Cerebrospinal Fluid Total Tau Research Articles

Age-adjusted CSF t-tau and NfL do not improve diagnostic accuracy for prodromal Alzheimer’s disease

Cerebrospinal fluid total-tau (t-tau) and neurofilament light chain (NfL) are biomarkers of neurodegeneration and are increased in Alzheimer’s disease (AD). In order to adjust for age-related increases in t-tau and NfL, cross-sectional age-adjusted norms were developed based on amyloid negative cognitively normal (CN) adults aged 41–78 years (CN, n = 137). The age-adjusted norms for t-tau and NfL did not improve receiver operating curve based diagnostic accuracies in individuals with mild cognitive impairment (MCI) due to AD (AD-MCI, n = 144). Furthermore, while NfL was correlated with higher age in AD-MCI, no significant correlation was found for t-tau. The cox proportional hazard models, applied in 429 participants with baseline t-tau and NfL, showed higher hazard ratio of progression to MCI or dementia without age-adjustments (HR = 3.39 for t-tau and HR = 3.17 for NfL), as compared to using our norms (HR = 2.29 for t-tau and HR = 1.89 for NfL). Our results indicate that utilizing normative reference data could obscure significant age-related increases in these markers associated with neurodegeneration and AD leading to a potential loss of overall diagnostic accuracy.

Longitudinal trajectories of Alzheimer's disease CSF biomarkers and blood pressure in cognitively healthy subjects.

We examined whether hypertension (HTN) was associated with Alzheimer's disease-related biomarkers in cerebrospinal fluid (CSF) and how changes in blood pressure (BP) related to changes in CSF biomarkers over time. A longitudinal observation of cognitively healthy normotensive subjects (n=134, BP<140/90, withno antihypertensive medication), controlled HTN(n=36, BP<140/90, taking antihypertensive medication), and 35 subjects with uncontrolled HTN (BP ≥ 140/90). The follow-up range was 0.5to15.6 years. Total tau (T-tau) and phospho-tau181 (P-tau 181) increased in allbut controlled HTN subjects (group×timeinteraction: p<0.05 for both), but no significant Aβ42 changes were seen. SignificantBP reduction wasobserved in uncontrolled HTN, andit was related to increase in T-tau (p=0.001) and P-tau 181 (p<0.001). Longitudinal increases in T-tau and P-tau 181 were observed in most subjects; however, onlyuncontrolled HTN had both markers increase alongside BPreductions. We speculatecumulative vascular injury renders thebrain susceptible to relative hypoperfusion with BP reduction. Over the course of the study, participants with uncontrolled HTN at baseline showed greater accumulation of CSF total tau and phospho-tau181 (P-tau 181) than subjects with normal BP or with controlled HTN. In the group with uncontrolled HTN, increases in total tau and P-tau 181 coincided with reduction in BP. We believe this highlights the role of HTN in vascular injury and suggests decline in cerebral perfusion resulting in increased biomarker concentrations in CSF. Medication use was the main factor differentiating controlled from uncontrolled HTN, indicating that earlier treatment was beneficial for preventing accumulations of pathology.

Cerebrospinal fluid α-synuclein adds the risk of cognitive decline and is associated with tau pathology among non-demented older adults

BackgroundThe role of α-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood.MethodsA total of 331 non-demented individuals were included in the study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their α-synuclein levels: one with lower levels (α-synuclein-L) and another with higher levels (α-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of α-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between α-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition.ResultsHigher CSF α-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the α-synuclein-H group. Further correlation and regression analysis indicated that the CSF α-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF α-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF α-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1.ConclusionsThese findings elucidate a significant connection between elevated levels of CSF α-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF α-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia.

Biomarkers of neurodegeneration in schizophrenia: systematic review and meta-analysis

QuestionDoes neurodegenerative disease underlie the increased rate of dementia observed in older people with schizophrenia? Several studies have reported a higher prevalence of dementia in people with schizophrenia compared with...

Cardiovascular Risk Scales Association with Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cardiovascular Low Cardiovascular Risk Regions.

Cardiovascular risk factors are associated with Alzheimer's Disease (AD) development. However, few studies compare the overall cardiovascular risk with AD biomarkers, and when done, they are mainly performed in moderate cardiovascular risk regions. To determine whether cardiovascular risk in older adults is associated with pathological cerebrospinal fluid (CSF) biomarkers of AD in a low cardiovascular risk population. This is a cross-sectional study performed between 2017 and 2020. The present work included patients between 50 and 75 years old who were negative for CSF AD biomarkers and had minimum cognitive alterations (controls) and patients with positive CSF AD biomarkers and in early stages of AD (cases). CSF biomarkers included total tau, phosphorylated tau 181 and amyloid ß42 (Aß42). Analytical variables were obtained. ERICE, SCORE2 and Framingham scales were used to calculate the overall patient's cardiovascular risk. The Aß42/Aß40 ratio and neurofilaments were explored when available. Two hundred and thirty-three patients were included. Nearly 76% of the sample had AD. AD patients had higher cardiovascular risk than controls (p-value < 0.05). ERICE and SCORE2 were associated with AD presence. Framingham was not. A correlation between elevated cardiovascular risk and higher total tau and NfL levels was observed when adjusted by age. Cardiovascular risk assessment may be helpful in neurodegenerative disorders detection, as it is associated with CSF total tau and NfL. ERICE and SCORE2 may be useful scales in low cardiovascular risk regions to improve cardiovascular control and prevent neurodegenerative pathologies.

Tau seeds from Alzheimer's disease brains trigger tau spread in macaques while oligomeric-Aβ mediates pathology maturation.

The "prion-like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid-β (Aβ) have never been experimentally studied in primates phylogenetically close to humans. We injected 17 macaques in the entorhinal cortex with nanograms of seeding-competent tau aggregates purified from AD brains or control extracts from aged-matched healthy brains, with or without intracerebroventricular co-injections of oligomeric-Aβ. Pathological tau injection increased cerebrospinal fluid (CSF) p-tau181 concentration after 18 months. Tau pathology spreads from the entorhinal cortex to the hippocampal trisynaptic loop and the cingulate cortex, resuming the experimental progression of Braak stage I to IV. Many AD-related molecular networks were impacted by tau seeds injections regardless of Aβ injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total-tau concentration, and pre- and postsynaptic degeneration only in Aβ co-injected macaques. Oligomeric-Aβ mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading. This study supports the "prion-like" properties of misfolded tau extracted from AD brains. This study empirically validates the Braak staging in an anthropomorphic brain. This study highlights the role of oligomeric Aβ in driving the maturation and toxicity of tau pathology. This work establishes a novel animal model of early sporadic AD that is closer to the human pathology.

Serum neurofilament light chain levels in patients with cognitive deficits and movement disorders: comparison of cerebrospinal and serum neurofilament light chain levels with other biomarkers.

Serum neurofilament light chain (S NfL) is a non-specific marker of neuronal damage, including Alzheimer's disease (AD). We aimed to verify the reference interval (RI) of serum NfL using a highly sensitive ELISA, and to estimate the optimal cut-off value for neuronal damage. Our second objective was to compare NfL in cerebrospinal fluid (CSF) and serum (S) with the routine neurodegeneration biomarkers used in AD, and to assess their concentrations relative to the degree of cognitive deficit. Samples from 124 healthy volunteers were used to estimate the S NfL RI. For the comparison study, we used CSF and S samples from 112 patients with cognitive disorders. Cognitive functions were assessed using the mini-mental state examination. ELISA assays were used to determine the CSF and S NfL levels, CSF β-amyloid peptide42 (Aβ42), CSF β-amyloid peptide40 (Aβ40), CSF total tau protein (tTau), CSF phosphorylated tau protein (pTau), and CSF alpha-synuclein (αS). The estimated RI of S NfL were 2.25-9.19 ng.L-1. The cut-off value of S NfL for assessing the degree of neuronal impairment was 10.5 ng.L-1. We found a moderate statistically significant correlation between S NfL and CSF Aβ42 in the group with movement disorders, without dementia (rs = 0.631; p = 0.016); between S NfL and CSF Aβ40 in the group with movement disorder plus dementia (rs = -0.750; p = 0.052); between S NfL and CSF tTau in the control group (rs = 0.689; p = 0.009); and between S NfL and CSF pTau in the control group (rs = 0.749; p = 0.003). The non-parametric Kruskal-Wallis test revealed statistically significant differences between S NfL, CSF NfL, CSF Aβ42, CSF tTau, and CSF pTau and diagnosis within groups. The highest kappa coefficients were found between the concentrations of S NfL and CSF NfL (κ = 0.480) and between CSF NfL and CSF tTau (κ = 0.351). Our results suggested that NfL and tTau in CSF of patients with cognitive decline could be replaced by the less-invasive determination of S NfL using a highly sensitive ELISA method. S NfL reflected the severity of cognitive deficits assessed by mini-mental state examination (MMSE). However, S NfL is not specific to AD and does not appear to be a suitable biomarker for early diagnosis of AD.

PD‐L1 blockade therapeutic effect in Tau P301S (line PS19) mouse model of tauopathy

AbstractBackgroundThere is a growing understanding that Alzheimer’s disease (AD) and tauopathies are not merely brain‐centric conditions, but encompass also dysfunction of the peripheral immune system that impacts disease onset and progression. We have previously shown, in several mouse models of AD, that blockade of the PD‐1/PD‐L1 immune checkpoint pathway facilitates homing of specialized immune cells to the brain, where these cells mitigate different pathomechanisms, ultimately leading to function improvement. Here, we tested PD‐L1 blockade in the Tau P301S (line PS19) mouse model of tauopathy.MethodsTau P301S mice were treated with anti‐PD‐L1 antibody, or isotype control, and tested for the functional effect of the treatment on parameters of cognitive performance and brain pathology, at different time points after treatment. Pharmacokinetic and pharmacodynamic events following treatment were evaluated to monitor the peripheral and central immune response. Treatment effects were also evaluated in TREM2 knockout Tau P301S mice.ResultsDose‐dependent effect of anti‐PD‐L1 treatment was detected at 14‐ and 28‐days post‐treatment, with respect to cognitive performance of PS19 mice, as measured by T maze task. At the different timepoints following treatment we found reduction in cerebrospinal fluid total tau protein levels, and reduction in cortical phosphorylated tau (Ser404) protein levels. The functional effect on improvement of cognitive performance following anti‐PD‐L1 administration was also observed in TREM2 knockout Tau P301S mice, suggesting that the therapeutic effect of anti‐PD‐L1, is independent of TREM2 expression.ConclusionsPD‐L1 blockade evokes an immune response that leads to functional improvement on cognitive performance and reduced brain pathology in Tau P301S mice. These findings, taken together with our previous reports of anti‐PD‐L1 therapeutic effect in other AD or tauopathy mouse models, substantiate the generalization of this treatment approach ‐ targeting the peripheral immune system in order to drive brain tissue repair in neurodegenerative conditions.

Synaptic proteins in pre‐symptomatic Alzheimer’s disease: biomarkers for early detection of Cognitive Decline

AbstractBackgroundSynaptic proteins in the cerebrospinal fluid (CSF) may reveal changes in the pre‐symptomatic stages of Alzheimer’s disease (AD), thus may be candidate biomarkers for early detection of the disease.MethodThe PREVENT‐AD cohort includes symptom‐free (upon enrolment) elderly participants who are at risk of developing AD from their family history. We used enzyme‐linked immunosorbent assay kits to assess CSF samples from 129 such participants for the “classical” AD biomarkers total tau, phosphorylated (181) tau and Aβ42. We also used neuroimaging data (MRI, PET) and neuropsychological assessments (MMSE, RBANS) as potential indicators disease progression. We then used in the CSF samples to measure the soluble synaptic biomarkers ADAM 22 (post‐synaptic), ADAM23 (pre‐synaptic). Immunoprecipitated SYT1 (pre‐synaptic) from CSF were analyyzed using high‐resolution selected ion monitoring analyses on a quadrupole–orbitrap mass spectrometer Q Exactive. Statistical analysis of the association of these markers with evidence of disease in analyses were done included sex and APOE e4 status as covariates.ResultAmong participants who remained cognitively unimpaired, we observed significant correlations between baseline CSF ADAM 22 levels and t‐tau (R2 = 0.22, p &lt; 0.0001), p‐tau (R2 = 0.22, p &lt; 0.0001), and Aβ42 (R2 = 0.06, p = 0.01488). We also found similarly suggestive correlations also between CSF ADAM 23, CSF SYT1 and the same disease markers. Covariate analyses suggested little or no variation in the associations between these synaptic proteins with t‐tau and p‐tau by sex, APOE e4 status, negative PET amyloid positivity (standardized uptake value ratio ≤ 1.37) and negative CSF total tau positivity (≤ 335pg/ul). PET amyloid positivity was significantly associated with ADAM22 and p‐tau interactions whereas SYT1 was significantly associated with t‐tau and p‐tau in CSF tau‐positive participants. In linear regression analyses, baseline CSF ADAM22 levels correlated with the language cognitive performance trajectory slopes estimated over the course of 5 to 8 years on the RBANS (R2 = 0.04, p = 0.03912). We found no significant interaction between other baseline CSF synaptic protein levels and other subscales of the RBANS.ConclusionCSF synaptic protein levels show promising correlation with landmark AD proteins and emerging cognitive deficits.

Insulin-like growth factor binding protein-2 in at-risk adults and autopsy-confirmed Alzheimer brains.

Insulin, insulin-like growth factors (IGF) and their receptors are highly expressed in the adult hippocampus. Thus, disturbances in the insulin-IGF signalling pathway may account for the selective vulnerability of the hippocampus to nascent Alzheimer's disease (AD) pathology. In the present study, we examined the predominant IGF-binding protein in the CSF, IGFBP2. CSF was collected from 109 asymptomatic members of the parental history-positive PREVENT-AD cohort. CSF levels of IGFBP2, core AD and synaptic biomarkers were measured using proximity extension assay, ELISA and mass spectrometry. Cortical amyloid-beta (Aβ) and tau deposition were examined using 18F-NAV4694 and flortaucipir. Cognitive assessments were performed during up to 8 years of follow-up, using the Repeatable Battery for the Assessment of Neuropsychological Status. T1-weighted structural MRI scans were acquired, and neuroimaging analyses were performed on pre-specified temporal and parietal brain regions. Next, in an independent cohort, we allocated 241 dementia-free ADNI-1 participants into four stages of AD progression based on the biomarkers CSF Aβ42 and total-tau (t-tau). In this analysis, differences in CSF and plasma IGFBP2 levels were examined across the pathological stages. Finally, IGFBP2 mRNA and protein levels were examined in the frontal cortex of 55 autopsy-confirmed AD and 31 control brains from the Quebec Founder Population (QFP) cohort, a unique population isolated from Eastern Canada. CSF IGFBP2 progressively increased over 5 years in asymptomatic PREVENT-AD participants. Baseline CSF IGFBP2 was positively correlated with CSF AD biomarkers and synaptic biomarkers, and negatively correlated with longitudinal changes in delayed memory (P = 0.024) and visuospatial abilities (P = 0.019). CSF IGFBP2 was negatively correlated at a trend-level with entorhinal cortex volume (P = 0.082) and cortical thickness in the piriform (P = 0.039), inferior temporal (P = 0.008), middle temporal (P = 0.014) and precuneus (P = 0.033) regions. In ADNI-1, CSF (P = 0.009) and plasma (P = 0.001) IGFBP2 were significantly elevated in Stage 2 [CSF Aβ(+)/t-tau(+)]. In survival analyses in ADNI-1, elevated plasma IGFBP2 was associated with a greater rate of AD conversion (hazard ratio = 1.62, P = 0.021). In the QFP cohort, IGFBP2 mRNA was reduced (P = 0.049); however, IGFBP2 protein levels did not differ in the frontal cortex of autopsy-confirmed AD brains (P = 0.462). Nascent AD pathology may induce an upregulation in IGFBP2 in asymptomatic individuals. CSF and plasma IGFBP2 may be valuable markers for identifying CSF Aβ(+)/t-tau(+) individuals and those with a greater risk of AD conversion.

Intrathecal production of anti-Epstein-Barr virus viral capsid antigen IgG is associated with neurocognition and tau proteins in people with HIV.

HIV and Epstein-Barr virus (EBV) co-infection has been linked to increased immune activation and larger HIV reservoir. We assessed whether anti-EBV humoral responses are associated with increased cerebrospinal fluid (CSF) inflammation and with neurocognitive impairment (NCI) in people with HIV (PWH). Cross-sectional analysis in 123 EBV-seropositive PWH either on antiretroviral therapy ( n = 70) or not. Serum and CSF anti-EBV viral capsid antigen immunoglobulin G (anti-EVI) and CSF EBV DNA were measured by commercial immunoassay and RT-PCR. Seventy-eight participants without neurological confounding factors underwent neurocognitive assessment (Global Deficit Score, GDS). CSF total tau and 181-phosphorylated-tau (ptau) were measured by immunoassays together with biomarkers of blood-brain barrier (BBB) integrity, immune activation, astrocytosis, and intrathecal synthesis. Logistic and linear regressions and moderation analysis were used to investigate the relationships between CSF anti-EVI, GDS, and biomarkers. Twenty-one (17.1%) and 22 participants (17.9%) had detectable CSF anti-EVI (10.5-416.0 U/ml) and CSF EBV DNA (25-971 copies/ml). After adjusting for BBB integrity, age, and clinical factors, the presence of CSF anti-EVI was only associated with serum levels of anti-EVI, and not with CSF EBV DNA. CSF anti-EVI, tau and ptau showed reciprocal interactions affecting their associations with GDS. After adjusting for demographics and clinical parameters, higher CSF anti-EVI levels were associated with worse GDS (aβ 0.45, P < 0.001), and CSF levels of tau and ptau had a moderation effect on the strength of this association (models' P < 0.001). Humoral immune responses against EBV within the central nervous system may contribute to NCI in PWH through mechanisms that involve neuronal injury.

Exploring the Potential Association Between Self-Reported Psychological Stress and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease in Midlife: A Cross-Sectional Study.

Psychological stress is associated with dementia risk. However, the underlying mechanisms are unclear. This cross-sectional study examined the association between self-reported psychological stress and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease and neurodegeneration in 73 cognitively unimpaired middle-aged adults from the Healthy Brain Project (mean age = 58±7 years). Linear regression analyses did not reveal any significant associations of psychological stress with CSF amyloid-β42, phosphorylated tau-181, total tau, or neurofilament light chain. Cohen's f2 effect sizes were small in magnitude (f2≤0.08). Further research is needed to replicate our findings, particularly given that the sample reported on average low levels of stress.

Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency

BackgroundCreatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). The disorder is marked by developmental delay, especially speech delay. The biomarkers Aβ40, Aβ42 and total tau are abnormal in Alzheimer disease (AD), a common neurodegenerative disorder pathologically characterized by Aβ peptide containing amyloid plaques and tau neurofibrillary tangles. Although CTD results in neuronal energy deficiency, the pathological processes underlying the CTD phenotype are not fully characterized. MethodsCerebral spinal fluid (CSF) was collected as an optional part of a natural history study of CTD. Aβ40, Aβ42 and total tau levels were quantified in CSF from individuals with CTD and from age-appropriate comparison samples. Neuro3-Plex enzyme-linked immunoassay was performed on a Quanterix SR-X instrument. The Vineland Adaptive Behavior Scale, 3rd Edition was used to determine an overall Adaptive Behavior Composite (ABC) standard score. ResultsCSF from 12 individuals with CTD and 23 age appropriate non-CTD comparison samples were analyzed. We found that levels of total tau [t(32) = 4.05, p = 0.0003], Aβ40 [t(31) = 6.11, p < 0.0001], and Aβ42 [t(32) = 3.20, p = 0.003] were elevated in the participants with CTD relative to the comparison group. Additionally, except for one individual that we considered an outlier, all three biomarkers correlated inversely with the adaptive behavior score (total tau: ρ = −0.60 [−0.88, 0.005]; Aβ40: ρ = −0.67 [−0.91, −0.12]; Aβ42: ρ = −0.62 [−0.89, −0.02]). ConclusionWe describe here the novel finding of elevated protein biomarkers in the CSF of individuals with CTD. Aβ40, Aβ42 and total tau are markedly elevated in individuals with CTD compared to comparison samples, and increased levels of these biomarkers inversely correlated with ABC scores. We hypothesize that elevated CSF levels of Aβ40 and Aβ42 are due to cellular energy deficiency. Elevated CSF total tau levels may indicate ongoing neuronal damage. The observed inverse correlation of Vineland ABC scores with increased biomarker levels needs to be confirmed in a larger CTD cohort; however, our observation of increased Aβ40, Aβ42 and total tau levels in CSF from individuals with CTD may provide insight into pathological mechanisms contributing to the CTD phenotype and may prove useful as supportive data in future therapeutic trials.

Machine learning-based prediction of longitudinal cognitive decline in early Parkinson’s disease using multimodal features

Patients with Parkinson’s Disease (PD) often suffer from cognitive decline. Accurate prediction of cognitive decline is essential for early treatment of at-risk patients. The aim of this study was to develop and evaluate a multimodal machine learning model for the prediction of continuous cognitive decline in patients with early PD. We included 213 PD patients from the Parkinson’s Progression Markers Initiative (PPMI) database. Machine learning was used to predict change in Montreal Cognitive Assessment (MoCA) score using the difference between baseline and 4-years follow-up data as outcome. Input features were categorized into four sets: clinical test scores, cerebrospinal fluid (CSF) biomarkers, brain volumes, and genetic variants. All combinations of input feature sets were added to a basic model, which consisted of demographics and baseline cognition. An iterative scheme using RReliefF-based feature ranking and support vector regression in combination with tenfold cross validation was used to determine the optimal number of predictive features and to evaluate model performance for each combination of input feature sets. Our best performing model consisted of a combination of the basic model, clinical test scores and CSF-based biomarkers. This model had 12 features, which included baseline cognition, CSF phosphorylated tau, CSF total tau, CSF amyloid-beta1-42, geriatric depression scale (GDS) scores, and anxiety scores. Interestingly, many of the predictive features in our model have previously been associated with Alzheimer’s disease, showing the importance of assessing Alzheimer’s disease pathology in patients with Parkinson’s disease.

Sleep Dysregulation Is Associated with 18F-FDG PET and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease.

Sleep impairment has been commonly reported in Alzheimer's disease (AD) patients. The association between sleep dysregulation and AD biomarkers has been separately explored in mild cognitive impairment (MCI) and AD patients. The present study investigated cerebrospinal-fluid (CSF) and 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) biomarkers in MCI and AD patients in order to explore their association with sleep parameters measured with polysomnography (PSG). MCI and AD patients underwent PSG, 18F-FDG-PET, and CSF analysis for detecting and correlating these biomarkers with sleep architecture. Thirty-five patients were included in the study (9 MCI and 26 AD patients). 18F-FDG uptake in left Brodmann area 31 (owing to the posterior cingulate cortex) correlated negatively with REM sleep latency (p = 0.013) and positively with REM sleep (p = 0.033). 18F-FDG uptake in the hippocampus was negatively associated with sleep onset latency (p = 0.041). Higher CSF orexin levels were associated with higher sleep onset latency (p=0.042), Non-REM stage 1 of sleep (p=0.031), wake after sleep onset (p=0.028), and lower sleep efficiency (p=0.045). CSF levels of Aβ42 correlated negatively with the wake bouts index (p = 0.002). CSF total-tau and phosphorylated tau levels correlated positively with total sleep time (p=0.045) and time in bed (p=0.031), respectively. Sleep impairment, namely sleep fragmentation, REM sleep dysregulation, and difficulty in initiating sleep correlates with AD biomarkers, suggesting an effect of sleep on the pathological processes in different AD stages. Targeting sleep for counteracting the AD pathological processes represents a timely need for clinicians and researchers.

IgG index of cerebrospinal fluid can reflect pathophysiology associated with Lewy bodies in Parkinson's disease

BackgroundNeuroinflammation is one of the pathophysiologies of Parkinson's disease (PD). Lewy bodies, the pathological hallmark of PD, emerge as a consequence of α-synuclein aggregation, and neuroinflammation is induced concurrently with this aggregation. Imaging and cerebrospinal fluid (CSF) biomarkers that reflect PD pathophysiology have been developed or are under investigation. The IgG index of CSF is a marker of inflammation, and may also reflect the pathophysiology of PD. AimWe examined if the IgG index reflects the pathophysiology of PD in drug-naïve PD patients. MethodThe subjects were 20 consecutive PD patients who underwent 123I-MIBG scintigraphy for assessment of the heart to mediastinum (H/M) ratio and wash out rate, 123I-Ioflupane SPECT for examination of the specific binding ratio in the striatum, and lumbar puncture before treatment. The CSF IgG index and levels of pathogenic proteins (total α-synuclein, oligomeric α-synuclein, total tau, phosphorylated tau and amyloid Aβ1–42) were determined. The IgG index was compared with the other parameters using Spearman correlation analysis. ResultsThe IgG index showed a significant correlation with the H/M ratio in early (r = −0.563, p = 0.010) and delayed (r = −0.466, p = 0.038) images in 123I-MIBG scintigraphy and with the CSF total tau level (r = −0.513, p = 0.021). ConclusionNeuroinflammation is involved in PD pathophysiology in some patients, and a higher IgG index indicates the presence of neuroinflammation accompanied by emergence of Lewy bodies.

Biomarkers of Alzheimer’s disease in Black and/or African American Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants

Majority of dementia research is conducted in non-Hispanic White participants despite a greater prevalence of dementia in other racial groups. To obtain a better understanding of biomarker presentation of Alzheimer’s disease (AD) in the non-Hispanic White population, this study exclusively examined AD biomarker abnormalities in 85 Black and/or African American participants within the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants were classified by the ADNI into 3 clinical groups: cognitively normal, mild cognitive impairment, or dementia. Data examined included demographics, apolipoprotein E (APOE) ε4, cerebrospinal fluid (CSF) Aβ1-42, CSF total tau (t-tau), CSF phosphorylated tau (p-tau), 3T magnetic resonance imaging (MRI), and measures of cognition and function. Analyses of variance and covariance showed lower cortical thickness in 5 of 7 selected MRI regions, lower hippocampal volume, greater volume of white matter hyperintensities, lower measures of cognition and function, lower measures of CSF Aβ1-42, and greater measures of CSF t-tau and p-tau between clinical groups. Our findings confirmed greater AD biomarker abnormalities between clinical groups in this sample.

Thimet oligopeptidase as a potential CSF biomarker for Alzheimer's disease: A cross-platform validation study.

Our previous antibody-based cerebrospinal fluid (CSF) proteomics study showed that Thimet oligopeptidase (THOP1), an amyloid beta (Aβ) neuropeptidase, was increased in mild cognitive impairment with amyloid pathology (MCI-Aβ+) and Alzheimer's disease (AD) dementia compared with controls and dementia with Lewy bodies (DLB), highlighting the potential of CSF THOP1 as an early specific biomarker for AD. We aimed to develop THOP1 immunoassays for large-scale analysis and validate our proteomics findings in two independent cohorts. We developed in-house CSF THOP1 immunoassays on automated Ella and Simoa platforms. The performance of the different assays were compared using Passing-Bablok regression analysis in a subset of CSF samples from the discovery cohort (n = 72). Clinical validation was performed in two independent cohorts (cohort 1: n = 200; cohort 2: n = 165) using the Ella platform. THOP1 concentrations moderately correlated between proteomics analysis and our novel assays (Rho>0.580). In both validation cohorts, CSF THOP1 was increased in MCI-Aβ+ (>1.3-fold) and AD (>1.2-fold) compared with controls; and between MCI-Aβ+ and DLB (>1.2-fold). Higher THOP1 concentrations were detected in AD compared with DLB only when both cohorts were analyzed together. In both cohorts, THOP1 correlated with CSF total tau (t-tau), phosphorylated tau (p-tau), and Aβ40 (Rho>0.540) but not Aβ42. Validation of our proteomics findings underpins the potential of CSF THOP1 as an early specific biomarker associated with AD pathology. The use of antibody-based platforms in both the discovery and validation phases facilitated the translation of proteomics findings, providing an additional workflow that may accelerate the development of biofluid-based biomarkers.

Association of the fibronectin type III domain-containing protein 5 rs1746661 single nucleotide polymorphism with reduced brain glucose metabolism in elderly humans.

Fibronectin type III domain-containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer's disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer's disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-β deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer's Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-β PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-β42, phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer's disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans.

Point of care measurement of blood tau in Alzheimer’s dementia

AbstractBackgroundSeveral assays reliably measure cerebrospinal fluid (CSF) total tau (t‐tau) protein for Alzheimer’s diseases (AD) diagnosis. However, CSF sampling is invasive and hampers availability of biomarker testing in AD. Therefore, less invasive blood t‐tau assays are needed, preferably on different platforms to enable implementation in different clinical settings. Point‐of‐care (POC) platforms enable the development of practical and easily implemented assays. Here, we aim to develop and compare two blood t‐tau POC‐assays, (1)on the Ella microfluidics platform and (2)using upconversion‐nanoparticle based lateral flow (UCNP‐LF), for use in AD diagnosis.MethodThe prototype assays were developed with the same pair of antibodies (capture‐mAb: ADx205 and detector‐mAb: ADx204 having epitopes in respectively the regions aa 194‐204 and 1‐20) and were calibrated using a recombinant protein (2N4R tau). For the Ella‐assay, we validated the analytical sensitivity, precision (4 different runs) and parallelism. The acceptance range was set to &lt;15% coefficient of variation (CV) for precision and 85‐115% of slope‐accuracy for parallelism. Detectability of t‐tau was assessed using 20 plasma samples, including 10 AD‐dementia patients (age: 64±9y, 60%F) and 10 controls (age: 67±8y, 50%F). For the UCNP‐LF assay, spiked buffer and serum were used for preliminary performance testing.ResultFor the Ella assay, we determined a limit of detection (LoD) of 3 pg/mL based on mean signal of 16 blanks plus 10x SD (figure1). The assay quantified t‐tau in the clinical samples above assay blank with an average intra‐assay CV of 5.3%. Average intra‐ and inter‐assay CV for QC plasma samples were 8% and 11.4%. The assay showed robust mean parallelism response of (95%) (figure 2). Median t‐tau concentration in AD samples was 36.9 pg/mL vs 8 pg/mL in controls. The prototype UCNP‐LF assay showed a LoD of 92 pg/mL, based upon spiked buffer with the recombinant protein, and 102 pg/mL for spiked serum (figure3). The UCNP‐LF assay has a read‐out time of 30 minutes.ConclusionThe prototype assays showed promising preliminary performance. Next, a technology comparison using Bland‐Altman graphs on samples of at least two different clinical groups, would be measured using a reference immunoassay platform, such as Simoa.