Cerebrospinal Fluid Tau Concentrations Research Articles

Abstract WMP14: Cerebrospinal Fluid Beta-Amyloid Concentration and MRI Manifestations of Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is associated with reduced cerebrospinal fluid (CSF) levels of the beta-amyloid (Aβ) 40- and 42-amino acid species, thought to reflect the burden of vascular Aβ deposition in the brain. Little is known regarding the association of CSF Aβ reduction with specific MRI manifestations of CAA. Methods: We identified 31 patients with CAA per Boston criteria v2.0 (1 definite, 27 probable, and 3 possible), who underwent CSF sampling for measurement of Aβ42, total tau (t-tau), and phospho-tau (p-tau) as part of their evaluation with ADmark (Athena Diagnostics). We assessed the following MRI manifestations of CAA while blinded to CSF biomarkers: the presence of cortical superficial siderosis (cSS), number of lobar cerebral microbleeds (CMBs), pattern and severity of white matter hyperintensities (WMH), and number of enlarged perivascular spaces in centrum semiovale (CSO-EPVS). Results: Median age of presentation was 69 years (range 56-89). Out of 31 patients, 19 were female (61.3%), 20 (64.5%) presented with cognitive impairment, 9 (29%) with intracerebral hemorrhage, and 2 (6.5%) with transient focal neurologic events. Mean (±SD) CSF Aβ42 concentration in our cohort was 359.3±126.7 pg/ml, substantially reduced relative to that reported in healthy controls. MRI manifestations associated with reduced Aβ42 without altered tau were presence of cSS (310±136 vs. 406±101, p=0.03) and higher burden of CSO-EPVS (307±101 vs. 431±127, p=0.005). Patients presented with cognitive impairment had higher tau levels (t-tau: 551±320 vs. 317±141, p=0.03; p-tau: 75.7±39.8 vs. 49.2±22.4, p=0.05) without altered Aβ42. Similar results were obtained when patients with possible CAA were excluded. Discussion: Our results suggest that presence of cSS and higher burden of CSO-EPVS are associated with lower Aβ42 concentration in CSF, potentially reflecting higher overall burden of vascular Aβ deposition in the brain. We found that higher tau concentrations in CSF are associated with cognitive impairment, presumably reflecting concomitant Alzheimer’s disease pathology. These results help inform interpretation of this clinically accessible test in practice and suggest potential mechanisms for specific CAA-related pathologies.

Structural irregularities in MR corpus callosal images and their association with cerebrospinal fluid biomarkers in Mild Cognitive Impairments

In this study, irregularity measures from MR images of corpus callosal brain structures in healthy and Mild Cognitive Impairment (MCI) conditions are extracted and their association with Cerebrospinal Fluid (CSF) biomarkers are analyzed. For this, MR images of healthy controls, Early MCI (EMCI) and Late MCI (LMCI) subjects are considered from a public database. The considered images are preprocessed and corpus callosal structure is segmented. Structural irregularity measures are extracted from the segmented regions using Fourier analysis. Statistical tests are performed to identify the significant features which can characterize the MCI stages. Association of these measures with CSF amyloid beta and tau concentrations are further investigated. Results demonstrate that Fourier spectral analysis is able to characterize the non-periodic variations in the corpus callosal structures of healthy, EMCI and LMCI MR images. The callosal irregularity measures increase as the disease progresses from healthy to LMCI. Phosphorylated tau concentrations in CSF demonstrate a positive correlation with irregularity measures across the diagnostic groups. Significant association of callosal measures and amyloid beta levels are found to be absent in MCI stages. As corpus callosal structural irregularities due to early MCI condition and their association with CSF markers remain uncharacterized in the literature, this study seems to be clinically significant for the timely intervention of pre-symptomatic MCI stages.

Subtle Differences in Cognition in 70-Year-Olds with Elevated Cerebrospinal Fluid Neurofilament Light and Neurogranin: A H70 Cross-Sectional Study.

Most research on cerebrospinal fluid (CSF) neurofilament light protein (NfL) as a marker for neurodegeneration and neurogranin (Ng) for synaptic dysfunction has largely focused on clinical cohorts rather than population-based samples. We hypothesized that increased CSF levels of NfL and Ng are associated with subtle cognitive deficits in cognitively unimpaired (CU) older adults. The sample was derived from the Gothenburg H70 Birth Cohort Studies and comprised 258 CU 70-year-olds, with a Clinical Dementia Rating score of zero. All participants underwent extensive cognitive testing. CSF levels of NfL and Ng, as well as amyloid β1-42, total tau, and phosphorylated tau, were measured. Participants with high CSF NfL performed worse in one memory-based test (Immediate recall, p = 0.013) and a language test (FAS, p = 0.016). Individuals with high CSF Ng performed worse on the memory-based test Supra Span (p = 0.035). When stratified according to CSF tau and Aβ42 concentrations, participants with high NfL and increased tau performed worse on a memory test than participants normal tau concentrations (Delayed recall, p = 0.003). In participants with high NfL, those with pathologic Aβ42 concentrations performed worse on the Delayed recall memory (p = 0.044). In the high Ng group, participants with pathological Aβ42 concentrations had lower MMSE scores (p = 0.027). However, in regression analysis we found no linear correlations between CSF NfL or CSF Ng in relation to cognitive tests when controlled for important co-variates. Markers of neurodegeneration and synaptic pathology might be associated with subtle signs of cognitive decline in a population-based sample of 70-year-olds.

The Association between Tau Protein Level in Cerebrospinal Fluid and Cognitive Status: A Large-Scale Analysis of GAAIN Database.

Alzheimer’s disease (AD) and the associated neurodegenerative dementia have become of increasing concern in healthcare. The tau protein has been considered a key hallmark of progressive neurodegeneration. In this paper, a large-scale analysis of five datasets (more than 2500 people) from the Global Alzheimer’s Association Interactive Network (GAAIN) databases was performed to investigate the association between the level of tau protein, including total tau and phosphorylated tau (p-tau), in cerebrospinal fluid (CSF) and cognitive status. Statistically significant (or marginally significant) high total tau or p-tau concentrations in CSF were observed in dementia patients compared with healthy people in all datasets. There is also a statistically significant (or marginally significant) negative correlation between p-tau concentrations in CSF and Folstein Mini-Mental State Examination (MMSE) scores. In addition, transcriptomic data derived from mouse microglial cells showed multiple genes upregulated in Toll-like receptor signaling and Alzheimer’s disease pathways, including TNF, TLR2, IL-1β, and COX subunits, suggesting that the mechanism of action that relates p-tau and MMSE scores may be through overactivation of pro-inflammatory microglial activity by Aβ peptides, TNF-mediated hyperphosphorylation of tau, and the infectious spread of pathological tau across healthy neurons. Our results not only confirmed the association between tau protein level and cognitive status in a large population but also provided useful information for the understanding of the role of tau in neurodegeneration and the development of dementia.

Saliva Neurofilament Light Chain Is Not a Diagnostic Biomarker for Neurodegeneration in a Mixed Memory Clinic Population.

Neurodegeneration and axonal injury result in an increasing release of neurofilament light chain (NfL) into bodily fluids, including cerebrospinal fluid (CSF) and blood. Numerous studies have shown that NfL levels in CSF and blood are increased in neurodegenerative disorders and monitor neurodegeneration. Saliva is an easily accessible biofluid that could be utilized as a biofluid measurement of Alzheimer’s disease (AD) biomarkers. In this study, for the first time, salivary NfL was measured and compared to plasma NfL in a consecutive cohort of patients referred to cognitive assessments. In two mixed memory clinic cohorts, saliva samples were taken from 152 patients, AD (n = 49), mild cognitive impairment (MCI) (n = 47), non-AD (n = 56), and also 17 healthy controls. In addition, 135 also had a matching plasma sample. All saliva and plasma samples were analyzed for NfL, and the association between saliva and plasma NfL and CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and beta amyloid 1–42 (Aβ42) were investigated. In total, 162/169 had quantifiable levels of salivary NfL by single molecule array (Simoa). No statistically significant differences were found in salivary NfL concentration across the diagnostic groups, but as expected, significant increases were found for plasma NfL in dementia cases (P < 0.0001). There was no association between saliva and plasma NfL levels. Furthermore, saliva NfL did not correlate with CSF Aβ42, p-tau, or tau concentrations. In conclusion, NfL is detectable in saliva but does not reflect neurodegeneration in the brain.

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.

A prognostic model for overall survival in sporadic Creutzfeldt-Jakob disease.

We developed a prognostic model for overall survival after diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) using data from a German surveillance study. We included 1226 sCJD cases (median age 66 years, range 19-89 years; 56.8% women with information on age, sex, codon 129 genotype, 14-3-3 in the cerebrospinal fluid (CSF), and CSF tau concentrations. The prognostic accuracy for overall survival was measured by the c statistics of multivariable Cox proportional hazard models. A score chart was derived to predict 6-month survival and median survival time. A model containing age, sex, codon 129 genotype, and CSF tau (with two-way interactions) was selected as the model with the highest c statistic (0.686, 95% confidence interval: 0.665-0.707) in a cross-validation approach. We developed the first prognostic model for overall survival of sCJD patients based on readily available information only. The developed score chart serves as a hands-on prediction tool for clinical practice.

Cerebrovascular disease promotes tau pathology in Alzheimer's disease.

Small vessel cerebrovascular disease, visualized as white matter hyperintensities on T2-weighted magnetic resonance imaging, contributes to the clinical presentation of Alzheimer’s disease. However, the extent to which cerebrovascular disease represents an independent pathognomonic feature of Alzheimer's disease or directly promotes Alzheimer’s pathology is unclear. The purpose of this study was to examine the association between white matter hyperintensities and plasma levels of tau and to determine if white matter hyperintensities and tau levels interact to predict Alzheimer’s disease diagnosis. To confirm that cerebrovascular disease promotes tau pathology, we examined tau fluid biomarker concentrations and pathology in a mouse model of ischaemic injury. Three hundred ninety-one participants from the Alzheimer’s Disease Neuroimaging Initiative (74.5 ± 7.1 years of age) were included in this cross-sectional analysis. Participants had measurements of plasma total-tau, cerebrospinal fluid beta-amyloid, and white matter hyperintensities, and were diagnosed clinically as Alzheimer’s disease (n = 97), mild cognitive impairment (n = 186) or cognitively normal control (n = 108). We tested the relationship between plasma tau concentration and white matter hyperintensity volume across diagnostic groups. We also examined the extent to which white matter hyperintensity volume, plasma tau, amyloid positivity status and the interaction between white matter hyperintensities and plasma tau correctly classifies diagnostic category. Increased white matter hyperintensity volume was associated with higher plasma tau concentration, particularly among those diagnosed clinically with Alzheimer’s disease. Presence of brain amyloid and the interaction between plasma tau and white matter hyperintensity volume distinguished Alzheimer’s disease and mild cognitive impairment participants from controls with 77.6% and 63.3% accuracy, respectively. In 63 Alzheimer’s Disease Neuroimaging Initiative participants who came to autopsy (82.33 ± 7.18 age at death), we found that higher degrees of arteriosclerosis were associated with higher Braak staging, indicating a positive relationship between cerebrovascular disease and neurofibrillary pathology. In a transient middle cerebral artery occlusion mouse model, aged mice that received transient middle cerebral artery occlusion, but not sham surgery, had increased plasma and cerebrospinal fluid tau concentrations, induced myelin loss, and hyperphosphorylated tau pathology in the ipsilateral hippocampus and cerebral hemisphere. These findings demonstrate a relationship between cerebrovascular disease, operationalized as white matter hyperintensities, and tau levels, indexed in the plasma, suggesting that hypoperfusive injury promotes tau pathology. This potential causal association is supported by the demonstration that transient cerebral artery occlusion induces white matter damage, increases biofluidic markers of tau, and promotes cerebral tau hyperphosphorylation in older-adult mice.

Cerebrospinal fluid levels of YKL-40 in prodromal Alzheimer’s disease

Recently, cerebrospinal fluid (CSF) YKL-40 levels were reported to be a promising candidate biomarker of glial inflammation in Alzheimer’s disease (AD). To detect how APOE ε4 affects CSF YKL-40 levels in cognitively normal (CN) states, mild cognitive impairment (MCI) and AD dementia, data from 35 CN subjects, 63 patients with MCI, and 11 patients with AD from a cross-sectional study in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were investigated. The results showed that CSF YKL-40 concentrations were increased in the AD dementia group than in the CN group. CSF YKL-40 levels were higher in APOE ε4 carriers than in noncarriers with MCI. No statistically significant difference was found in CSF YKL-40 levels between APOE ε4 carrier and noncarriers in AD and CN subjects. CSF YKL-40 concentrations were tightly related to CSF tau and p-tau concentrations in the MCI group. Analysis implied that APOE ε4 might affect CSF YKL-40 levels in MCI subjects, suggesting a crucial role of APOE ε4 in neuroinflammation in detecting individuals who might convert to AD from MCI and, thus, as an effective predictive factor.

Gray matter T1-w/T2-w ratios are higher in Alzheimer's disease.

Myelin determines the conduction of neuronal signals along axonal connections in networks of the brain. Loss of myelin integrity in neuronal circuits might result in cognitive decline in Alzheimer's disease (AD). Recently, the ratio of T1‐weighted by T2‐weighted MRI has been used as a proxy for myelin content in gray matter of the cortex. With this approach, we investigated whether AD dementia patients show lower cortical myelin content (i.e., a lower T1‐w/T2‐w ratio value). We selected structural T1‐w and T2‐w MR images of 293 AD patients and 172 participants with normal cognition (NC). T1‐w/T2‐w ratios were computed for the whole brain and within 90 automated anatomical labeling atlas regions using SPM12, compared between groups and correlated with the neuronal injury marker tau in cerebrospinal fluid (CSF) and Mini Mental State Examination (MMSE). In contrast to our hypothesis, AD patients showed higher whole brain T1‐w/T2‐w ratios than NC, and regionally in 31 anatomical areas (p < .0005; d = 0.21 to 0.48), predominantly in the inferior parietal lobule, angular gyrus, anterior cingulate, and precuneus. Regional higher T1‐w/T2‐w values were associated with higher CSF tau concentrations (p < .0005; r = .16 to .22) and worse MMSE scores (p < .0005; r = −.16 to −.21). These higher T1‐w/T2‐w values in AD seem to contradict previous pathological findings of demyelination and disconnectivity in AD. Future research should further investigate the biological processes reflected by increases in T1‐w/T2‐w values.

Elevated Cerebrospinal Fluid Tau Protein Concentrations on Admission Are Associated With Long-term Neurologic and Cognitive Impairment in Ugandan Children With Cerebral Malaria.

Elevated concentrations of cerebrospinal fluid (CSF) tau, a marker of axonal injury, have been associated with coma in severe malaria (cerebral malaria [CM]). However, it is unknown whether axonal injury is related to long-term neurologic deficits and cognitive impairment in children with CM. Admission CSF tau concentrations were measured in 145 Ugandan children with CM and compared to clinical and laboratory factors and acute and chronic neurologic and cognitive outcomes. Elevated CSF tau concentrations were associated with younger age, increased disease severity (lower glucose and hemoglobin concentrations, malaria retinopathy, acute kidney injury, and prolonged coma duration, all P < .05), and an increased CSF:plasma albumin ratio, a marker of blood-brain barrier breakdown (P < .001). Admission CSF tau concentrations were associated with the presence of neurologic deficits at hospital discharge, and at 6, 12, and 24 months postdischarge (all P ≤ .02). After adjustment for potential confounding factors, elevated log10-transformed CSF tau concentrations correlated with worse cognitive outcome z scores over 2-year follow-up for associative memory (β coefficient, -0.31 [95% confidence interval [CI], -.53 to -.10]) in children <5 years of age, and for overall cognition (-0.69 [95% CI, -1.19 to -.21]), attention (-0.78 [95% CI, -1.34 to -.23]), and working memory (-1.0 [95% CI, -1.68 to -.31]) in children ≥5 years of age (all P < .006). Acute axonal injury in children with CM is associated with long-term neurologic deficits and cognitive impairment. CSF tau concentrations at the time of the CM episode may identify children at high risk of long-term neurocognitive impairment.

The 12-Word Philadelphia Verbal Learning Test Performances in Older Adults: Brain MRI and Cerebrospinal Fluid Correlates and Regression-Based Normative Data

Background/Aims: This study evaluated neuroimaging and biological correlates, psychometric properties, and regression-based normative data of the 12-word Philadelphia Verbal Learning Test (PVLT), a list-learning test. Methods: Vanderbilt Memory and Aging Project participants free of clinical dementia and stroke (n = 230, aged 73 ± 7 years) completed a neuropsychological protocol and brain MRI. A subset (n = 111) underwent lumbar puncture for analysis of Alzheimer’s disease (AD) and axonal integrity cerebrospinal fluid (CSF) biomarkers. Regression models related PVLT indices to MRI and CSF biomarkers adjusting for age, sex, race/ethnicity, education, APOE-ε4 carrier status, cognitive status, and intracranial volume (MRI models). Secondary analyses were restricted to participants with normal cognition (NC; n = 127), from which regression-based normative data were generated. Results: Lower PVLT performances were associated with smaller medial temporal lobe volumes (p < 0.05) and higher CSF tau concentrations (p < 0.04). Among NC, PVLT indices were associated with white matter hyperintensities on MRI and an axonal injury biomarker (CSF neurofilament light; p < 0.03). Conclusion: The PVLT appears sensitive to markers of neurodegeneration, including temporal regions affected by AD. Conversely, in cognitively normal older adults, PVLT performance seems to relate to white matter disease and axonal injury, perhaps reflecting non-AD pathways to cognitive change. Enhanced normative data enrich the clinical utility of this tool.

Validity and Normative Data for the Biber Figure Learning Test: A Visual Supraspan Memory Measure.

The Biber Figure Learning Test (BFLT), a visuospatial serial figure learning test, was evaluated for biological correlates and psychometric properties, and normative data were generated. Nondemented individuals (n = 332, 73 ± 7, 41% female) from the Vanderbilt Memory & Aging Project completed a comprehensive neuropsychological protocol. Adjusted regression models related BFLT indices to structural brain magnetic resonance imaging and cerebrospinal fluid (CSF) markers of brain health. Regression-based normative data were generated. Lower BFLT performances (Total Learning, Delayed Recall, Recognition) related to smaller medial temporal lobe volumes and higher CSF tau concentrations but not CSF amyloid. BFLT indices were most strongly correlated with other measures of verbal and nonverbal memory and visuospatial skills. The BFLT provides a comprehensive assessment of all aspects of visuospatial learning and memory and is sensitive to biomarkers of unhealthy brain aging. Enhanced normative data enriches the clinical utility of this visual serial figure learning test for use with older adults.

Association Between Later Life Lifestyle Factors and Alzheimer's Disease Biomarkers in Non-Demented Individuals: A Longitudinal Descriptive Cohort Study.

Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer's disease (AD) remains unclear. To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-β 1-42 (Aβ42) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI. We selected individuals with SCD (n = 111) and MCI (n = 353) from the DESCRIPA and Kuopio Longitudinal MCI studies. CSF Aβ42 and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only. Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results. Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI.

Deficit in Central Auditory Processing as a Biomarker of Pre-Clinical Alzheimer's Disease.

Prevention of dementia due to Alzheimer’s disease (d/AD) requires interventions that slow the disease process prior to symptom onset. To develop such interventions, one needs metrics that assess pre-symptomatic disease progression. Familiar measures of progression include cerebrospinal fluid (CSF) biochemical and imaging analyses, as well as cognitive testing. Changes in the latter can sometimes be difficult to distinguish from effects of “normal” aging. A different approach involves testing of “central auditory processing” (CAP), which enables comprehension of auditory stimuli amidst a distracting background (e.g., conversation in a noisy bar or restaurant). Such comprehension is often impaired in d/AD. Similarly, effortful or diminished auditory comprehension is sometimes reported by cognitively healthy elders, raising the possibility that CAP deficit may be a marker of pre-symptomatic AD. In 187 cognitively and physically healthy members of the aging, AD family history-positive PREVENT-AD cohort, we therefore evaluated whether CAP deficits were associated with known markers of AD neurodegeneration. Such markers included CSF tau concentrations and magnetic resonance imaging volumetric and cortical thickness measures in key AD-related regions. Adjusting for age, sex, education, pure-tone hearing, and APOE ɛ4 status, we observed a persistent relationship between CAP scores and CSF tau levels, entorhinal and hippocampal cortex volumes, cortical thickness, and deficits in cognition (Repeatable Battery for Assessment of Neuropsychological Status total score, and several of its index scales). These cross-sectional observations suggest that CAP may serve as a novel metric for pre-symptomatic AD pathogenesis. They are therefore being followed up longitudinally with larger samples.

Relation of Odor Identification with Alzheimer's Disease Markers in Cerebrospinal Fluid and Cognition.

Impaired olfactory function is an early characteristic of Alzheimer's disease (AD), but it remains unclear if odor identification also relates to early markers of AD in cerebrospinal fluid (CSF). To investigate the association between odor identification and amyloid-β 1-42 (Aβ42) and total tau (t-tau) concentrations in CSF. In addition, to examine the relation between odor identification and cognitive function at baseline and at follow-up, and whether these associations are moderated by CSF Aβ42 and t-tau and apolipoprotein E (APOE) genotype. We included 160 individuals (40 with normal cognition, 45 with mild cognitive impairment (MCI), 42 with AD-type dementia, and 26 individuals with non-AD dementia) from the EDAR study. Individuals were recruited from six memory clinics across Europe. Odor identification was tested with the brief University of Pennsylvania Smell Identification Test. CSF Aβ42 and t-tau were assessed with INNO-BIA AlzBio3 Luminex assay. Neuropsychological assessment included tests for verbal memory, verbal fluency, attention, executive function, and visuoconstruction. Follow-up was performed within 3 years after baseline. Lower odor identification scores correlated with increased CSF t-tau concentrations and with lower scores on all cognitive measures at baseline independent of diagnostic group. Lower odor identification scores predicted decline on the MMSE in the total group, and decline on wordlist learning and delayed recall in APOE ɛ4 carriers and in individuals with abnormal Aβ42. Odor identification impairment may be an indicator of neuronal injury rather than amyloid pathology.

Plasma and cerebrospinal fluid tau and neurofilament concentrations in rapidly progressive neurological syndromes: a neuropathology-based cohort.

Cerebrospinal fluid (CSF) tau and neurofilament light chain (NF-L) proteins have proved to be reliable biomarkers for neuronal damage; however, there is a strong need for blood-based tests. The present study included 132 autopsy cases with rapidly progressive neurological syndromes, including Alzheimer disease (AD) (21), sporadic (65) and genetic (21) Creutzfeldt-Jakob disease (CJD), 25 cases with vascular, neoplastic and inflammatory alterations, and additionally 18 healthy control individuals. CSF tau and NF-L concentrations were measured by enzyme-linked immunosorbent assay. Plasma tau and NF-L concentrations were measured using ultra-sensitive single molecule array technology. Plasma and CSF tau (R = 0.59, P < 0.001) and NF-L (R = 0.69, P < 0.001) levels correlated significantly (Spearman test). Plasma tau and NF-L levels were significantly higher in all disease groups compared to healthy controls (P < 0.001). Receiver operating characteristic curves were used and area under the curve values for comparisons with controls were 0.82 (AD), 0.94 (sporadic CJD), 0.92 (genetic CJD) and 0.83 (other neurological disorders) for plasma tau and 0.99, 0.99, 1.00 and 0.96 for plasma NF-L, respectively. Molecular subtyping of sporadic CJD showed a strong effect (linear logistic regression) on plasma tau (P < 0.001) but not NF-L levels (P = 0.19). Plasma tau and NF-L concentrations are strongly increased in CJD and show similar diagnostic performance to the corresponding CSF measure. Molecular subtypes of sporadic CJD show different levels of plasma tau. Although not disease-specific, these findings support the use of plasma tau and NF-L as tools to identify, or to rule out, neurodegeneration.

Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer′s and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies

α-Synuclein (αSyn) is a major constituent of proteinaceous aggregates in neurodegenerative diseases such as Parkinson's disease (PD) and a potential biomarker candidate for diagnosis and treatment effects. However, studies about αSyn in cerebrospinal fluid (CSF) in diseases are inconsistent and mainly based on immunological assays. Quantitative information about β-synuclein (βSyn) and γ-synuclein (γSyn) in CSF is not available.Here, we present an alternative method for the simultaneous quantification of αSyn, βSyn and γSyn in CSF by multiple reaction monitoring (MRM) with a high sequence coverage (70%) of αSyn to validate previous, ELISA-based results and characterize synucleins in CSF in more detail.The MRM has high sensitivity in the low pg/ml range (3-30pg/ml full-length αSyn) using 200 μl CSF. A high portion of CSF αSyn is present in the N-terminally acetylated form and the concentration of unmodified peptides in the nonamyloid component region is about 40% lower than in the N-terminal region. Synuclein concentrations show a high correlation with each other in CSF (r>0.80) and in contrast to αSyn and γSyn, βSyn is not affected by blood contamination. CSF αSyn, βSyn and γSyn concentrations were increased in Alzheimer's and Creutzfeldt-Jakob disease but not altered in PD, PD dementia (PDD), Lewy body dementia and atypical parkinsonian syndromes. The ratio βSyn/αSyn was increased in PDD (1.49 ± 0.38, p < 0.05) compared with PD (1.11 ± 0.26) and controls (1.15 ± 0.28). βSyn shows a high correlation with CSF tau concentrations (r = 0.86, p < 0.0001, n = 125).In conclusion, we could not confirm previous observations of reduced αSyn in PD and our results indicate that CSF synuclein concentrations are rather general markers of synaptic degeneration than specific for synucleinopathies. βsyn is an attractive biomarker candidate that might be used as an alternative to or in combination with tau in AD and CJD diagnosis and in combination with αSyn it is a biomarker candidate for PDD.

Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative condition with no therapeutic intervention known to alter disease progression, but several trials are ongoing and biomarkers of disease progression are needed. Tau is an axonal protein, often altered in neurodegeneration, and recent studies pointed out its role on HD neuropathology. Our goal was to study whether cerebrospinal fluid (CSF) tau is a biomarker of disease progression in HD. After informed consent, healthy controls, pre‐symptomatic and symptomatic gene expansion carriers were recruited from two HD clinics. All participants underwent assessment with the Unified HD Rating Scale ’99 (UHDRS). CSF was obtained according to a standardized lumbar puncture protocol. CSF tau was quantified using enzyme‐linked immunosorbent assay. Comparisons between two groups were tested using ancova. Pearson's correlation coefficients were calculated for disease progression. Significance level was defined as p < 0.05. Seventy‐six participants were included in this cross‐sectional multicenter international pilot study. Age‐adjusted CSF tau was significantly elevated in gene expansion carriers compared with healthy controls (p = 0.002). UHDRS total functional capacity was significantly correlated with CSF tau (r = −0.29, p = 0.004) after adjustment for age, and UHDRS total motor score was significantly correlated with CSF tau after adjustment for age (r = 0.32, p = 0.002). Several UHDRS cognitive tasks were also significantly correlated with CST total tau after age‐adjustment. This study confirms that CSF tau concentrations in HD gene mutation carriers are increased compared with healthy controls and reports for the first time that CSF tau concentration is associated with phenotypic variability in HD. These conclusions strengthen the case for CSF tau as a biomarker in HD. In the era of novel targeted approaches to Huntington's disease, reliable biomarkers are needed. We quantified Tau protein, a marker of neuronal death, in cerebrospinal fluid and found it was increased in patients with Huntington's disease and predicted motor, cognitive, and functional disability in patients. It is therefore likely to be a biomarker of disease progression, and possibly of therapeutic response. Read the Editorial Highlight for this article on page 9.

Modulation of β-amyloid by a single dose of GSK933776 in patients with mild Alzheimer’s disease: a phase I study

IntroductionIn this study, we evaluated the safety and pharmacodynamic effects of the Fc-inactivated anti-β-amyloid (anti-Aβ) monoclonal antibody GSK933776 in patients with mild Alzheimer’s disease and mild cognitive impairment. Aβ and tau levels were investigated in cerebrospinal fluid (CSF), and the relationship between Aβ levels and Aβ modulation in plasma was explored. The feasibility of a continuous sampling method using a lumbar catheter was assessed.MethodsThis trial was a phase I, open-label, uncontrolled, single-dose, exploratory experimental medicine study of intravenous GSK933776 at doses of 1 mg/kg, 3 mg/kg or 6 mg/kg (n = 6/group). The time course of plasma and CSF concentrations of GSK933776 and Aβ was assessed. Sample size was based on feasibility, and no formal statistical analyses were performed.ResultsFollowing administration of GSK933776 at doses of 1 mg/kg, 3 mg/kg and 6 mg/kg, there were decreases from baseline in CSF Aβ1–42 (from 0 to 12 hours) by 22.8 pg/ml (6.2%), 43.5 pg/ml (9.2%) and 60.5 pg/ml (12.5%), respectively. Plasma concentrations of total Aβ18–35 and Aβ4228–42 increased immediately after infusion and CSF tau concentration increased slightly, but did not significantly change, following administration of all doses of GSK933776. Pharmacokinetics confirmed the presence of GSK933776 in the CSF, which exhibited a dose–response relationship. One patient underwent minor surgery without sequelae following a ruptured lumbar catheter.ConclusionGSK933776 demonstrated pharmacological activity and target engagement in CSF and plasma, and the continuous sampling method via a catheter successfully assessed the Aβ changes following single-dose administration of GSK933776.Trial registrationClinicalTrials.gov Identifier: NCT01424436. Registered 4 August 2011