The relation of a cerebrospinal fluid profile associated with Alzheimer's disease with cognitive function and neuropsychiatric symptoms in sporadic cerebral amyloid angiopathy.

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.

Proximity extension assay in cerebrospinal fluid identifies neurofilament light chain as biomarker of neurodegeneration in sporadic cerebral amyloid angiopathy.

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.

Serum and cerebrospinal fluid neurofilament light chain and glial fibrillary acid protein levels in early and advanced stages of cerebral amyloid Angiopathy.

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.

Normal cerebrospinal fluid concentrations of PDGFRß in patients with cerebral amyloid angiopathy and Alzheimer's disease.

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.

Clinical and Paraclinical Measures Associated with Outcome in Cerebral Amyloid Angiopathy with Related Inflammation.

BACKGROUND: Cerebral amyloid angiopathy with related inflammation (CAA-ri) is a rare age-associated disorder characterized by an inflammatory response to amyloid in cerebral blood vessels. CAA-ri is often treated with corticosteroids, but response to treatment is variable. OBJECTIVE: To assess the relationship between clinical and paraclinical measures and outcomes in patients with CAA-ri treated with high doses of methylprednisolone. METHODS: Longitudinal clinical course, and results from serum and cerebrospinal fluid (CSF) testing, electroencephalography, and neuroimaging were reviewed from 11 prospectively-accrued CAA-ri patients diagnosed, treated, and followed at Barnes Jewish Hospital (St. Louis, MO, USA). Magnetic resonance imaging (MRI) changes were quantified using a scoring system validated in cases of amyloid related imaging abnormality (ARIA-E). Clinical outcomes were assessed as change in modified Rankin Scale (ΔmRS) from baseline to final assessment (median 175 days from treatment with high doses of methylprednisolone; range, 31-513). RESULTS: Worse outcomes following methylprednisolone treatment were associated with requirement for intensive care unit admission (median ΔmRS, 5 versus 1.5; p = 0.048), CSF pleocytosis (median ΔmRS 4.5 versus 1; p = 0.04), or lower CSF Aß40 at presentation (rho = -0.83; p = 0.02), and diffusion restriction (median ΔmRS 4 versus 1.5; p = 0.03) or higher late ARIA-E scores (rho = 0.70; p = 0.02) on MRI, but not preexisting cognitive decline (median ΔmRS 2 versus 2; p = 0.66). CONCLUSION: Clinical and paraclinical measures associated with outcomes may inform clinical counseling and treatment decisions in patients with CAA-ri. Baseline cognitive status was not associated with treatment responsiveness.

Cerebrospinal fluid cytokines and metalloproteinases in cerebral amyloid angiopathy-related inflammation.

OBJECTIVES: To clarify pathomechanisms of cerebral amyloid angiopathy-related inflammation/vasculitis (CAA-ri). METHODS: We collected cerebrospinal fluid (CSF) samples of nine patients with CAA-ri of before (acute CAA-ri group) and after treatment (post-treatment CAA-ri group) and nine patients with CAA (CAA without inflammation group). We examined anti-amyloid ß protein (Aß) antibody titer by ELISA, and measured 27 Cytokines, nine matrix metalloproteinases (MMPs), and four tissue inhibitors of MMPs (TIMPs) by multiplexed fluorescent bead-based immunoassay. RESULTS: We demonstrated TIMP-2 (median) in CSF of the acute CAA-ri group (30,994.49 pg/ml, p = 0.007) and the post-treatment CAA-ri group (36,430.97 pg/ml, p = 0.001) was significantly elevated compared to that of the CAA without inflammation group (22,013.58 pg/ml). TIMP-1 was also higher in the post-treatment CAA-ri group than that in the CAA without inflammation group (58,167.75 pg/ml vs. 45,770.03 pg/ml, p = 0.005). There was a significant positive correlation between TIMP-1 and anti-Aß antibodies in CAA-ri (rs  = 0.900, p = 0.037). Median MMP-2 tended to be higher in the acute and post-treatment CAA-ri groups (10,619.82 pg/ml and 8396.98 pg/ml, respectively) than in the CAA without inflammation group (4436.34 pg/ml). Platelet-derived growth factor (PDGF)-BB levels before treatment were higher than those after treatment (median, 12.66 pg/ml vs. 6.39 pg/ml; p = 0.011) and correlated with the titer of anti-Aß antibodies (rs  =0.900, p = 0.037). CONCLUSIONS: Elevated levels of MMP-2, TIMP-1, and TIMP-2 might be related to the development of CAA-ri. Elevation of PDGF-BB could be a useful marker for clinical diagnosis of CAA-ri.

Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy.

BACKGROUND: There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-ß (Aß) cerebral amyloid angiopathy (CAA). OBJECTIVE: To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA. METHODS: We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer's disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service. RESULTS: We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p < 0.01) median concentrations of Aß38, Aß40, Aß42, sAßPPα, and sAßPPß. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p < 0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aß38, Aß40, Aß42, and sAßPPß. Comparing CAA patients with amyloid-PET positive (n = 5) and negative (n = 5) scans, PET positive individuals had lower (p < 0.05) concentrations of CSF Aß42, and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an "AD-like" profile. CONCLUSION: CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed.

Cerebral Amyloid Angiopathy and Cerebral Amyloid Angiopathy-Related Inflammation: Comparison of Hemorrhagic and DWI MRI Features.

BACKGROUND: Cerebral amyloid angiopathy (CAA) can be associated with primary vasculitis of small/medium-sized leptomeningeal and cortical arteries, called CAA-related inflammation (CAA-ri). OBJECTIVE: To compare hemorrhagic and diffusion-weighted imaging (DWI) MRI features in CAA and CAA-ri. METHODS: We prospectively scored in a consecutive CAA and CAA-ri cohort: presence/number of chronic intracerebral hemorrhage (ICH), cerebral microbleeds (CMB), and cortical superficial siderosis (CSS) on initial T2*-weighted imaging, and DWI lesions on both initial and follow-up imaging. In a subgroup, ApoE, CSF, and 18F-florbetaben-positron emission tomography (FBB-PET) were also analyzed. RESULTS: In CAA-ri, CMB presence was more frequent (100% versus 40%, p < 0.001) and CMB numbers higher (mean 137 versus 8, p < 0.001). No difference was observed for chronic ICH or CSS. DWI lesions were more frequent in acute compared to chronic CAA-ri (p = 0.025), whereas no such difference was observed between acute and chronic CAA (p = 0.18). Both ApoE4 (genotyping available in 22 CAA-ri and 48 CAA patients) carriers and homozygosity were more frequent in CAA-ri (48% versus 19% [p = 0.014] and 32% versus 2% [p < 0.001] respectively). CSF biomarker analyses (performed in 20 CAA-ri and 45 CAA patients) showed lower Aß42 levels in CAA-ri compared to CAA (median 312 versus 422 pg/mL, p = 0.0032). FBB-PET (performed in 11 CAA-ri and 20 CAA patients) showed higher standardized uptake value ratios in CAA-ri compared with CAA, only significant when the pons was used as reference (p = 0.037). CONCLUSION: Compared to CAA, CAA-ri was associated with higher CMB numbers, more frequent ApoE4 carriers and homozygotes, lower CSF Aß42 levels, and more severe amyloid load on FBB-PET.

Core cerebrospinal fluid biomarker profile in cerebral amyloid angiopathy: A meta-analysis.

OBJECTIVE: To perform a meta-analysis of 4 core CSF biomarkers (ß-amyloid [Aß]42, Aß40, total tau [t-tau], and phosphorylated tau [p-tau]) to assess which of these are most altered in sporadic cerebral amyloid angiopathy (CAA). METHODS: We systematically searched PubMed for eligible studies reporting data on CSF biomarkers reflecting amyloid precursor protein metabolism (Aß42, Aß40), neurodegeneration (t-tau), and tangle pathology (p-tau) in symptomatic sporadic CAA cohorts vs controls and patients with Alzheimer disease (AD). Biomarker performance was assessed in random-effects meta-analysis based on ratio of mean (RoM) biomarker concentrations: (1) in patients with CAA vs healthy controls and (2) in patients with CAA vs patients with AD. RoM >1 indicates higher biomarker concentration in patients with CAA vs comparison population and RoM <1 indicates higher concentration in comparison groups. RESULTS: Three studies met inclusion criteria. These comprised 5 CAA patient cohorts (n = 59 patients) vs healthy controls (n = 94 cases) and AD cohorts (n = 158). Three core biomarkers differentiated CAA from controls: CSF Aß42 (RoM 0.49, 95% confidence interval [CI] 0.38-0.64, p < 0.003), Aß40 (RoM 0.70, 95% CI 0.63-0.78, p < 0.0001), and t-tau (RoM 1.54, 95% CI 1.15-2.07, p = 0.004); p-tau was marginal (RoM 1.24, 95% CI 0.99-1.54, p = 0.062). Differentiation between CAA and AD was strong for CSF Aß40 (RoM 0.76, 95% CI 0.69-0.83, p < 0.0001), but not Aß42 (RoM 1.00; 95% CI 0.81-1.23, p = 0.970). For t-tau and p-tau, average CSF ratios in patients with CAA vs patients with AD were 0.63 (95% CI 0.54-0.74, p < 0.0001) and 0.60 (95% CI 0.50-0.71, p < 0.0001), respectively. CONCLUSION: Specific CSF patterns of Aß42, Aß40, t-tau, and p-tau might serve as molecular biomarkers of CAA, but analyses in larger CAA cohorts are needed.

Neurodegenerative disease biomarkers Aß1-40, Aß1-42, tau, and p-tau181 in the vervet monkey cerebrospinal fluid: Relation to normal aging, genetic influences, and cerebral amyloid angiopathy.

Background: The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits. Results: Aß1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aß1-40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions: Overall, these results support the vervet as a non-human primate model of amyloid-related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aß1-40 and p-tau181 as potentially valuable biomarkers of these processes.

Clinical pathologic case report: A 70-year-old man with inflammatory cerebral amyloid angiopathy causing headache, cognitive impairment, and aphasia.

A 70-year-old man presented with two months of worsening cognitive impairment, hallucinations, and difficulty speaking, with superimposed headaches. Cerebrospinal fluid analysis was notable for lymphocytic pleocytosis and elevated protein. Imaging studies revealed multiple acute and subacute infarcts with cortical microhemorrhages. The patient underwent a stereotactic brain biopsy. In this article, we discuss the patient's differential diagnosis, pathologic findings, ultimate diagnosis, and clinical outcome.

Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease.

INTRODUCTION: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). METHODS: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid ß (Aß) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). RESULTS: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aß040 levels between groups or between subjects with and without CAA. DISCUSSION: CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aß40 levels are not a useful biomarker for CAA in AD.

Comparison of cerebrospinal fluid profiles in Alzheimer's disease with multiple cerebral microbleeds and cerebral amyloid angiopathy-related inflammation.

Brain magnetic resonance imaging (MRI) of patients with Alzheimer's disease (AD) sometimes reveals multiple cerebral microbleeds (CMBs) and confluent white matter hyperintensities (WMHs) similar to those observed in cerebral amyloid angiopathy-related inflammation (CAA-I). To determine whether there might be common pathophysiological mechanisms underlying the MRI findings of multiple CMBs and confluent WMHs, we investigated the cerebrospinal fluid (CSF) profiles of 38 AD, five amnestic mild cognitive impairment (MCI), and six CAA-I patients. The AD and MCI patients were divided into groups of patients with (n = 10) or without (n = 33) multiple CMBs (n ≥ 2) on T2*-gradient echo sequences of brain MRI. We compared the CSF profiles of AD and MCI patients with or without multiple CMBs, and CAA-I patients. The brain MRIs of the patients with multiple CMBs revealed severe degrees of WMHs compared with the patients without multiple CMBs. The levels of CSF anti-amyloid ß autoantibody and interleukin 8, and CSF/serum albumin ratios and immunoglobulin G indexes, were significantly higher in CAA-I patients than the other groups. However, there were no significant differences in the CSF profiles of patients with or without multiple CMBs. Our study provides evidence for different pathophysiological mechanisms underlying these differential MRI findings in AD and CAA-I.

ß-Amyloid in CSF: Biomarker for preclinical cerebral amyloid angiopathy.

OBJECTIVE: To investigate CSF biomarkers in presymptomatic and symptomatic mutation carriers with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), a model for sporadic cerebral amyloid angiopathy, and to determine the earliest deposited form of ß-amyloid (Aß). METHODS: HCHWA-D mutation carriers and controls were enrolled in the cross-sectional EDAN (Early Diagnosis of Amyloid Angiopathy Network) study. The HCHWA-D group was divided into symptomatic carriers with a previous intracerebral hemorrhage and presymptomatic carriers. CSF concentrations of Aß40, Aß42, total tau, and phosphorylated tau181 proteins were compared to those of controls of a similar age. Correlations between CSF biomarkers, MRI markers, and age were investigated with multivariate linear regression analyses. RESULTS: We included 10 symptomatic patients with HCHWA-D (mean age 55 ± 6 years), 5 presymptomatic HCHWA-D carriers (mean age 36 ± 13 years), 31 controls <50 years old (mean age 31 ± 7 years), and 50 controls ≥50 years old (mean age 61 ± 8 years). After correction for age, CSF Aß40 and Aß42 were significantly decreased in symptomatic carriers vs controls (median Aß40 1,386 vs 3,867 ng/L, p < 0.001; median Aß42 289 vs 839 ng/L, p < 0.001) and in presymptomatic carriers vs controls (median Aß40 3,501 vs 4,684 ng/L, p = 0.011; median Aß42 581 vs 1,058 ng/L, p < 0.001). Among mutation carriers, decreasing CSF Aß40 was associated with higher lobar microbleed count (p = 0.010), increasing white matter hyperintensity volume (p = 0.008), and presence of cortical superficial siderosis (p = 0.02). CONCLUSIONS: Decreased levels of CSF Aß40 and Aß42 occur before HCHWA-D mutation carriers develop clinical symptoms, implicating vascular deposition of both Aß species as early steps in cerebral amyloid angiopathy pathogenesis. CSF Aß40 and Aß42 may serve as preclinical biomarkers of cerebral amyloid angiopathy pathology.

Cerebral Amyloid Angiopathy-Related Microbleeds and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) commonly accompanies cerebral amyloid angiopathy (CAA). OBJECTIVE: We aimed to reveal associations between CAA-related brain microbleeds and cerebrospinal fluid (CSF) markers in AD patients. METHODS: Patients with probable AD (n = 88) from consecutive patients in our memory clinic were evaluated for patient demographics, vascular risk factors, neuropsychological tests, apolipoprotein E phenotype, MRI including T2*-weighted image and fluid attenuated inversion recovery sequence, and CSF amyloid and tau markers. RESULTS: The 88 patients with AD included 15 with microbleeds only in cortical/subcortical regions (cortical microbleeds) that could be CAA-related, 16 with microbleeds only in deep locations (deep microbleeds), 3 with microbleeds in both cortical and deep locations (mixed microbleeds), and 54 without microbleeds. The CSF levels of amyloid ß-protein 1-40 (Aß40) and amyloid ß-protein 1-42 (Aß42) were significantly lower in patients with cortical microbleeds than in those without microbleeds (p = 0.001 and p = 0.027, respectively). The result remained unchanged after adjustment for age, sex, apolipoprotein E E4 presence, and leukoaraiosis. CONCLUSIONS: CAA-related cortical microbleeds would be associated with lower CSF levels of Aß40 and Aß42 in AD, reflecting the deposition of both Aß40 and Aß42 in the cerebrovasculature.

Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Isolated Supratentorial Cortical Superficial Siderosis.

We evaluated cerebrospinal fluid amyloid-ß 1-40 (Aß40), amyloid-ß 1-42 (Aß42), total and phosphorylated-tau (t-tau and p-tau) in patients with symptomatic isolated cortical supratentorial superficial siderosis (SS), by prospectively recruiting ten patients with SS in the absence of pre-existing cognitive dysfunction, and comparing biomarkers with lobar hematoma cerebral amyloid angiopathy patients (LH-CAA, n = 13), Alzheimer's disease patients (AD, n = 42), and controls (n = 16). Compared to controls, SS patients showed statistically significant higher t-tau (p = 0.019) and lower Aß42 (p = 0.0084). Compared to other groups, SS showed statistically significant lower t-tau, p-tau, and Aß40 compared to AD (p = 0.0063, p = 0.0004, and p = 0022, respectively), and higher p-tau compared to LH-CAA (p = 0.012).

Cortical superficial siderosis: Prevalence and biomarker profile in a memory clinic population.

OBJECTIVE: To gain further insight into cortical superficial siderosis (cSS), a new hemorrhagic neuroimaging marker of cerebral amyloid angiopathy (CAA), and to investigate the clinical, neuroimaging, genetic, and CSF biomarker profile of cSS in a large, consecutive memory clinic series. METHODS: We included 1,504 memory clinic patients undergoing dementia investigation including a brain MRI in our center. Routine CSF biomarker analysis was performed in 1,039 patients and APOE genotyping in 520 patients. MRIs were systematically evaluated for presumed marker of small vessel disease: cSS, cerebral microbleeds, enlarged perivascular spaces, white matter hyperintensities, and lacunes. RESULTS: cSS was detected in 40 patients (2.7%; 95% confidence interval [CI] 1.9-3.6); cSS was focal in 33 cases (2.2%; 95% CI 1.5-3.1) and disseminated in 7 (0.5%; 95% CI 0.2-1). Vascular dementia had the highest cSS prevalence (13%; 95% CI 5.4-24.9), followed by Alzheimer disease (5%; 95% CI 3.1-7.5). The most commonly affected area was the occipital lobe (70%; 95% CI 53.5-83.4). cSS was associated with lobar cerebral microbleeds (odds ratio [OR] 7.9; 95% CI 3.4-18.1; p < 0.001), high-degree centrum semiovale perivascular spaces (OR 1.7; 95% CI 1.2-2.6; p = 0.008), and white matter hyperintensities (OR 1.5; 95% CI 1.0-2.2; p = 0.062). APOE ε4/4 genotype was more common in cSS cases compared to those without. CSF ß-amyloid 42 was lower in patients with cSS (coefficient -0.09; 95% CI -0.15 to -0.03; p = 0.004). CONCLUSIONS: Our large series of memory clinic patients provides evidence that cSS is related to cerebrovascular disease and may be a manifestation of severe CAA, even in patients without intracerebral hemorrhage.

Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cerebral Amyloid Angiopathy-Related Inflammation.

BACKGROUND: Decreased cerebrospinal fluid (CSF) amyloid-ß 1-40 (Aß40) and amyloid-ß 1-42 (Aß42) and increased total and phosphorylated tau (t-tau, p-tau) concentrations have been described in cerebral amyloid angiopathy (CAA). OBJECTIVE: Our aim was to analyze these biomarkers in patients with CAA-related inflammation (CAA-I). METHODS: We prospectively recruited nine patients with acute phase CAA-I fulfilling Chung criteria. CSF was analyzed for t-tau, p-tau, Aß42, and Aß40. Data were compared to controls (n = 14), patients with Alzheimer's disease (AD, n = 42), CAA (n = 10), and primary angiitis of the central nervous system (PACNS, n = 3). RESULTS: For the CAA-I group, statistically significant differences were: lower Aß42 (p = 0.00053) compared to the control group; lower t-tau (p = 0.018), p-tau (p <  0.001), and Aß40 (p <  0.001) compared to AD; lower Aß42 (p = 0.027) compared to CAA; lower Aß42 (p = 0.012) compared to PACNS. Nearly significantly lower Aß40 (p = 0.051) and higher t-tau (p = 0.051) were seen in CAA-I compared to controls. CONCLUSION: CSF biomarkers profile similar to that of CAA was observed in CAA-I (with even lower levels of Aß42 compared to CAA). Based on our findings, high p-tau seems more specific for AD, whereas low Aß42 differentiates CAA-I from CAA, PACNS, and controls, and low Aß40 differentiates CAA-I from AD.