Cerebrospinal Fluid Total Tau Levels Research Articles

Test-retest reliability and short-term variability of quantitative light reflex pupillometry in a mixed memory clinic cohort

BackgroundQuantitative light reflex pupillometry (qLRP) may be a promising digital biomarker in neurodegenerative diseases such as Alzheimer's disease (AD), as neuropathological changes have been found in the midbrain structures governing the light reflex. Studies investigating test-retest reliability and short-term, intra-subject variability of qLRP in these patient groups are missing. Our objective was therefore to investigate the test-retest reliability and short-term, intra-subject variability of qLRP in a memory clinic setting, where patients with neurodegenerative disease are frequently evaluated. MethodsTest-retest reliability study. We recruited patients from a tertiary memory clinic and qLRP was carried out at a baseline visit and then repeated on day 3–14 and on day 21–35 using a hand-held pupillometer. We evaluated the test-retest reliability of qLRP by calculating intraclass correlation coefficients (ICCs) and intra-subject, short-term variability by fitting linear mixed models. We compared ICCs for subgroups based on age, sex, disease severity (MCI vs. mild dementia), AD diagnosis, and amount of neurodegeneration (cerebrospinal fluid-total tau levels). ResultsIn total, 40 patients (mean age 72 years, 15 female, 22 with mild dementia) were included in the study. We found good-excellent reliability (ICC range 0.86–0.93) for most qLRP parameters. qLRP parameters exhibited limited intra-subject variability and we found no large sources of variability when examining subgroups. ConclusionqLRP was found to have acceptable test-retest reliability and the study results pave the way for research using longitudinal or cross-sectional measurements to assess the construct in identifying and prognosticating neurodegenerative diseases.

High diagnostic performance of plasma and cerebrospinal fluid beta‐synuclein in the differential diagnosis of sporadic Creutzfeldt‐Jakob disease

AbstractBackgroundBeta‐synuclein (beta‐syn) is an emerging biofluid marker for synaptic damage in several neurological diseases. In particular, patients with prion disease showed significantly higher cerebrospinal fluid (CSF) and blood beta‐syn levels compared to controls and subjects with other neurodegenerative disorders. However, to date, no study explored the biomarker distribution and prognostic value across the heterogeneous spectrum of sporadic Creutzfeldt‐Jakob disease (sCJD) as well as its diagnostic performance in the real‐life setting of patients with rapidly progressive dementia (RPD).MethodUsing in house established immunoassays we measured CSF and/or plasma beta‐syn concentrations in 150 patients with sCJD, belonging to the most prevalent molecular subtypes [MM(V)1, VV2 and MV2K], and in 106 subjects with non‐prion RPD. In the same cohort, we assessed CSF levels of total tau (t‐tau) and protein 14‐3‐3. We compared the diagnostic performance of CSF/plasma beta‐syn with that of classic CSF markers and we tested the possible associations of CSF/plasma beta‐syn with survival in patients with sCJD.ResultsCJD patients showed higher CSF and plasma beta‐syn levels compared to non‐prion RPD subjects (p<0.001 for both) (Figure 1A, B). Different CSF and blood profiles of beta‐syn were observed for the most prevalent sCJD molecular subtypes (Figure 1C, D). Concerning the diagnostic value, CSF beta‐syn outperformed 14‐3‐3 (AUC 0.95 vs. 0.89, p = 0.028) but not t‐tau (AUC 0.92, p = 0.212). Further, the discriminative accuracy of plasma beta‐syn (AUC 0.91) was not inferior to that of classic CSF markers (t‐tau, p = 0.765 and 14‐3‐3, p = 0.447) and CSF beta‐syn (p = 0.135). In the whole sCJD cohort, CSF and plasma beta‐syn were significantly associated with survival at univariate analyses but not after accounting for codon 129 genotype or molecular subtype.ConclusionCSF beta‐syn performed similar or better compared to t‐tau and 14‐3‐3, respectively, thus, the marker might represent an alternative first‐level test in patients with suspected sCJD. Most interestingly, the high diagnostic value of beta‐syn in plasma, which was comparable to that of classic CSF surrogate markers, suggests that beta‐syn might be used as highly accurate blood surrogate marker in sCJD for patient screening and monitoring.

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.

RT-QuIC Testing for Prions: Applying a Sensitive but Imperfect Test in Clinical Practice (P5-12.010)

<h3>Objective:</h3> Identify the clinical, laboratory, and pathologic features associated with false negative real-time quaking-induced conversion (RT-QuIC) testing for prions. <h3>Background:</h3> Heterogeneity in clinical presentation, abundant mimics, and potential for iatrogenic transmission emphasize the need for accurate diagnostic tests for Creutzfeldt-Jakob disease (CJD). While RT-QuIC is an excellent test, false negative results are recognized in clinical practice. <h3>Design/Methods:</h3> One-hundred twelve patients with probable or definite prion disease were assessed at two tertiary care centers from 2013–2021. RT-QuIC testing for prions was performed in cerebrospinal fluid (CSF) in all patients via the National Prion Disease Pathology Surveillance Center (Cleveland, OH). Demographic data, clinical features, and results of common tests and laboratory studies were abstracted from electronic medical records, and differences between RT-QuIC positive and negative patients considered using univariate statistics. <h3>Results:</h3> Initial RT-QuIC testing was negative in 12/112 patients (sensitivity 89%). Median age at presentation was younger in RT-QuIC negative patients (56.9 vs 66 years, p&lt;0.01), who were also less likely to present with ataxia (3/12 vs 61/100, p=0.03). CSF cell count, protein, and glucose levels were similar between cohorts, while rates of 14-3-3 positivity (2/12 vs 77/100, p&lt;0.01) and median CSF total tau levels were lower in RT-QuIC negative patients (2318 vs 4001 pg/mL, p&lt;0.01). RT-QuIC negative patients also had a longer median days from symptom onset to first presentation (125 vs 47, p=0.04), and longer symptomatic disease duration (530 vs 148, p&lt;0.01). Two RT-QuIC-negative patients underwent repeat testing, of which both were positive. <h3>Conclusions:</h3> RT-QuIC is a sensitive yet imperfect measure necessitating incorporation of other test results when prion disease is suspected. Patients with negative RT-QuIC had lower CSF biomarkers of neuronal damage (total-tau and 14-3-3) and longer symptomatic duration of prion disease raising the possibility that false negative RT-QuIC testing may associate with a more indolent disease course. <b>Disclosure:</b> Dr. Jones has nothing to disclose. Dr. Lazar has nothing to disclose. Dr. Porter has nothing to disclose. Dr. Prusinski has nothing to disclose. Dr. Brier has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. The institution of Dr. Brier has received research support from NIH. Dr. Bucelli has received personal compensation for serving as an employee of Biogen. Dr. Bucelli has received personal compensation for serving as an employee of Biogen. Dr. Bucelli has received personal compensation for serving as an employee of Neuroquestions. Dr. Bucelli has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen . Dr. Bucelli has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Bucelli has stock in Neuroquestions.com. An immediate family member of Dr. Bucelli has stock in Neuroquestions.com. The institution of Dr. Bucelli has received research support from Biogen. The institution of Dr. Bucelli has received research support from Ionis. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Parabon Nanolabs. The institution of Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eli Lilly. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for DynaMed (EBSCO Health). Dr. Day has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Barrow Law. Dr. Day has stock in ANI Pharmaceuticals. The institution of Dr. Day has received research support from National Institutes of Health / NIA. The institution of Dr. Day has received research support from Chan Zuckerberg Initiative. The institution of Dr. Day has received research support from Alzheimer’s Association. The institution of Dr. Day has received research support from National Institutes of Health / NINDS. The institution of Dr. Day has received research support from Horizon Therapeutics. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as a Presenter at Annual Meeting (CME) with American Academy of Neurology. Dr. Day has received personal compensation in the range of $500-$4,999 for serving as a Content Development (CME) with PeerView, Inc. Dr. Day has received personal compensation in the range of $5,000-$9,999 for serving as a Content Development (CME) with Continuing Education, Inc. Dr. Day has a non-compensated relationship as a Clinical Director with AntiNMDA Receptor Encephalitis Foundation that is relevant to AAN interests or activities.

Real-Time Quaking-Induced Conversion Assays for Prions: Applying a Sensitive but Imperfect Test in Clinical Practice.

Real-time quaking-induced conversion (RT-QuIC) assays offer a sensitive and specific means for detection of prions, although false negative results are recognized in clinical practice. We profile the clinical, laboratory, and pathologic features associated with false negative RT-QuIC assays and extend these to frame the diagnostic approach to patients with suspected prion disease. 113 patients with probable or definite prion disease were assessed at Mayo Clinic (Rochester, MN; Jacksonville, FL; Scottsdale, AZ) or Washington University School of Medicine (St. Louis, MO) from 2013-2021. RT-QuIC testing for prions was performed in CSF at the National Prion Disease Pathology Surveillance Center (Cleveland, OH). Initial RT-QuIC testing was negative in 13/113 patients (sensitivity 88.5%). RT-QuIC negative patients were younger (median 52.0 years vs 66.1 years, p<0.001). Other demographic and presenting features, and CSF cell count, protein, and glucose levels were similar in RT-QuIC negative and positive patients. Frequency of 14-3-3 positivity (4/13 vs 77/94, p<0.001) and median CSF total tau levels were lower in RT-QuIC negative patients (2517 vs 4001 pg/mL, p=0.020), while time from symptom onset to first presentation (153 vs 47 days, p=0.001) and symptomatic duration (710 vs 148 days, p=0.001) were longer. RT-QuIC is a sensitive yet imperfect measure necessitating incorporation of other test results when evaluating patients with suspected prion disease. Patients with negative RT-QuIC had lower markers of neuronal damage (CSF total-tau and protein 14-3-3) and longer symptomatic duration of disease suggesting that false negative RT-QuIC testing associates with a more indolent course.

Creutzfeldt-Jakob Disease in a Patient with Previous COVID-19 Infection: "The Virus Caused the Derangement in My Brain".

Recent studies have speculated a link between Creutzfeldt-Jakob disease (CJD) and COVID-19, following the description of CJD cases after COVID-19 infection. We report the case of a 71-year-old female patient who developed neuropsychiatric and neurological symptoms after COVID-19 infection and was later diagnosed with CJD. Cerebrospinal fluid (CSF) total tau levels were slightly increased. She resulted prion protein gene (PRNP) M129V heterozygous. We aim to emphasize the role of the polymorphism at codon 129 of PRNP gene on the clinical phenotype and duration of CJD, and the CSF total tau levels that likely correlate with the rate of disease progression.

What are the most important prognosticators of Alzheimer's disease progression? – Answers from machine learning

AbstractBackgroundNumerous variables that influence the risk of decline in Alzheimer’s disease (AD) have been identified. Previous studies have only examined a relatively small number of these variables. To our knowledge, no study has compared all variables in a large dataset to determine which are the most important.We hypothesised that the most important variables are neuropsychological assessment (NPA) scores and neuroimaging findings; moreover, the prognostic value of all variables will vary with disease stage: normal control (NC), mild cognitive impairment (MCI) or dementia. Secondly, we hypothesised that non‐NPA variables, such as imaging, cerebrospinal fluid (CSF) and genetics, will add prognostic value to that provided by NPA variables alone.MethodWe analysed all relevant variables in the Alzheimer’s Disease Neuroimaging Initiative database – the largest open‐access dataset of subjects with or at risk of AD. With machine learning, we identified those variables which are the strongest predictors of the annual rate of change in up to the first 10 years of Alzheimer’s Disease Assessment Scale – Cognitive Subscale, 13‐item version (ADAS‐Cog13) and Clinical Dementia Rating, Sum of Boxes (CDR‐SB) scores. We repeated this analysis for each disease stage subgroup. Secondly, we compared models that only used NPA‐related variables (NPA‐only) with those that used up to 2 non‐NPA modalities (NPA‐plus) and contrasted the findings between the same subgroups.ResultAcross all subjects, the strongest predictors of the rate of change of both ADAS‐Cog13 and CDR‐SB scores are CSF total tau and amyloid levels, fluorodeoxyglucose (FDG) positron emission tomography (PET) findings, and certain NPA measures. At the NC and MCI stages, CSF and imaging variables are strong predictors, but only NPA variables remained useful at the dementia stage. Secondly, NPA‐plus models consistently outperformed NPA‐only models. The non‐NPA modalities which added the most predictive power varied based on a subject’s disease stage in a manner similar to the previous findings.ConclusionWe identified a multi‐modal set of variables that have the strongest impact on predicting decline during different stages of AD. Our findings are clinically relevant as they recommend the investigations that are of most prognostic yield for clinicians to undertake at each stage of AD progression.

Mining CSF_tau associated genes with deep learning in AD patients

AbstractBackgroundTau protein abnormalities have been attracting more and more attention in Alzheimer’s disease (AD) pathophysiology. Tau spreads in a hierarchical pattern in the AD brain, likely by trans‐synaptic propagation between neurons. Discovering genetic risk factors associated with tau pathology could be key for improving our ability to predict and treat AD. In this study, we leveraged the non‐linear analytic approach of deep learning to identify genes that are associated with cerebrospinal fluid (CSF) total tau levels.MethodWe selected 384 subjects [118 normal control and 266 mild cognitive impairment (MCI)] from ADNI cohort. We designed a deep neuron network model that predicted CSF total tau levels using peripheral blood transcriptomic data. More specifically, we developed an occlusion map approach to rank 2,364 transcripts, which were initially selected from 49,386 transcripts by dimension reduction. The occlusion map aimed to rank the transcripts and identified the critical ones.ResultOur deep neural network successfully predicted CSF total tau levels with an accuracy of 67% and the occlusion map identified the critical genes for the prediction. The list included genes like TTL5, AKIRIN2, CPEB1, PTPN7, CIRBP and RPS23, which have been previously reported to be related to AD. For example, TTL5 relates to missorting of tau protein. AKIRIN2 is essential for the formation of the cerebral cortex. CPEB is found to be an interacting factor of amyloid‐precursor protein (APP). PTPN7 belongs to protein tyrosine phosphatases family, among which PTPN1&amp; PTPN5 has been reported to tau pathology and amyloid pathology. CIRBP is reported to exert protective effects against neuronal amyloid toxicity. RPS23 regulates amyloid level and tau phosphorylation.ConclusionUncovering the genes that have critical association with tau protein abnormalities is critically important for improving our understanding of the drivers of neurodegeneration in prodromal AD. Our deep learning algorithm has shown promising results in identifying the critical genes for tau pathology. This study has demonstrated the effectiveness of deep learning in genetic analysis for AD research.1. Bahureksa, L., et al. (2017)2. Wilcockson, T.D.W., et al. (2019)3. Tomoeda, C. K. (2001)4. Feldman, H. H., et al. (2008)5. Winblad, B., et al. (2016)6. Thomann, A. E., et al. (2018)

The associations of cerebrospinal fluid biomarkers with cognition, and rapid eye movement sleep behavior disorder in early Parkinson's disease.

In Parkinson's disease (PD), levels of cerebrospinal fluid (CSF) biomarkers and progression of non-motor symptoms are associated, but the specifics are not yet clear. The aim of this study was to investigate the associations of non-motor symptoms with CSF biomarkers in PD. We assessed 487 individuals from the Parkinson's Progression Markers Initiative (PPMI), consisting of 155 healthy controls (HCs) and 332 individuals with PD. Patients with PD were grouped according to non-motor symptoms and compared CSF α-synuclein (α-syn), amyloid-beta 1-42 (Aβ1-42), and total tau (t-tau) levels. Multiple linear regressions were used in baseline analysis and linear mixed-effects models in longitudinal analysis. Analyses of mediating effects between cognition and CSF biomarkers were also performed. At baseline, PD patients with cognitive impairment (PDCI) exhibited significantly lower CSF α-syn (β = -0.1244; P = 0.0469), Aβ (β = -0.1302; P = 0.0447), and t-tau (β = -0.1260; P = 0.0131) levels than PD patients without cognitive impairment (PDCU). Moreover, a faster decline of α-syn (β = -0.2152; P = 0.0374) and Aβ (β = -0.3114; P = 0.0023) and a faster rise of t-tau (β = -0.1534; P = 0.0274) have been found in longitudinal analysis. The Aβ positive group showed an earlier decline in cognitive performance (β = -0.5341; P = 0.0180) compared with the negative Aβ group in both analyses. In addition, we found that PD patients with probable rapid eye movement sleep behavior disorder (pRBD) showed decreased CSF α-syn (β = -0.1343; P = 0.0033) levels. Finally, mediation analysis demonstrated that olfactory function partially mediated the relationship between cognition and CSF biomarkers levels. Our study shows that CSF biomarkers are associated with cognition at baseline and longitudinally. Cognitive impairment is more severe in patients with a heavier Aβ burden. CSF α-syn decreased in PD patients with pRBD. This study suggests that early recognition of the increased risk of non-motor symptoms is important for disease surveillance and may be associated with the pathological progression of CSF markers.

Association of Klotho Protein Levels and KL-VS Heterozygosity With Alzheimer Disease and Amyloid and Tau Burden

Identification of proteins and genetic factors that reduce Alzheimer disease (AD) pathology is of importance when searching for novel AD treatments. Heterozygosity of the KL-VS haplotype has been associated with reduced amyloid and tau burden. Whether this association is mediated by the Klotho protein remains unclear. To assess concentrations of Klotho in cerebrospinal fluid (CSF) and plasma among cognitively healthy controls and patients with AD and to correlate these findings with KL-VS heterozygosity status and amyloid and tau burden. This case-control study combined 2 independent case-control AD cohorts consisting of 243 referred patients with AD and volunteer controls recruited from January 1, 2009, to December 31, 2018. Klotho levels were measured in CSF and plasma and correlated with KL-VS heterozygosity status and levels of CSF amyloid-β 42 (Aβ42), total tau, and phosphorylated tau. Statistical analysis was performed from January 1, 2021, to March 1, 2022. Associations of Klotho levels in CSF and plasma with levels of CSF biomarkers were analyzed using linear regression. Association analyses were stratified separately by clinical groups, APOE4 status, and KL-VS heterozygosity. Pearson correlation was used to assess the correlation between CSF and plasma Klotho levels. A total of 243 participants were included: 117 controls (45 men [38.5%]; median age, 65 years [range, 41-84 years]), 102 patients with mild cognitive impairment due to AD (AD-MCI; 59 men [57.8%]; median age, 66 years [range, 46-80 years]), and 24 patients with dementia due to AD (AD-dementia; 12 men [50.0%]; median age, 64.5 years [range, 54-75 years]). Median CSF Klotho levels were higher in controls (1236.4 pg/mL [range, 20.4-1726.3 pg/mL]; β = 0.103; 95% CI, 0.023-0.183; P = .01) and patients with AD-MCI (1188.1 pg/mL [range, 756.3-1810.3 pg/mL]; β = 0.095; 95% CI, 0.018-0.172; P = .02) compared with patients with AD-dementia (1073.3 pg/mL [range, 698.2-1661.4 pg/mL]). Higher levels of CSF Klotho were associated with lower CSF Aβ42 burden (β = 0.519; 95% CI, 0.201-0.836; P < .001) and tau burden (CSF total tau levels: β = -0.884; 95% CI, 0.223 to -0.395; P < .001; CSF phosphorylated tau levels: β = -0.672; 95% CI, -1.022 to -0.321; P < .001) independent of clinical, KL-VS heterozygosity, or APOE4 status. There was a weak correlation between Klotho CSF and plasma levels among the entire cohort (Pearson correlation r = 0.377; P < .001). The findings of this case-control study suggest that Klotho protein levels were associated with clinical stages of AD, cognitive decline, and amyloid and tau burden and that these outcomes were more clearly mediated by the protein directly rather than the KL-VS heterozygosity variant. When selecting individuals at risk for clinical trials, the Klotho protein level and not only the genetic profile should be considered.

Analysis of Clinical Features, Diagnostic Tests, and Biomarkers in Patients With Suspected Creutzfeldt-Jakob Disease, 2014-2021

Detection of prion proteins in cerebrospinal fluid (CSF) using real-time quaking-induced conversion (RT-QuIC) assays has transformed the diagnostic approach to sporadic Creutzfeldt-Jakob disease (CJD), facilitating earlier and more complete recognition of affected patients. It is unclear how expanded recognition of affected patients may affect the diagnostic and prognostic relevance of clinical features and diagnostic tests historically associated with CJD. To evaluate clinical features and diagnostic testing in patients presenting with CJD and determine the associations of these features with prognosis. This cohort study incorporated data from electronic medical records of patients with CJD treated at Mayo Clinic Enterprise tertiary care centers in Rochester, Minnesota; Jacksonville, Florida; and Scottsdale, Arizona. Participants included patients with definite or probable CJD assessed from 2014 to 2021. Data were analyzed October 2021 to January 2022. Dominant presentation, clinical features, and diagnostic tests associated with CJD. The outcomes of interest were the sensitivity and prognostic value of clinical features and accessible diagnostic tests at presentation with possible CJD. A total of 115 patients were identified, including 40 patients (35%) with definite CJD. Mean (SD) age at symptom onset was 64.8 (9.4) years, and 68 patients were women (59%). The sensitivity of clinical markers (myoclonus) and tests historically considered in patients with suspected CJD was poor (eg, stereotyped electroencephalography anomalies: 17 of 105 patients [16%]; elevated CSF protein 14-3-3 levels: 54 of 90 patients [60%]). By comparison, biomarkers with good diagnostic sensitivity at presentation included RT-QuIC (66 of 71 patients [93%]), CSF total tau (T-tau) level greater than 1149 pg/mL (81 of 92 patients [88%]), and characteristic signal anomalies on magnetic resonance imaging (88 of 115 patients [77%]). Multivariable linear regression confirmed shorter survival in patients with myoclonus (difference, -125.9 [95% CI, -236.3 to -15.5] days; P = .03), visual or cerebellar signs (difference, -180.2 [95% CI, -282.2 to -78.2] days; P < .001), elevated CSF protein 14-3-3 levels (difference, -193 [95% CI, -304.9 to -82.9] days; P < .001), and elevated T-tau level (difference for every 1000 pg/mL elevation, -9.1 [95% CI, -17.7 to -1.0] days; P = .04). These findings suggest that CSF RT-QuIC, elevated CSF T-tau level, and stereotyped magnetic resonance imaging anomalies were associated with the diagnosis of CJD, while other clinical findings (eg, myoclonus), stereotyped electroencephalography anomalies, and CSF protein 14-3-3 levels offered less diagnostic value. Visual or cerebellar features, myoclonus, and CSF 14-3-3 and T-tau levels may be associated with disease duration, justifying continued inclusion in the evaluation of patients suspected to have CJD.

Associations of plasma angiostatin and amyloid-β and tau levels in Alzheimer’s disease

Angiostatin, an endogenous angiogenesis inhibitor generated by the proteolytic cleavage of plasminogen, was recently reported to contribute to the development of Alzheimer’s disease (AD). However, whether there are pathological changes in angiostatin levels in individuals with AD dementia is unclear, and whether plasma angiostatin has a relationship with major AD pathological processes and cognitive impairment remains unknown. To examine plasma angiostatin levels in patients with AD dementia and investigate the associations of angiostatin with blood and cerebrospinal fluid (CSF) AD biomarkers, we conducted a cross-sectional study including 35 cognitively normal control (CN) subjects and 59 PiB-PET-positive AD dementia patients. We found that plasma angiostatin levels were decreased in AD dementia patients compared to CN subjects. Plasma angiostatin levels were negatively correlated with plasma Aβ42 and Aβ40 levels in AD dementia patients and positively correlated with CSF total tau (t-tau) levels and t-tau/Aβ42 in AD dementia patients with APOE-ε4. In addition, plasma angiostatin levels had the potential to distinguish AD from CN. These findings suggest a link between angiostatin and AD pathogenesis and imply that angiostatin might be a potential diagnostic biomarker for AD.

Serum neurofilament light as biomarker of seizure-related neuronal injury in status epilepticus.

Biomarkers of neuronal damage in status epilepticus (SE) would be of great relevance for clinical and research purposes. In a retrospective cross‐sectional study, serum neurofilament light chain (NfL) levels were measured in patients with SE (30 subjects), patients with drug‐resistant epilepsy (30 subjects), and healthy controls (30 subjects). Serum NfL levels were higher in patients with SE (median = 26.15 pg/ml) compared to both epilepsy patients (median = 7.35 pg/ml) and healthy controls (median = 6.81 pg/ml; p < .001). In patients with SE, serum NfL levels showed a high correlation with cerebrospinal fluid (CSF) NfL (τ = .68, p < .001) as well as with CSF total tau (t‐tau) levels (τ = .627, p < .001); they were higher in SE lasting >24 h (p = .013), in refractory/superrefractory SE (p = .004), and in patients who died within 30 days or who presented a worsening of clinical conditions (p = .001). Values of >28.8 pg/ml predicted 30‐day clinical worsening or death (odds ratio [OR] = 10.83, 95% confidence interval [CI] = 1.96–59.83, p = .006) and SE refractoriness (OR = 9.33, 95% CI = 1.51–57.65, p = .016). In conclusion, serum NfL levels are increased in SE and correlate with SE treatment response, duration, and outcomes, therefore representing a promising biomarker of seizure‐related neuronal damage.

Distinct conformers of amyloid beta accumulate in the neocortex of patients with rapidly progressive Alzheimer's disease

Amyloid beta (Aβ) deposition in the neocortex is a major hallmark of Alzheimer's disease (AD), but the extent of deposition does not readily explain phenotypic diversity and rate of disease progression. The prion strain–like model of disease heterogeneity suggests the existence of different conformers of Aβ. We explored this paradigm using conformation-dependent immunoassay (CDI) for Aβ and conformation-sensitive luminescent conjugated oligothiophenes (LCOs) in AD cases with variable progression rates. Mapping the Aβ conformations in the frontal, occipital, and temporal regions in 20 AD patients with CDI revealed extensive interindividual and anatomical diversity in the structural organization of Aβ with the most significant differences in the temporal cortex of rapidly progressive AD. The fluorescence emission spectra collected in situ from Aβ plaques in the same regions demonstrated considerable diversity of spectral characteristics of two LCOs—quatroformylthiophene acetic acid and heptaformylthiophene acetic acid. Heptaformylthiophene acetic acid detected a wider range of Aβ deposits, and both LCOs revealed distinct spectral attributes of diffuse and cored plaques in the temporal cortex of rapidly and slowly progressive AD and less frequent and discernible differences in the frontal and occipital cortex. These and CDI findings indicate a major conformational diversity of Aβ accumulating in the neocortex, with the most notable differences in temporal cortex of cases with shorter disease duration, and implicate distinct Aβ conformers (strains) in the rapid progression of AD.

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.

High performance liquid chromatography determination of L-glutamate, L-glutamine and glycine content in brain, cerebrospinal fluid and blood serum of patients affected by Alzheimer's disease.

Altered glutamatergic neurotransmission is thought to play a crucial role in the progression of Alzheimer's disease (AD). Accordingly, the identification of peculiar biochemical patterns reflecting AD-related synaptopathy in blood and cerebrospinal fluid (CSF) could have relevant diagnostic and prognostic implications. In this study, we measured by High-Performance Liquid Chromatography the amount of glutamate, glutamine and glycine in post-mortem brain samples of AD patients, as well as in CSF and blood serum of drug-free subjects encompassing the whole AD clinical spectrum (pre-clinical AD, n = 18, mild cognitive impairment-AD, n = 29, dementia AD, n = 30). Interestingly, we found that glutamate and glycine levels, as well as total tau protein content, were significantly reduced in the superior frontal gyrus of patients with AD, compared with non-demented controls. No significant change was also found in glutamate, glutamine and glycine CSF concentrations between AD patients and neurological controls. Remarkably, serum glutamate levels were significantly higher in patients affected by early AD phases compared to controls, and were negatively correlated with CSF total tau levels. Conversely, serum glutamine concentration was significantly increased in AD patients, with a negative correlation with MMSE performances. Finally, we reported a significant correlation between serumL-glutamate concentrations and CDR score in female but not in male cohort of AD subjects. Overall, our results suggest that serum glutamate and glutamine levels in AD patients could vary across disease stages, potentially reflecting the progressive alteration of glutamatergic signaling during neurodegenerative processes.

Calmodulin level is significantly increased in the cerebrospinal fluid of patients with sporadic Creutzfeldt-Jakob disease.

Human prion diseases (PrDs) are a group of fatal and transmissible neurodegenerative disorders that are diagnosed definitively in post mortem brains. Calmodulin (CaM) is a ubiquitous calcium-binding protein. Increased brain CaM level has been reported in prion-infected rodent models and some scrapie-infected cells. However, the putative alteration of CaM in cerebrospinal fluid (CSF) of human PrDs is uncertain. Here, we try to figure out the profiles of CSF CaM in sporadic Creutzfeldt-Jacob disease. Cerebrospinal fluid samples of 40 Chinese patients with probable sporadic Creutzfeldt-Jacob disease (sCJD) and 40 cases without sCJD (non-PrDs) were recruited in this study. The presence of CaM in the CSF was assessed by Western blot, while total tau levels were measured using an enzyme-linked immunosorbent assay kit. In addition, the presence of CaM in another CSF panel consisting of 30 definite sCJD cases and 30 non-PrD cases was evaluated using CaM-specific Western blot analysis. Cerebrospinal fluid CaM positivity was observed in 28/40 cases of probable sCJD and in 9/40 non-PrD cases. The CSF tau levels in the probable sCJD cases were markedly higher than those in the non-PrD cases. Logistic regression established a significant correlation between CSF CaM signal and total CSF tau level. Similar results were observed in the panel of cases with definite sCJD: the rates of CSF CaM positivity in the definite sCJD cases and the non-PrD cases were 22/30 and 6/30, respectively. Although CSF CaM positivity might not be a sCJD-specific phenomenon, a significantly high rate of CaM-positive CSF in sCJD cases, especially in those with high CSF tau levels, rendered it a valuable diagnostic biomarker for sCJD.

Clinical Correlation of Cerebrospinal Fluid Total tau Levels and MMSE Score in a memory clinic

Tau protein levels in cerebrospinal fluid are a biomarker of Alzheimer’s disease. We correlated MMSE severity to CSF tau levels in a large memory clinic sample. We retrospectively analyzed data from patients attending a memory clinic in the south shore of Boston from 2010 to 2020, and had a lumbar puncture to obtain CSF Tau levels. We compiled cognitive screen data from MMSE scores. Univariate analyses used Spearman correlation as data were non-normal. A multivariate model was created including covariates of age, sex, and race. 965 patients attended the memory clinic from 2010 to 2020. 711 had available MMSE scores. 129 subjects had lumbar punctures and available CSF tau levels. Univariate analyses showed that cognition as measured by MMSE total was not correlated to total tau levels in the CSF (rho=-0.07, p>0.05), but caucasian race was inversely associated with CSF tau levels (rho= -0.217, p<0.05). In a multivariate model, tau levels in the CSF were not associated with MMSE, race, gender, or age. In a large memory clinic sample, CSF tau levels did not correlate to MMSE scores, age, race or gender.

Clinical correlation of cerebrospinal fluid total tau levels and depression as measured by PHQ9 total in a memory clinic

AbstractBackgroundTau protein levels in cerebrospinal fluid is indicative of Alzheimer's dementia. We correlated PHQ‐9 screen severity of depression to CSF tau levels in a memory clinic sample.MethodWe analyzed data from patients attending a memory clinic in the south shore of Boston from 2010 to 2019 who had a lumbar puncture to obtain CSF tau levels. We correlated depression screening data from PHQ9 scores. Univariate analyses used Spearman correlation. A multivariate regression model was created including covariates of age, sex, and race.ResultsDepression as measured by PHQ9 total was not correlated to total tau levels in CSF.ConclusionIn a memory clinic sample, CSF tau levels did not correlate to PHQ9 scores.

Multimodal in vivo and postmortem assessments of tau in Lewy body disorders

We compared regional retention of 18F-flortaucipir between 20 patients with Lewy body disorders (LBD), 12 Alzheimer’s disease patients with positive amyloid positron emission tomography (PET) scans (AD+Aβ) and 15 healthy controls with negative amyloid PET scans (HC−Aβ). In LBD subjects, we compared the relationship between 18F-flortaucipir retention and cerebrospinal fluid (CSF) tau, cognitive performance, and neuropathological tau at autopsy. The LBD cohort was stratified using an Aβ42 cut-off of 192 pg/mL to enrich for groups likely harboring tau pathology (LBD+Aβ = 11, LBD−Aβ = 9). 18F-flortaucipir retention was higher in LBD+AB than HC−Aβ in five, largely temporal-parietal regions with sparing of medial temporal regions. Higher retention was associated with higher CSF total-tau levels (p = 0.04), poorer domain-specific cognitive performance (p = 0.02–0.04), and greater severity of neuropathological tau in corresponding regions. While 18F-flortaucipir retention in LBD is intermediate between healthy controls and AD, retention relates to cognitive impairment, CSF total-tau, and neuropathological tau. Future work in larger autopsy-validated cohorts is needed to define LBD-specific tau biomarker profiles.