& 3). Despite the uniform patterns of raised CSF tau le- vels in AD as compared to controls, there was wide range of effect size among 41 articles under study (22 to 614 pg/ml) with pooled estimate of 289.146. Sunderland et al.  have also reported the pattern of uniform cha- nge in CSF tau levels in AD with higher CSF tau levels vs controls. Similarly, van Harten et al.  reported that increased CSF concentration of tau can be interpreted as evidence for a diagnosis of AD with specificity excee- ding 85% as compared to Dementia with Lewy Bodies (DLB) and Vascular Dementia (VaD), in their meta-ana- lysis on tau and p-tau as CSF biomarkers in Dementia, confirming that increased concentration of tau serves as potential biomarker for AD. In this meta-analysis 23 out of 25 studies show significant reductions in CSF Aβ 42
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In the present study, more than half of the subjects were healthy individuals; thus, it is not known whether the non-AD subjects with a thin LC or an elevated CSF tau had subclinical AD. Although data were not presented be- cause of the small number of samples, a subgroup analysis performed within the healthy group revealed a marginal but not significant linear association of a lower total MMSE score with thinner LCT ( β = 10.417, P = 0.061). This may indicate that the LCT could also serve as a potential candidate marker representing cognitive func- tion as well as the CSF tau level. A long-term follow-up study is required to verify whether these subjects are more susceptible to developing AD. Additionally, a study that includes subjects with mild cognitive impairment may help to answer this question.
KLK6 appears to exhibit an anti-amyloidogenic poten- tial  and has been linked to AD: in extracts of differ- ent brain regions of patients with AD, KLK6 levels are lower as compared to controls [21, 22], KLK6 mRNA levels are decreased in the hippocampus as well . In blood, current results are conflicting: one study did not detect any significant difference in KLK6 levels in the serum of AD patients as compared to cognitively normal control (NC) , whereas in another study a striking 10-fold increase in the blood was reported . In the cerebrospinal fluid (CSF), KLK6 levels were increased in histopathologically confirmed AD patients ( n = 10) of undisclosed clinical severity compared to controls (n = 10) . In another study, CSF KLK6 levels did not differ neither between subjective cognitive impairment ( n = 43) and AD ( n = 43), nor between clinically diag- nosed normal controls (n = 58) and clinically diagnosed AD ( n = 28) or clinically diagnosed progressive mild cognitive impairment (MCI) ( n = 28) .
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A key component of AD neuropathology is the presence of neurofibrillary tangles, which are typically observed in the medial temporal lobe (MTL) first, and in the hippocampus in particular (11). The degree of neurofibrillary tangle burden has been associated with levels of total (T) and P tau in clinical-postmortem comparison studies (12-14, but see 15), suggesting that in vivo CSF levels of T and P tau may serve as surrogate measures for the degree of hippocampal and cortical neurofibrillary pathology. CSF levels of T and P tau have been found to associate with short term memory performance in AD (16), and to correlate negatively with hippocampal volume both in individuals with AD (17) and MCI (18). Moreover, P tau is considered a key factor in entorhinal cortex degeneration in cognitively intact participants (19).
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Importantly, no study included APOE (Apolipoprotein E) genotyping, which may affect AD independently, or in association with, CSF biomarkers depending on the age of the subject . The ε4 allele of APOE, an apolipo- protein thought to be partially responsible for amyloid clearance in the CNS, is one of the greatest known risk factors for late-onset sporadic AD [8,9]. Large cohort studies have provided conflicting results regarding the role of APOE in HIV+ persons with HAND. A study based on the Hawaii Aging with HIV Cohort  (N = 182) associ- ated APOE ε4 carriage with HAND, but only in older participants. The largest study conducted in an ethnic- ally diverse cohort  (Wilford Hall Medical Center, WHMC; 1,267 HIV-seropositive adults and 1,132 ethnic- ally similar HIV-seronegative controls) found an associ- ation between APOE ε4/ε4 genotype and acceleration of HIV disease, but not with HAD. However the authors only assessed HAD rather than the complete HAND spectrum. Moreover, it is not clear how HAD was defined and assessed. More recently the CNS HIV Antiretroviral Ther- apy Effects Research (CHARTER) study  of 466 HIV+ participants (mean age = 44) who received a comprehen- sive HAND assessment showed no association between APOE ε4 carriage and HAND. They similarly found no association when they restricted their analyses to those with moderate HAND (Mild Neurocognitive Disorder (MND) and HAD). Age did not influence their results, but their sample included only 3.7% of persons aged 60+, compared to 25% in the Hawaii Aging with HIV Cohort . The authors conclude that within the age-group they investigated APOE was not associated with HAND, confirming other smaller studies in same-age or younger samples [13-15], but stated that their results does not “preclude emergence of an association between APOE status and HAND as this population ages”, so further studies are needed.
bar puncture was performed with a 20- or 24-gauge spinal needle at the baseline visit after an overnight fast. The CSF samples were transferred into polypropylene transfer tubes, frozen on dry ice within 1 hour after collection, and shipped on dry ice overnight to a single designated laboratory. After thawing for 1 hour at room temperature and gentle mixing, 0.5-mL aliquots were prepared from these samples. The aliquots were then stored in bar-code– labeled polypropylene vials at ⫺80°C and measured by using the xMAP Luminex platform (Luminex, Austin, Texas) with INNO-BIA AlzBio3 (Innogenetics, Ghent, Belgium) immunoassay kit-based reagents. Monoclonal antibodies specific for A ␤ and p-tau, which have been found to be useful in predicting AD, were used as re- agents. 17 Total CSF tau level was not included in this analysis,
Finally, spindle density and CSF tau levels could be asso- ciated by being common downstream consequences of an upstream process. For example, tau is released in response to axonal injuries (often from traumatic brain injury) at the time of injury and before frank evidence of neurode- generation is present. Because we observed associations of sleep spindles with both CSF T-tau and P-tau, we cannot completely infer whether any association is more strongly tied to axonal injury versus formation of neurofibrillary tangles. In subjects with moderate to severe diffuse axonal injury, sleep spindle amplitude and peak frequency were significantly reduced acutely with subsequent return to baseline levels commensurate with functional improve- ment over 1 year . Tauopathy is also observed in other neurodegenerative disorders including frontotem- poral dementia, progressive supranuclear palsy (PSP), primary age related tauopathy and chronic traumatic encephalopathy. If there is a common upstream process that generally promotes tauopathy, reduced spindle density could be a corresponding consequence. In a study that included analysis of sleep spindles in subjects with PSP, spindle density was markedly reduced , supporting this idea.
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After applying stringent quality control, our dataset con- tained CSF levels of YKL-40 for 379 individuals from the Charles F. and Joanne Knight Alzheimer’s Disease Re- search Center (Knight-ADRC; Table 1). We used logistic regression including age, gender, and sample batch as covariates to test whether levels of YKL-40 were associ- ated with AD status defined by CDR. Cases (defined by CDR at lumbar puncture >0) had significantly higher CSF levels of YKL-40 than controls (cases: 366.37 ± 136.48 ng/mL; controls: 290.18 ± 92.44 ng/mL; p = 0.015, β = 0.698; Additional file 3: Figure S1). We used linear regression to test if APOE genotype influenced YKL-40 and found there was no effect on YKL-40 levels (p = 0.704). Several studies indicate that CSF Tau/Aβ 42 ratio
In the case reported here, complete neurocognitive recov- ery was paralleled by normalisation of CSF-levels of NFL and HIV-1 RNA, indicating that the process of axonal damage might have been halted by the CSF penetrating combination of zidovudine, lamivudine, ritonavir and indinavir. It seemed as if CSF NFL decrease was slow com- pared to the decrease in CSF Tau and GFAP levels. Slow CSF NFL normalisation has been reported in herpes sim- plex type 1 encephalitis, focal brain ischemia, and multi- ple sclerosis[19,39]. Whether this reflects slow metabolic degradation and a long half-life of NFL in CSF or different immunopathological pathways that lag behind the decrease in HIV-1 replication in CNS is not clear. In our patient CSF WBC and neopterin followed the same pat- tern as CSF NFL indicating a correlation with intrathecal immune activation. The decline in albumin ratio and IgG index values was in concordance with previous reports on effects of HAART on BBB integrity and intrathecal anti- body production.
controls. 5–9 Preliminary evidence indicates that CSF tau and PET tau measures correlate, 6,10 but those results stem from populations mainly consisting of controls, including few cases with AD dementia. A key unresolved question is therefore if CSF and PET tau measures have similar or diﬀerent di- agnostic performance for AD. It is also not clear if CSF and PET tau measures are signiﬁcantly better than MRI measures of brain structure to identify AD. To address these questions, we compared CSF t-tau and p-tau, 18 F-AV-1451 PET, hip-
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The present study has some limitations: first and most important, the patient sample is relatively small. Statistical power is limited with respect to analyses of CSF biomarkers in relation to a small sample of patients that homozygous ApoE ε 4 carriers. The unicenter design with patients from one specialized memory clinic may limit the generalization of the results to the whole population of patients with AD. However, this study reflects the real-life practice in a specialized memory clinic. Furthermore, a unicenter study allows the use of harmonized procedures for the measure- ment of CSF biomarkers, avoiding assay-related preanalyti- cal and analytical factors between laboratory variability. The strengths of the study lie in its detailed cognitive assessment protocol and careful diagnostic ascertain- ment. The diagnoses were performed by a trained team of psychiatrists and neuropsychologists highly specialized in
In our case of rapidly progressive dementia, the brain MRI abnormalities, EEG findings, and elevation of CSF 14-3-3 and tau protein were initially compatible with a clinical diagnosis of probable sCJD. Only the clinical course and the positivity for anti-LGI1 antibodies led to the right diagnosis. The presence of faciobrachial tonic seizures that may be associated with VGKC antibody– associated encephalitis led us to the decision to treat with immunosuppressants even though the hypothe- sis of autoimmune encephalitis was not supported by
sion of t-tau in this series is that both ADC/HIVE and opportunistic infections may increase t-tau leakage into the CSF, but not consistently. The relatively modest changes in t-tau levels in ADC, as compared to Alzhe- imer's disease, may relate to the predominating subcorti- cal pathology of ADC/HIVE , since tau is expressed most prominently in non-myelinated cortical axons . The inconsistency of t-tau elevations and the apparent limited sensitivity of t-tau to detect this type of injury likely also explain conflicts among previous reports. CSF p-tau exhibited an even more consistent contrast between HIV CNS diseases and Alzheimer's disease, remaining at normal levels in the former and, as expected, elevated in the latter. The observations of normal levels of p-tau in all the HIV+ subjects are also consistent with the lack of neurofibrillary tangles in ADC/HIVE, one of the neuropathological hallmarks of Alzheimer's disease [16,56]. Thus, while increases in brain tau deposition have been reported in HIV infection, frank neuronal tan- gles are an uncommon and inconsistent finding [57,58]. This difference further supports the broader concept that ADC/HIVE and Alzheimer's disease do not share major mechanisms of neuronal injury.
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The study population consisted of clinically diagnosed AD patients (n = 45), definite frontotemporal lobar de- generation (FTLD) patients (n = 45, of which 33 were FTLD-TDP, 10 FTLD-tau, and 2 FTLD-UPS), both clinical and definite Lewy body dementia (DLB) patients (n = 45, of which 19 definite), definite Creutzfeldt-Jakob disease (CJD) patients (n = 21), and cognitively healthy controls (n = 20). To ensure high diagnostic accuracy in the clinically diagnosed patients, only patients with clin- ical follow-up were included. All CSF samples were se- lected from the Institute Born-Bunge Biobank, Antwerp, Belgium [1, 11]. Patient and control-associated informa- tion included in the statistical analyses consisted of gen- der, age at CSF sampling, and age at death (if applicable). This study was approved by the ethics com- mittee of UAntwerp, Antwerp, Belgium. Informed con- sent was obtained from all subjects.
In the present study, the CSF MMP-9/TIMP-1 ratio was increased in AD patients, and correlated with the neuro- nal degeneration marker tau. More importantly, cogni- tively healthy elderly individuals, with increased risk of developing AD in the future, had elevated CSF MMP-3 and MMP-9 levels and an increased CSF MMP-3/ TIMP-1 ratio, indicating that MMP-3 and MMP-9 might be involved in early pathogenesis of AD. More- over, CSF levels of MMP-3 and MMP-9 correlated with both CSF T-tau and P-tau in elderly controls, suggesting that MMPs could be associated with neuronal degenera- tion and/or the formation of P-tau-containing neuro- fibrillary tangles in individuals who have not yet developed any overt cognitive dysfunction.
Compromised BBB integrity that can be demonstrated in the hippocampus in normal ageing and is exacerbated in MCI, as revealed by advanced dynamic contrast-en- hanced MRI, is associated with elevated CSF sPDGFRβ . Nation et al. reported that elevated CSF sPDGFRβ in mild cognitive impairment was related to BBB integrity but was independent of CSF Aβ42 or tau . Elevated CSF sPDGFRβ likely reflects release of a soluble frag- ment of pericyte PDGFRβ, due to its cleavage by ADAM-10, as was shown in vitro in response to simu- lated ischemia or Aβ peptide [5, 6]. Here we show that elevation of CSF sPDGFRβ in AD is associated with BBB leakiness but also correlates with established CSF markers of AD progression, i.e. elevated CSF t-tau and p-tau, although as in the Nation et al. study we did not detect a direct relationship between CSF sPDGFRβ and Aβ42. Larger cohort studies are needed to assess the value of elevated sPDGFRβ in CSF, and perhaps even serum, as a marker of progressive cognitive dysfunction and the development of AD.
TREM2 rare variants may influence CSF sTREM2 (as described here and in ), all the following analyses are excluding participants carrying these rare variants. Nevertheless, including the TREM2 rare variants carriers did not change the results. In order to test whether the differences in CSF sTREM2 among TREM2 rare variants are influenced by differences in the antibody affinity to the mutant sTREM2, we transfected HEK293T cells with an epitope tagged wild type ( wt ) and mutated TREM2 and measured sTREM2 released in the media with the same ELISA used for the quantification of CSF sTREM2 and with an ELISA using an antibody against the epitope tag (Additional file 1: Figure S1). This revealed that the p.R47H, p.R62H and p.H157Y TREM2 rare variants were detected with a slightly reduced efficiency in our ELISA; therefore, the increased levels of CSF sTREM2 found in subjects bearing the p.R47H rare variants are even slightly underestimated. On the other hand, the p.L211P TREM2 rare variants were detected efficiently, independently of their individual amino acid exchanges. However, the p.D87N TREM2 rare variant was detected with significant less affinity in our ELISA than using the
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lysate) was applied to cells transfected with tau-PL-V5 plasmid (Tau-PL-V5). In contrast, insoluble tau was in- duced only in tau-PL-V5 transfected cells treated with brain lysate from rTg4510 transgenic mice (Fig. 1b, Tg lys- ate +; Tau-PL-V5 +). Insoluble tau was V5 positive, dem- onstrating that it is converted from cellular soluble tau, not from residual brain lysate. Taking into consideration that the intensity of insoluble PHF1 bands is about half of the soluble PHF1 (Fig. 1b) and that approximately 5-fold more insoluble proteins than soluble proteins were loaded, we estimated that the conversion rate is roughly 1/10 (in- soluble/soluble), consistent with low conversion efficiency reported in previous studies . It is known that patho- logical tau accumulates with aging in the brain of rTg4510 mice. To further confirm that insoluble tau is induced by seeding, we used brain lysate from different ages of the mice as seeds (Fig. 1c). As expected, the amount of insol- uble tau (both PHF1 and V5 positive) was increased in cells treated with older Tg brain lysate compared to cells treated with younger lysate, suggesting that the seeding activity of Tg brain lysate increases in an age dependent manner. Besides the brain lysate, synthetic tau fibrils have also been used as seeds to induce tau pathology [13, 14]. We thus used PFFs prepared from recombinant synthetic K18-PL that contains the microtubule-binding domain of tau with the same P301L mutation as seeds. As shown in Fig. 1d, K18-PL PFF also induced insoluble tau in tau-PL- V5 transfected cells similar to the brain lysate. In our study, neither the rTg4510 brain lysates nor K18-PL PFF was able to convert the wild type tau to insoluble form (data not shown). Further, application of the same amount of insoluble seeds as that of rTg4510 from another tau transgenic mice, PS19, which expresses the P301S instead of P301L mutation, failed to convert the tau-PL-V5 to in- soluble form at any appreciable levels (Fig. 1e, compare rTg4510 vs. PS19, Insoluble vs. Soluble), suggesting that either the conversion requires the same host-agent se- quence or that the conversion efficiency induced by differ- ent mutations is too low to be detected in our assay.
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CJD became the primary suspected diagnosis, we decided to repeat the brain MRI and perform CSF 14-3-3 and total tau (t-tau) analyses. Speciﬁcally, we searched for ﬂuid- attenuated inversion recovery (FLAIR) or diﬀusion- weighted imaging (DWI) hyperintensities in the striatum or at least 2 cerebral cortical regions, or a positive protein 14- 3-3 assay or increased t-tau levels above 1,250 pg/mL, all supporting the clinical diagnosis of probable CJD with good sensitivity and speciﬁcity. 8,9
AD and iNPH have different pathomechanism, but recent studies pointed out common pathomechanism between the two diseases [5,6]. However there is still controversy about the clinical implications of the coexist- ence of AD pathology in iNPH patients. Some suggested that AD was only a bystander and the rate of coexistence of AD was similar to that of normal population [7-9] while the others reported the poor shunt response was possibly due to AD pathology [4,10]. Since the introduction of ELISA method to detect cerebrospinal fluid (CSF) bio- markers for AD, there have been many studies about the differential role of levels of the β -amyloid 1 – 42 (A β 42), T-tau protein (T-tau) and tau phosphorylated at position threonine 181 (P-tau) in CSF of iNPH patients [11-15]. However, there are still debates about the level of each