Cerebrospinal Fluid Beta-amyloid Research Articles

Neurofilament light chain and \u03b1-synuclein RT-QuIC as differential diagnostic biomarkers in parkinsonisms and related syndromes

Neurofilament light chain (NfL) and α-synuclein oligomeric seeds (α-syn-s) are promising biomarkers for patients with parkinsonism. We assessed their performance in discriminating Parkinson disease (PD) from atypical parkinsonisms (APDs) and evaluated the association between NfL levels and clinical measures of disease severity. We measured NfL in cerebrospinal fluid (CSF) and/or plasma by immunoassays and α-syn-s in CSF by real-time quaking-induced conversion (RT-QuIC) in patients with PD (n = 153), multiple system atrophy (MSA) (n = 80), progressive supranuclear palsy/cortico-basal syndrome (PSP/CBS) (n = 58), dementia with Lewy bodies (n = 64), isolated REM-sleep behaviour disorder (n = 19), and isolated autonomic failure (n = 30). Measures of disease severity included disease duration, UPDRS-III score, Hoehn and Yahr stage, orthostatic hypotension, MMSE score, and CSF amyloid-beta profile. Both CSF NfL (cNfL) and plasma NfL (pNfL) levels were markedly elevated in APDs, and allowed differentiation with PD (vs. APDs, cNfL AUC 0.96; pNfL AUC 0.95; vs. MSA cNfL AUC 0.99; pNfL AUC 0.97; vs. PSP/CBS cNfL AUC 0.94; pNfL AUC 0.94). RT-QuIC detected α-syn-s in 91.4% of PD, but only 2.5% of APDs (all MSA). In PD/PDD, motor scales significantly correlated with cNfL levels. Although pNfL and both cNfL and α-syn-s accurately distinguished PD from APDs, the combined assessment of CSF markers provided a higher diagnostic value (PD vs. APDs AUC 0.97; vs. MSA AUC 0.97; vs. PSP/CBS AUC 0.99) than RT-QuIC alone (p = 0.047 vs. APDs; p = 0.002 vs MSA; p = 0.007 vs PSP/CBS), or cNfL alone (p = 0.011 vs. APDs; p = 0.751 vs MSA; p = 0.0001 vs. PSP/CBS). The results support the use of these assays in specialised clinics.

BDNF-Met polymorphism and amyloid-beta in relation to cognitive decline in cognitively normal elderly: the SCIENCe project

Brain-derived neurotrophic factor (BNDF) plays a role in synapse integrity. We investigated in 398 cognitively normal adults (60±8years, 41% female, MMSE=28±1) the joint association of the Val66Met polymorphism of the BDNF gene (Met+/-) and plasma BDNF levels and abnormal cerebrospinal fluid (CSF) amyloid-beta status (A+/-) with cognitive decline and dementia risk. Age-, sex- and education-adjusted linear mixed models showed that compared to Met-A-, Met+A+ showed steeper decline on tests of global cognition, memory, language, attention and executive functioning, while Met-A+ showed steeper decline on a smaller number of tests. There were no associations between Met+A- and cognitive decline. Cox models showed that compared to Met-A-, Met+A+ participants were at increased risk of dementia (HR=8.8, 95%CI: 2.8–27.9), as were Met-A+ participants (HR=6.5, 95%CI: 2.2–19.5). Lower plasma BDNF was associated with an increased risk of progression to dementia in the A+ participants. Our results imply that Met-carriage on top of amyloid-beta pathology might increase rate of cognitive decline to dementia.

Cerebrospinal fluid amyloid beta and response of cognition to a tap test in idiopathic normal pressure hydrocephalus: a case-control study.

To examine the relationship between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and tap test response to elucidate the effects of comorbidity of AD in idiopathic normal-pressure hydrocephalus (iNPH). Case-control study. Osaka University Hospital. Patients with possible iNPH underwent a CSF tap test. Concentrations of amyloid beta (Aβ) 1-40, 1-42, and total tau in CSF were measured. The response of tap test was judged using Timed Up and Go test (TUG), 10-m reciprocation walking test (10MWT), Mini-Mental State Examination (MMSE), and iNPH grading scale. The ratio of Aβ1-42 to Aβ1-40 (Aβ42/40 ratio) and total tau concentration was compared between tap test-negative (iNPH-nTT) and -positive (iNPH-pTT) patients. We identified 27 patients as iNPH-nTT and 81 as iNPH-pTT. Aβ42/40 ratio was significantly lower (mean [SD] = 0.063 [0.026] vs. 0.083 [0.036], p = 0.008), and total tau in CSF was significantly higher (mean [SD] = 385.6 [237.2] vs. 293.6 [165.0], p = 0.028) in iNPH-nTT than in iNPH-pTT. Stepwise logistic regression analysis revealed that low Aβ42/40 ratio was significantly associated with the negativity of the tap test. The response of cognition was significantly related to Aβ42/40 ratio. The association between Aβ42/40 ratio and tap test response, especially in cognition, remained after adjusting for disease duration and severity at baseline. A low CSF Aβ42/40 ratio is associated with a poorer cognitive response, but not gait and urinary response, to a tap test in iNPH. Even if CSF biomarkers suggest AD comorbidity, treatment with iNPH may be effective for gait and urinary dysfunction.

Patterns of Cerebrospinal Fluid Biomarkers and Amyloid Positron Emission Tomography in a Patient with Cerebral Amyloid Angiopathy-Related Inflammation

Cerebral amyloid angiopathy-related inflammation (CAA-RI) is a distinct subset of cerebral amyloid angiopathy characterized by the auto-inflammatory response to amyloid-laden small arteries of cerebral cortex and leptomeninges. Clinical features include cognitive-behavioral change, headache, focal neurologic deficits and seizure. Because anti-inflammatory treatments can rapidly relieve neurologic symptoms, early diagnosis is critical. Herein, we report a CAA-RI case with distinct laboratory findings of a decreased cerebrospinal fluid amyloid beta 1-42 level and relatively reduced florbetaben uptake in the focal inflammatory lesion during the acute phase of CAA-RI.

Mediterranean and Western diet effects on Alzheimer's disease biomarkers, cerebral perfusion, and cognition in mid-life: A randomized trial.

IntroductionMid‐life dietary patterns are associated with Alzheimer's disease (AD) risk, although few controlled trials have been conducted.MethodsEighty‐seven participants (age range: 45 to 65) with normal cognition (NC, n = 56) or mild cognitive impairment (MCI, n = 31) received isocaloric diets high or low in saturated fat, glycemic index, and sodium (Western‐like/West‐diet vs. Mediterranean‐like/Med‐diet) for 4 weeks. Diet effects on cerebrospinal fluid (CSF) biomarkers, cognition, and cerebral perfusion were assessed to determine whether responses differed by cognitive status.ResultsCSF amyloid beta (Aβ)42/40 ratios increased following the Med‐diet, and decreased after West‐diet for NC adults, whereas the MCI group showed the reverse pattern. For the MCI group, the West‐diet reduced and the Med‐diet increased total tau (t‐tau), whereas CSF Aβ42/t‐tau ratios increased following the West‐diet and decreased following the Med‐diet. For NC participants, the Med‐diet increased and the West‐diet decreased cerebral perfusion.DiscussionDiet response during middle age may highlight early pathophysiological processes that increase AD risk.

Serum and cerebrospinal fluid Neutrophil gelatinase-associated lipocalin (NGAL) levels as biomarkers for the conversion from mild cognitive impairment to Alzheimer's disease dementia

Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that has been reported as a potential marker for pre-dementia stages of Alzheimer's disease (AD). Longitudinal studies for its association with the conversion of mild cognitive impairment to AD is still lacking. This study included n = 268 study participants with subjective cognitive decline (SCD) (n=82), mild cognitive impairment (MCI) (n=98) and AD dementia (n=88) at baseline and two-year follow-up clinical assessments. Serum and cerebrospinal fluid (CSF)NGAL, CSF amyloid beta1-42, total-Tau, and phospho-Tau levels were measured with ELISA analysis. CSF NGAL levels were significantly lower in MCI participants compared to people with SCD at baseline. Lower baseline CSF NGAL levels predicted MCI converters to AD dementia vs. non-converters after 2-years follow-up. A positive correlation between CSF NGAL and amyloid beta1-42 was found particularly in MCI participants at baseline. NGAL in CSF holds potential to be used as a predictive marker for the conversion of MCI to AD dementia and may reflect pathophysiological processes of prodromal AD neuropathology.

Interaction of amyloid and tau on cortical microstructure in cognitively unimpaired adults.

Neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion-weighted imaging (DWI) model, may be useful for detecting early cortical microstructural alterations in Alzheimer's disease prior to cognitive impairment. Using neuroimaging (NODDI and T1-weighted magnetic resonance imaging [MRI]) and cerebrospinal fluid (CSF) biomarker data (measured using Elecsys® CSF immunoassays) from 219 cognitively unimpaired participants, we tested the main and interactive effects of CSF amyloid beta (Aβ)42 /Aβ40 and phosphorylated tau (p-tau) on cortical NODDI metrics and cortical thickness, controlling for age, sex, and apolipoprotein E ε4. We observed a significant CSF Aβ42 /Aβ40 × p-tau interaction on cortical neurite density index (NDI), but not orientation dispersion index or cortical thickness. The directionality of these interactive effects indicated: (1) among individuals with lower CSF p-tau, greater amyloid burden was associated with higher cortical NDI; and (2) individuals with greater amyloid and p-tau burden had lower cortical NDI, consistent with cortical neurodegenerative changes. NDI is a particularly sensitive marker for early cortical changes that occur prior to gross atrophy or development of cognitive impairment.

Water exchange rate across the blood-brain barrier is associated with CSF amyloid-β 42 in healthy older adults.

IntroductionWe tested if water exchange across the blood‐brain barrier (BBB), estimated with a noninvasive magnetic resonance imaging (MRI) technique, is associated with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and neuropsychological function.MethodsForty cognitively normal older adults (67–86 years old) were scanned with diffusion‐prepared, arterial spin labeling (DP‐ASL), which estimates water exchange rate across the BBB (kw). Participants also underwent CSF draw and neuropsychological testing. Multiple linear regression models were run with kw as a predictor of CSF concentrations and neuropsychological scores.ResultsIn multiple brain regions, BBB kw was positively associated with CSF amyloid beta (Aβ)42 concentration levels. BBB kw was only moderately associated with neuropsychological performance.DiscussionOur results suggest that low water exchange rate across the BBB is associated with low CSF Aβ42 concentration. These findings suggest that kw may be a promising noninvasive indicator of BBB Aβ clearance functions, a possibility which should be further tested in future research.

Effects of amyloid pathology and the APOE ε4 allele on the association between cerebrospinal fluid Aβ38 and Aβ40 and brain morphology in cognitively normal 70-years-olds

The association between cerebrospinal fluid (CSF) amyloid beta (Aβ) Aβ38 or Aβ40 and brain grey- and white matter integrity is poorly understood. We studied this in 213 cognitively normal 70-year-olds, and in subgroups defined by presence/absence of the APOE ε4 allele and Aβ pathology: Aβ−/APOE−, Aβ+/APOE−, Aβ−/APOE+ and Aβ+/APOE+. CSF Aβ was quantified using ELISA and genotyping for APOE was performed. Low CSF Aβ42 defined Aβ plaque pathology. Brain volumes were assessed using Freesurfer-5.3, and white matter integrity using tract-based statistics in FSL. Aβ38 and Aβ40 were positively correlated with cortical thickness, some subcortical volumes and white matter integrity in the total sample, and in 3 of the subgroups: Aβ−/APOE−, Aβ+/APOE− and Aβ−/APOE+. In Aβ+/APOE+ subjects, higher Aβ38 and Aβ40 were linked to reduced cortical thickness and subcortical volumes. We hypothesize that production of all Aβ species decrease in brain regions with atrophy. In Aβ+/APOE+, Aβ-dysregulation may be linked to cortical atrophy in which high Aβ levels is causing pathological changes in the gray matter of the brain.

A Western‐style dietary pattern is associated with cerebrospinal fluid biomarker levels for preclinical Alzheimer's disease—A population‐based cross‐sectional study among 70‐year‐olds

BackgroundDiet may be a modifiable factor for reducing the risk of Alzheimer's disease (AD). Western‐style dietary patterns are considered to increase the risk, whereas Mediterranean‐style dietary patterns are considered to reduce the risk. An association between diet and AD‐related biomarkers have been suggested, but studies are limited.AimTo investigate potential relations between dietary patterns and cerebrospinal fluid (CSF) biomarkers for AD among dementia‐free older adults.MethodsData were derived from the population‐based Gothenburg H70 Birth Cohort Studies, Sweden. A total of 269 dementia‐free 70‐year‐olds with dietary and cerebrospinal fluid (CSF) amyloid beta (Aβ42 and Aβ40), total tau (t‐tau), and phosphorylated tau (p‐tau) data were investigated. Dietary intake was determined by the diet history method, and four dietary patterns were derived by principal component analysis. A Western dietary pattern, a Mediterranean/prudent dietary pattern, a high‐protein and alcohol pattern, and a high‐total and saturated fat pattern. Logistic regression models, with CSF biomarker pathology (yes/no) as dependent variables, and linear regression models with continuous CSF biomarker levels as dependent variables were performed. The analyses were adjusted for sex, energy intake, body mass index (BMI), educational level, and physical activity level.ResultsThe odds ratio for having total tau pathology (odds ratio [OR] 1.43; 95% confidence interval [CI] 1.02 to 2.01) and preclinical AD (Aβ42 and tau pathology; OR 1.79; 95% CI 1.03 to 3.10) was higher among those with a higher adherence to a Western dietary pattern. There were no other associations between the dietary patterns and CSF biomarkers that remained significant in both unadjusted and adjusted models.DiscussionOur findings suggest that higher adherence to a Western dietary pattern may be associated with pathological levels of AD biomarkers in the preclinical phase of AD. These findings can be added to the increasing amount of evidence linking diet with AD and may be useful for future intervention studies investigating dietary intake in relation to AD.

Comparing CSF amyloid-beta biomarker ratios for two automated immunoassays, Elecsys and Lumipulse, with amyloid PET status.

IntroductionWe evaluated for two novel automated biomarker assays how cerebrospinal fluid (CSF) amyloid beta (Aβ)1– 42‐ratios improved the concordance with amyloid positron emission tomography (PET) positivity compared to Aβ1– 42 alone.MethodsWe selected 288 individuals from the Amsterdam Dementia Cohort across the Alzheimer's disease clinical spectrum when they had both CSF and amyloid PET visual read available, regardless of diagnosis. CSF Aβ1– 42, phosphorylated tau (p‐tau), and total tau (t‐tau) were measured with Elecsys and Lumipulse assays, and Aβ1–40 with Lumipulse. CSF cut‐points were defined using receiver operating characteristic (ROC) for amyloid PET positivity.ResultsFor both Elecsys and Lumipulse the p‐tau/Aβ1– 42, Aβ1– 42/Aβ1– 40, and t‐tau/Aβ1– 42 ratios showed similarly good concordance with amyloid PET (Elecsys: 93,90,90%; Lumipulse: 94,92,90%) and were higher than Aβ1– 42 alone (Elecsys 85%; Lumipulse 84%).DiscussionBiomarker ratios p‐tau/Aβ1– 42, Aβ1– 42/Aβ1– 40, t‐tau/Aβ1– 42 on two automated platforms show similar optimal concordance with amyloid PET in a memory clinic cohort.

Concordance of CSF measures of Alzheimer's pathology with amyloid PET status in a preclinical cohort: A comparison of Lumipulse and established immunoassays.

INTRODUCTIONWe assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau measured on the fully automated Lumipulse platform with pre‐symptomatic Alzheimer's disease (AD) pathology on amyloid positron emission tomography (PET).METHODSIn 72 individuals from the Insight 46 study, CSF Aβ40, Aβ42, total tau (t‐tau), and phosphorylated tau at site 181 (p‐tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays and inter‐platform Pearson correlations derived. Lumipulse Aβ42 measures were adjusted to incorporate standardization to certified reference materials. Logistic regressions and receiver operating characteristics analysis generated CSF cut‐points optimizing concordance with 18F‐florbetapir amyloid PET status (n = 63).RESULTSMeasurements of CSF Aβ, p‐tau181, and their ratios correlated well across platforms (r 0.84 to 0.94, P < .0001); those of t‐tau and t‐tau/Aβ42 correlated moderately (r 0.57 to 0.79, P < .0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut‐points of 0.075 for Lumipulse Aβ42/Aβ40, 0.087 for MSD Aβ42/Aβ40 and 17.3 for Lumipulse Aβ42/p‐tau181.DISCUSSIONThe Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre‐symptomatic AD pathology.

Interaction of CSF α-synuclein and amyloid beta in cognition and cortical atrophy.

IntroductionLewy body–related pathology is commonly observed at autopsy in individuals with dementia, but in vivo biomarkers for α‐synucleinopathy are lacking.MethodsBaseline cerebrospinal fluid (CSF) biomarkers, polygenic risk score (PRS) for Parkinson's disease (PRS‐PD) and Alzheimer's disease (PRS‐AD), longitudinal cognitive scores, and magnetic resonance imaging were measured in 217 participants from the Alzheimer's Disease Neuroimaging Initiative. Linear mixed models were used to find the relationship of CSF biomarkers and the PRS with cognition and cortical atrophy.ResultsHigher PRS‐PD and PRS‐AD were associated with lower CSF α‐synuclein and amyloid beta (Aβ), respectively. Lower CSF α‐synuclein and the interaction of CSF α‐synuclein and Aβ were associated with lower cognitive scores and global cortical atrophy most prominently in the occipital cortex.DiscussionLower CSF α‐synuclein could be a biomarker for α‐synucleinopathy, and the simultaneous evaluation of CSF biomarkers for AD and CSF α‐synuclein could reveal the independent and interactive effects on cognition and cortical atrophy.

Periodontal dysbiosis associates with reduced CSF Aβ42 in cognitively normal elderly.

IntroductionPeriodontal disease is a chronic, inflammatory bacterial dysbiosis that is associated with both Alzheimer's disease (AD) and Down syndrome.MethodsA total of 48 elderly cognitively normal subjects were evaluated for differences in subgingival periodontal bacteria (assayed by 16S rRNA sequencing) between cerebrospinal fluid (CSF) biomarker groups of amyloid and neurofibrillary pathology. A dysbiotic index (DI) was defined at the genus level as the abundance ratio of known periodontal bacteria to healthy bacteria. Analysis of variance/analysis of covariance (ANOVA/ANCOVA), linear discriminant effect‐size analyses (LEfSe) were used to determine the bacterial genera and species differences between the CSF biomarker groups.ResultsAt genera and species levels, higher subgingival periodontal dysbiosis was associated with reduced CSF amyloid beta (Aβ)42 (P = 0.02 and 0.01) but not with P‐tau.DiscussionWe show a selective relationship between periodontal disease bacterial dysbiosis and CSF biomarkers of amyloidosis, but not for tau. Further modeling is needed to establish the direct link between oral bacteria and Aβ.

Cerebrospinal fluid phosphorylated tau interacts with MMP2 and MMP3: Associations with cognitive performance in older adults

AbstractBackgroundMatrix metalloproteinases (MMPs) are enzymes that facilitate extracellular matrix remodeling. In Alzheimer’s disease (AD), the MMP system becomes dysregulated and may contribute to disease pathophysiology; however, limited work has examined clinical consequences of MMPs. Thus, we investigated cerebrospinal fluid (CSF) MMP2, MMP3, and MMP9 concentrations in relation to cognitive performance as well as the interaction between MMPs and AD core neuropathology (CSF amyloid beta (Aβ42) and phosphorylated tau (p‐tau)) on cognitive outcomes.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia underwent fasting lumbar puncture for CSF acquisition and neuropsychological assessment (n=153, 73±7 years, 67% male). CSF samples were analyzed in batch using commercially available ELISAs. Linear regression models individually related CSF MMP levels to neuropsychological performance, adjusting for age, sex, race/ethnicity, education, cognitive diagnosis, Framingham Stroke Risk Profile, and apolipoprotein E (APOE)‐ε4 carrier status. Models were repeated with CSF Aβ42 and p‐tau concentrations as interaction terms.ResultsIncreased CSF MMP9 related to worse language (p‐values&lt;0.03) and episodic memory performances (p=0.03); however, CSF MMP2 and MMP3 main effects were null (p‐values&gt;0.07). CSF Αβ42 did not interact with MMP2, MMP3, or MMP9 concentrations on any neuropsychological outcome (p‐values&gt;0.09). By contrast, CSF p‐tau interacted with CSF MMP2 and MMP3 levels on language performance (p‐values&lt;0.02), and CSF p‐tau interacted with CSF MMP2 levels on episodic memory performance (p=0.01). Increased CSF MMP2 and MMP3 associations with worse language and episodic memory performances were driven by p‐tau negative participants, whereas (unexpectedly) increased CSF MMP2 was associated with better language performance among p‐tau positive participants.ConclusionAmong older adults without clinical dementia or stroke, increased CSF MMP9 related to worse cognitive performance, suggesting extracellular matrix remodeling may be one pathway underlying the development of cognitive impairment. CSF p‐tau, but not Αβ42, interacted with MMP2 and MMP3 concentrations on cognitive performance. P‐tau may interact with MMPs on clinical expression of pathology in complex ways, such that increased CSF levels of MMPs may only be associated with worse cognition in non‐demented older adults in the absence of concomitant neuropathology. Funding: Alzheimer’s Association IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373.

Lipid peroxidation status in cerebrospinal fluid samples from Alzheimer disease

AbstractBackgroundOxidative stress has been postulated as one of the mechanisms implied in Alzheimer Disease (AD). Brain lipids are especially vulnerable against reactive species due to the high metabolic activity in the brain. Our previous studies reported the utility of lipid peroxidation biomarkers in plasma as potential AD diagnosis biomarkers. The aim of this work is to study the brain specificity for these biomarkers.MethodLipid peroxidation products (isoprostanes, isofurans, neuroprostanes, neurofurans) were determined in cerebrospinal fluid (CSF) and plasma samples from AD patients (n= 42) and non‐AD participants (n= 34). For this, an analytical method based on liquid chromatography coupled to mass spectrometry was used. Participants’ classification was carried out following the NIA‐AA criteria based on standard CSF biomarkers, structural neuroimaging and neuropsychological evaluation. Correlations between both biofluids were evaluated by means of Pearson Correlation.ResultMost of the determined analytes did not show correlation between plasma and CSF levels. Only the compound 17(RS)‐10‐epi‐SC‐Δ15‐11‐dihomo‐IsoF showed a slight correlation between both matrices. However, CSF lipid peroxidation levels showed correlation with CSF amyloid beta or tau levels.ConclusionCSF lipid peroxidation biomarkers levels could reflect amyloid pathology and cognitive impairment associated to AD. However, these levels are not directly correlated with the corresponding plasma concentrations, probably due to transport alterations through the blood brain barrier.

Tau kinetics in Alzheimer disease and primary tauopathies

AbstractBackgroundUnderstanding tau kinetics in the human central nervous system is critical for evaluating the effects of tau‐targeted therapies and designing clinical trials against tau in Alzheimer disease (AD) and other primary tauopathies. We hypothesized that tau production or clearance is altered in tauopathies and measured tau kinetics in AD and in a small set of participants with Progressive Supranuclear Palsy (PSP), Corticobasal Syndrome (CBS), or from Frontotemporal Dementia (FTD)‐MAPT families.Methods In vivo human tau Stable Isotope Labeling Kinetics (SILK) were performed in 65 participants including 10 young normal controls, 23 age‐matched controls, 16 AD and 16 primary tauopathies (2 PSP, 4 CBS, 10 MAPT mutation family). Briefly, participants received 16hr intravenous infusion of 13C6‐leucine and cerebrospinal fluid (CSF) was collected from five lumbar punctures over 120 days. Labeled tau was measured with mass spectrometry to obtain kinetic curves of tau. Production and clearance rates were calculated and compared across different tauopathies. CSF amyloid beta (Aβ), amyloid and tau Positron Emission Tomography (PET) imaging were measured in a subset of participants, and analyzed for correlation with SILK measures.ResultsFirst, we confirmed the reproducibility of previous results (Sato et al., 2018) and demonstrated that tau production rates increased with amyloid measured by PET or CSF Aβ. Second, CSF tau concentration correlated with CSF Aβ40 and Aβ42 in primary tauopathies but only with Aβ40 in those with abnormal Aβ levels. Third, 2 PSP patients had slower clearance of tau with tau half‐lives approximately 1.5‐2.5 times longer than other cohorts. Tau Fractional Synthesis Rate also negatively correlated with tau concentration in primary tauopathies, and CBS and FTD‐MAPT had different slopes, suggesting that they may have different kinetics.ConclusionsThe results from this study provide mechanistic insights into differences between AD and other primary tauopathies, which may be targeted differently when developing therapies against tau metabolism. In vivo tau kinetics can help evaluate the efficacy of tau‐targeted therapies and provide information for designing clinical trials targeting tau.

Nerve growth factor (NGF) pathway biomarkers in Down syndrome prior to and after the onset of clinical Alzheimer's disease: A paired CSF and plasma study.

BackgroundThe discovery that nerve growth factor (NGF) metabolism is altered in Down syndrome (DS) and Alzheimer's disease (AD) brains offered a framework for the identification of novel biomarkers signalling NGF deregulation in AD pathology.MethodsWe examined levels of NGF pathway proteins (proNGF, neuroserpin, tissue plasminogen activator [tPA], and metalloproteases [MMP]) in matched cerebrospinal fluid (CSF)/plasma samples from AD‐symptomatic (DSAD) and AD‐asymptomatic (aDS) individuals with DS, as well as controls (HC).ResultsProNGF and MMP‐3 were elevated while tPA was decreased in plasma from individuals with DS. CSF from individuals with DS showed elevated proNGF, neuroserpin, MMP‐3, and MMP‐9. ProNGF and MMP‐9 in CSF differentiated DSAD from aDS (area under the curve = 0.86, 0.87). NGF pathway markers associated with CSF amyloid beta and tau and differed by sex.DiscussionBrain NGF metabolism changes can be monitored in plasma and CSF, supporting relevance in AD pathology. These markers could assist staging, subtyping, or precision medicine for AD in DS.

Cholesterol metabolites and plant sterols in cerebrospinal fluid are associated with Alzheimer’s cerebral pathology and clinical disease progression

Background and PurposeAltered cholesterol metabolism is associated with increased risk of neurodegeneration and in particular with the development of Alzheimer’s disease (AD). Here, we investigate whether non-cholesterol sterols and oxysterols in the central nervous system are associated with (i) the presence of cerebral AD pathology, (ii) distinct aspects of AD pathology, i.e. amyloid pathology, neuronal injury, and tau pathology, and (iii) cognitive decline over time. Experimental ApproachOne hundred forty-two elder subjects with normal cognition, mild cognitive impairment, or mild dementia participating in a cohort study on cognitive decline and AD were included. Clinical and neuropsychological assessments were performed at inclusion and repeated at follow-up visits at 18 and 36 months. Concentrations of cholesterol, non-cholesterol sterols, and cholesterol metabolites were measured in cerebrospinal fluid (CSF), along with CSF beta-amyloid (Aβ)1−42; Aβ1−42/Aβ1−40 ratio, total-tau (tau), and tau phosphorylated at threonine 181 (p-tau) as markers of amyloid pathology, neuronal injury and tau pathology, respectively. Cognitive decline was assessed by changes in Mini-Mental State Examination and Clinical Dementia Rating sum of boxes at follow-up visits. Key ResultsCSF 24S-hydroxycholesterol (24S−OHC) and the 24S−OHC/27−OHC ratio were higher in subjects with AD pathology. CSF desmosterol correlated with Aβ1−42 levels. The 24S−OHC levels, the 24S−OHC/27−OHC ratio and the plant sterols campesterol and sitosterol were associated with the tau and p-tau levels. Both plant sterol concentrations along with the 24S−OHC/27−OHC ratio at baseline predicted cognitive decline at follow-up visits. Conclusions and ImplicationsWe show the importance of CSF levels of several non-cholesterol sterols and oxysterols to AD and core AD biomarkers. The plant sterols campesterol and sitosterol appear to be involved in tau pathology and neurodegeneration. CSF desmosterol level indicates CNS cholesterol synthesis and might be of relevance for clinical disease severity. Therefore these non-cholesterol sterols may represent intervention targets to slow down disease progression.

Amyloid, tau and risk of Alzheimer's disease: a Mendelian randomization study.

This study was carried out to assess the effect of amyloid and tau on Alzheimer's disease using two-sample Mendelian randomization design. Genetic associations with plasma amyloid species (amyloid precursor protein, amyloid-like protein 2, serum amyloid P-component, amyloid beta peptide), cerebrospinal fluid (CSF) amyloid beta, total tau, and phosphorylated tau181 were extracted from the largest genome-wide association study (GWAS) available. Genetic associations with Alzheimer's disease were obtained from a GWAS of proxy-cases based on family history of Alzheimer's disease with 314,278 participants from the UK Biobank and a GWAS with clinically diagnosed Alzheimer's disease from the International Genomics of Alzheimer's Project (IGAP) with 21,982 cases and 41,944 controls. Estimates were obtained using inverse variance weighting with sensitivity analyses including MR-Egger, weighted median and MR-PRESSO. Presence of bias due to selective survival and competing risk was also considered. Plasma amyloid species, CSF total tau and phosphorylated tau181 were not associated with Alzheimer's disease. For CSF Aβ42, no association was found using the proxy-cases but an inverse association was found after removing outliers with MR-PRESSO using IGAP. Higher genetically predicted (p < 1 × 10-5) plasma amyloid species, CSF total tau and phosphorylated tau181 (based on sample sizes ~ 3300) were not associated with Alzheimer's disease using family history or clinically diagnosed cases while effects of CSF Aβ42 were inconsistent between the family history and IGAP GWAS.