+ biomarker profile (A+T+[N+]) had increased PDGFRß levels compared to (A-T-[N-]) controls (P = .006). CONCLUSION: Our findings indicate that PDGFRß levels are associated with an AD+ biomarker profile but are not a suitable biomarker for CAA or aMCI/AD clinical syndrome.