Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration.

Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies and agreements with their corresponding CSF and neuroimaging biomarkers in the amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer's disease. However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer's disease while total-tau shows lack of correlation with CSF total-tau. Recent studies suggest that blood total-tau originates principally from peripheral, non-brain sources. We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed 'big tau' isoform. We applied this antibody to develop an ultrasensitive blood-based assay for brain-derived tau, and validated it in five independent cohorts (n = 609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts and memory clinic cohorts. In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P < 0.0001), while serum and CSF total-tau were not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau showed equivalent diagnostic performance as CSF total-tau and CSF brain-derived tau to separate biomarker-positive Alzheimer's disease participants from biomarker-negative controls. Furthermore, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer's disease from other neurodegenerative diseases (area under the curve = 86.4%) while neurofilament light did not (area under the curve = 54.3%). These performances were independent of the presence of concomitant pathologies. Plasma brain-derived tau (rho = 0.52-0.67, P = 0.003), but not neurofilament light (rho = -0.14-0.17, P = 0.501), was associated with global and regional amyloid plaque and neurofibrillary tangle counts. These results were further verified in two memory clinic cohorts where serum brain-derived tau differentiated Alzheimer's disease from a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%). Notably, plasma/serum brain-derived tau correlated with neurofilament light only in Alzheimer's disease but not in the other neurodegenerative diseases. Across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function. Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer's disease-type neurodegeneration. Thus, brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer's disease-dependent neurodegenerative processes for clinical and research purposes.

The heritability of blood-based biomarkers related to risk of Alzheimer's disease in a population-based sample of early old-age men.

INTRODUCTION: Despite their increased application, the heritability of Alzheimer's disease (AD)-related blood-based biomarkers remains unexplored. METHODS: Plasma amyloid beta 40 (Aß40), Aß42, the Aß42/40 ratio, total tau (t-tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (µ = 67.0, SD = 2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them. RESULTS: Additive genetics explained 44% to 52% of Aß42, Aß40, t-tau, and NfL. The Aß42/40 ratio was not heritable. Aß40 and Aß42 were genetically near identical (rg  = 0.94). Both Aß40 and Aß42 were genetically correlated with NfL (rg  = 0.35 to 0.38), but genetically unrelated to t-tau. DISCUSSION: Except for Aß42/40, plasma biomarkers are heritable. Aß40 and Aß42 share mostly the same genetic influences, whereas genetic influences on plasma t-tau and NfL are largely unique in early old-age men. The absence of genetic associations between the Aßs and t-tau is not consistent with the amyloid cascade hypothesis.

Cognitive reserve, cortisol, and Alzheimer's disease biomarkers: A memory clinic study.

INTRODUCTION: Cognitive reserve might mitigate the risk of Alzheimer's dementia among memory clinic patients. No study has examined the potential modifying role of stress on this relation. METHODS: We examined cross-sectional associations of the cognitive reserve index (CRI; education, occupational complexity, physical and leisure activities, and social health) with cognitive performance and AD-related biomarkers among 113 memory clinic patients. The longitudinal association between CRI and cognition over a 3-year follow-up was assessed. We examined whether associations were influenced by perceived stress and five measures of diurnal salivary cortisol. RESULTS: Higher CRI scores were associated with better cognition. Adjusting for cortisol measures reduced the beneficial association of CRI on cognition. A higher CRI score was associated with better working memory in individuals with higher (favorable) cortisol AM/PM ratio, but not among individuals with low cortisol AM/PM ratio. No association was found between CRI and AD-related biomarkers. DISCUSSION: Physiological stress reduces the neurocognitive benefits of cognitive reserve among memory clinic patients. HIGHLIGHTS: Physiological stress may reduce the neurocognitive benefits accrued from cognitively stimulating and enriching life experiences (cognitive reserve [CR]) in memory clinic patients. Cortisol awakening response modified the relation between CR and P-tau181, a marker of Alzheimer's disease (AD). Effective stress management techniques for AD and related dementia prevention are warranted.

Pilot Study of the Total and Phosphorylated Tau Proteins in Early-Stage Multiple Sclerosis.

Background and Objectives: Recent findings suggest that neurodegeneration starts early in the course of multiple sclerosis (MS) and significantly contributes to the progression of patients' disability. Tau is a microtubule-binding protein that is known to play a role in the pathophysiology of many neurodegenerative disorders. Newly emerging data on tau protein-induced neurodegenerative processes and its possible involvement in MS suggest that it may be involved in the pathology of early-stage MS. Therefore, this study aimed to test this hypothesis in patients with newly diagnosed MS. Materials and Methods: Cerebrospinal fluid (CSF) was collected from 19 patients with newly diagnosed MS and 19 control subjects. All MS patients underwent neurological examination, lumbar punction, and brain magnetic resonance imaging (MRI). CSF concentrations of total and phosphorylated tau (phospho-tau-181) protein were measured using commercial enzyme-linked immunosorbent assay kits. Results: The total tau concentration was significantly higher in the CSF of MS patients compared to controls (141.67 pg/mL, IQR 77.79-189.17 and 68.77 pg/mL, IQR 31.24-109.17, p = 0.025). In MS patients, the total tau protein positively correlated with total CSF protein (r = 0.471, p = 0.048). Significantly higher total tau concentration was measured in MS patients with higher lesion load in brain MRI (≥9 versus <9 lesions; 168.33 pg/mL, IQR 111.67-222.32 and 73.33 pg/mL, IQR -32.13-139.29-, p = 0.021). The CSF concentration of phospho-tau-181 protein was below the detection limit in both MS and control subjects. Conclusions: The concentration of total tau protein level is elevated, whereas phospho-tau-181 is undetectable in the CSF of patients with early-stage MS.

Cerebrospinal fluid neurofilament light chain and total-tau as biomarkers of neurodegeneration in Alzheimer's disease and frontotemporal dementia.

INTRODUCTION: CSF Neurofilament light chain(NfL) is a promising biomarker of neurodegeneration, but its utility in discriminating between Alzheimer's disease(AD) and frontotemporal dementia(FTD) is limited. METHODS: 105 patients with clinical-biological diagnosis of mild cognitive impairment(MCI) due to AD (N = 72) or clinical diagnosis of FTD (N = 33) underwent neuropsychological assessment and CSF Aß42/40, p-tau181, total-tau and NfL quantification. Group comparisons, correlations between continuous variables and ROC curve analysis were carried out to assess NfL role in discriminating between MCI due to AD and FTD, exploring the associations between NfL, ATN biomarkers and neuropsychological measures. RESULTS: NfL levels were significantly lower in the AD group, while levels of total-tau were higher. In the FTD group, significant correlations were found between NfL, p-tau181 and total-tau, and between NfL and cognitive performances. In the AD group, NfL levels were directly correlated with total-tau and p-tau181; Aß42/40 ratio was inversely correlated with total-tau and p-tau181, but not with NfL. Moreover, p-tau181 and t-tau levels were found to be associated with episodic memory and lexical-semantic impairment. Total-tau/NfL ratio differentiated prodromal-AD from FTD with an AUC of 0.951, higher than the individual measures. DISCUSSION & CONCLUSIONS: The results support that NfL and total-tau levels reflect distinct pathophysiological neurodegeneration mechanisms, independent and dependent of Aß pathology, respectively, Combining them may enhance both markers reliability, their ratio showing high accuracy in distinguishing MCI due to AD from FTD. Moreover, our results revealed associations between NfL and disease severity in FTD and between tauopathy and episodic memory and lexical-semantic impairment in prodromal-AD.

Second-generation Elecsys cerebrospinal fluid immunoassays aid diagnosis of early Alzheimer's disease.

OBJECTIVES: Timely diagnosis of Alzheimer's disease (AD) is critical for appropriate treatment/patient management. Cerebrospinal fluid (CSF) biomarker analysis is often used to aid diagnosis. We assessed analytical performance of second-generation (Gen II) Elecsys® CSF immunoassays (Roche Diagnostics International Ltd), and adjusted existing cut-offs, to evaluate their potential utility in clinical routine. METHODS: Analytical performance was assessed using CSF samples measured with Elecsys CSF Gen II immunoassays on cobas e analyzers. Aß42 Gen I/Gen II immunoassay method comparisons were performed (Passing-Bablok regression). Cut-off values were adjusted using estimated bias in biomarker levels between BioFINDER protocol aliquots/Gen I immunoassays and Gen II protocol aliquots/immunoassays. Distribution of Gen II immunoassay values was evaluated in AD, mild cognitive impairment (MCI), and cognitively normal cohorts; percentage observations outside the measuring range were derived. RESULTS: The Gen II immunoassays demonstrated good analytical performance, including repeatability, intermediate precision, lot-to-lot agreement (Pearson's r: ≥0.999), and platform agreement (Pearson's r: ≥0.995). Aß42 Gen I/Gen II immunoassay measurements were strongly correlated (Pearson's r: 0.985-0.999). Aß42 Gen II immunoassay cut-offs were adjusted to 1,030 and 800 ng/L, and pTau181/Aß42 ratio cut-offs to 0.023 and 0.029, for Gen II and I protocols, respectively. No observations were below the lower limit of the measuring range; above the upper limit, there were none from the AD cohort, and 2.6 and 6.8% from the MCI and cognitively normal cohorts, respectively. CONCLUSIONS: Our findings suggest that the Gen II immunoassays have potential utility in clinical routine to aid diagnosis of AD.

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

OBJECTIVES: To examine the relationship between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and tap test response to elucidate the effects of comorbidity of AD in idiopathic normal-pressure hydrocephalus (iNPH). DESIGN: Case-control study. SETTING: Osaka University Hospital. PARTICIPANTS: Patients with possible iNPH underwent a CSF tap test. MEASUREMENTS: Concentrations of amyloid beta (Aß) 1-40, 1-42, and total tau in CSF were measured. The response of tap test was judged using Timed Up and Go test (TUG), 10-m reciprocation walking test (10MWT), Mini-Mental State Examination (MMSE), and iNPH grading scale. The ratio of Aß1-42 to Aß1-40 (Aß42/40 ratio) and total tau concentration was compared between tap test-negative (iNPH-nTT) and -positive (iNPH-pTT) patients. RESULTS: We identified 27 patients as iNPH-nTT and 81 as iNPH-pTT. Aß42/40 ratio was significantly lower (mean [SD] = 0.063 [0.026] vs. 0.083 [0.036], p = 0.008), and total tau in CSF was significantly higher (mean [SD] = 385.6 [237.2] vs. 293.6 [165.0], p = 0.028) in iNPH-nTT than in iNPH-pTT. Stepwise logistic regression analysis revealed that low Aß42/40 ratio was significantly associated with the negativity of the tap test. The response of cognition was significantly related to Aß42/40 ratio. The association between Aß42/40 ratio and tap test response, especially in cognition, remained after adjusting for disease duration and severity at baseline. CONCLUSIONS: A low CSF Aß42/40 ratio is associated with a poorer cognitive response, but not gait and urinary response, to a tap test in iNPH. Even if CSF biomarkers suggest AD comorbidity, treatment with iNPH may be effective for gait and urinary dysfunction.

Preanalytical stability of plasma/serum brain-derived tau.

INTRODUCTION: We investigated the effects of matrix type and reagent batch changes on diagnostic performances and longitudinal trajectories of brain-derived tau (BD-tau). METHODS: We evaluated (i) Cohort 1: paired EDTA plasma and serum from Alzheimer biomarker-positive older adults versus controls (n = 26); and (ii) Cohort 2: n = 79 acute ischemic stroke patients with 265 longitudinal samples across four time points. RESULTS: In Cohort 1, plasma and serum BD-tau were strongly correlated (rho = 0.96, p < 0.0001) with similar diagnostic performances (AUCs >99%) and correlations with CSF total-tau (rho = 0.93-0.94, p < 0.0001). However, absolute concentrations were ∼40% higher in plasma versus serum. In Cohort 2, first and repeated BD-tau measurements showed a near-perfect correlation (rho = 0.96, p < 0.0001), with no significant between-batch concentration differences. In longitudinal analyses, substituting ∼10% of the first-run concentrations for the remeasured values showed overlapping estimated trajectories without significant differences at any time point. DISCUSSION: BD-tau has equivalent diagnostic accuracies, but non-interchangeable absolute concentrations, in plasma versus serum. Furthermore, the analytical robustness is unaffected by batch-to-batch reagent variations. HIGHLIGHTS: Brain-derived tau (BD-tau) is a novel blood-based biomarker that quantifies tau protein of CNS origin. Effects of preanalytical handling procedures on the quality and reproducibility of BD-tau measures are unknown. In two cohorts of n = 105 participants, we compared BD-tau concentrations and diagnostic performances in paired plasma and serum samples, and evaluated impacts of batch-to-batch reagent variations. Paired plasma and serum showed equivalent diagnostic performances to separate amyloid-positive AD from amyloid-negative controls, indicating both can be used independently. Repeated measurements and longitudinal trajectories of plasma BD-tau were unaffected by batch-to-batch reagent variation.

Association between CSF biomarkers of Alzheimer's disease and neuropsychiatric symptoms: Mayo Clinic Study of Aging.

INTRODUCTION: We examined the association between cerebrospinal fluid (CSF)-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms (NPS) in older non-demented adults. METHODS: We included 784 persons (699 cognitively unimpaired, 85 with mild cognitive impairment) aged ≥ 50 years who underwent CSF amyloid beta (Aß42), hyperphosphorylated tau 181 (p-tau), and total tau (t-tau) as well as NPS assessment using Beck Depression and Anxiety Inventories (BDI-II, BAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Lower CSF Aß42, and higher t-tau/Aß42 and p-tau/Aß42 ratios were associated with BDI-II and BAI total scores, clinical depression (BDI-II ≥ 13), and clinical anxiety (BAI ≥ 10), as well as NPI-Q-assessed anxiety, apathy, and nighttime behavior. DISCUSSION: CSF Aß42, t-tau/Aß42, and p-tau/Aß42 ratios were associated with NPS in community-dwelling individuals free of dementia. If confirmed by a longitudinal cohort study, the findings have clinical relevance of taking into account the NPS status of individuals with abnormal CSF biomarkers.

Herpes simplex virus alters Alzheimer's disease biomarkers - A hypothesis paper.

INTRODUCTION: Human herpes simplex virus 1 (HSV1) is discussed to induce amyloid-ß (Aß) accumulation and neurofibrillary tangles of hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) in cell culture and animal models. Aß appears to be virostatic. We investigated the association between intrathecal antibodies against HSV or cytomegalovirus (CMV) and cerebrospinal fluid (CSF) AD biomarkers. METHODS: Aß42 /Aß40 ratio, pTau, and tTau were measured in CSF of 117 patients with early AD positive for amyloid pathology (A+) and 30 healthy controls (A-). CSF-to-serum anti-HSV1/2-IgG antibody indices (AI-IgGHSV1/2 ) and CMV (AI-IgGCMV ) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Exclusively in HSV1-seropositive AD, pTau was positively and significantly predicted by AI-IgGHSV1/2 and negatively by the Aß42 /Aß40 ratio in both univariate and multivariate regression analyses. Furthermore, a significant and negative interaction between the AI-IgGHSV1/2 and Aß42 /Aß40 ratio on pTau was found. DISCUSSION: The results support the hypothesis that HSV infection contributes to AD. HIGHLIGHTS: HSV antibody index is positively associated with tau pathology in patients with AD. HSV antibody index is negatively associated with cerebral FDG metabolism. Amyloid modulates the association of HSV antibody index with CSF-pTau. HSV in AD offers a pathophysiological model connecting tau and amyloid.

Levels of Alzheimer's disease blood biomarkers are altered after food intake-A pilot intervention study in healthy adults.

INTRODUCTION: Blood biomarkers accurately identify Alzheimer's disease (AD) pathophysiology and axonal injury. We investigated the influence of food intake on AD-related biomarkers in cognitively healthy, obese adults at high metabolic risk. METHODS: One-hundred eleven participants underwent repeated blood sampling during 3 h after a standardized meal (postprandial group, PG). For comparison, blood was sampled from a fasting subgroup over 3 h (fasting group, FG). Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), amyloid-beta (Aß) 42/40, phosphorylated tau (p-tau) 181 and 231, and total-tau were measured via single molecule array assays. RESULTS: Significant differences were found for NfL, GFAP, Aß42/40, p-tau181, and p-tau231 between FG and PG. The greatest change to baseline occurred for GFAP and p-tau181 (120 min postprandially, p < 0.0001). CONCLUSION: Our data suggest that AD-related biomarkers are altered by food intake. Further studies are needed to verify whether blood biomarker sampling should be performed in the fasting state. HIGHLIGHTS: Acute food intake alters plasma biomarkers of Alzheimer's disease in obese, otherwise healthy adults. We also found dynamic fluctuations in plasma biomarkers concentration in the fasting state suggesting physiological diurnal variations. Further investigations are highly needed to verify if biomarker measurements should be performed in the fasting state and at a standardized time of day to improve the diagnostic accuracy.

Don't forget about tau: the effects of ApoE4 genotype on Alzheimer's disease cerebrospinal fluid biomarkers in subjects with mild cognitive impairment-data from the Dementia Competence Network.

ApoE4, the strongest genetic risk factor for Alzheimer's disease (AD), has been shown to be associated with both beta-amyloid (Aß) and tau pathology, with the strongest evidence for effects on Aß, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aß42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aß42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aß42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose-dependent manner. Comparisons of these associations stratified by MCI-progression groups showed a significant influence of ApoE4 carriership and diagnostic group on all CSF biomarker levels. The effect of ApoE4 was present in MCI-stable individuals but not in the other groups, with ApoE4 + carriers having decreased CSF Aß 42 levels, and increased concentration of t-tau and p-tau. Longitudinally, individuals with abnormal t-tau and Aß42 had a more rapid progression of cognitive and clinical decline, independently of ApoE4 genotype. Overall, our results contribute to an emerging framework in which ApoE4 involves mechanisms associated with both CSF amyloid-ß burden and tau aggregation at specific time points in AD pathogenesis.

Early plasma biomarker dynamic profiles are associated with acute ischemic stroke outcomes.

BACKGROUND: Early outcome prediction after acute ischemic stroke (AIS) might be improved with blood-based biomarkers. We investigated whether the longitudinal profile of a multi-marker panel could predict the outcome of successfully recanalized AIS patients. METHODS: We used ultrasensitive single-molecule array (Simoa) to measure glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), total-tau (t-tau) and ELISA for brevican in a prospective study of AIS patients with anterior circulation large vessel occlusion successfully submitted to thrombectomy. Plasma was obtained at admission, upon treatment, 24 h and 72 h after treatment. Clinical and neuroimaging outcomes were assessed independently. RESULTS: Thirty-five patients (64.8%) had good early clinical or neuroimaging outcome. Baseline biomarker levels did not distinguish between outcomes. However, longitudinal intra-individual biomarker changes followed different dynamic profiles with time and according to outcome. GFAP levels exhibited an early and prominent increase between admission and just after treatment. NfL increase was less pronounced between admission and up to 24 h. T-tau increased between treatment and 24 h. Interestingly, GFAP rate-of-change (pg/ml/h) between admission and immediately after recanalization had a good discriminative capacity between clinical outcomes (AUC = 0.88, p < 0.001), which was higher than admission CT-ASPECTS (AUC = 0.75, p < 0.01). T-tau rate-of-change provided moderate discriminative capacity (AUC = 0.71, p < 0.05). Moreover, in AIS patients with admission CT-ASPECTS <9 both GFAP and NfL rate-of-change were good outcome predictors (AUC = 0.82 and 0.77, p < 0.05). CONCLUSION: Early GFAP, t-tau and NfL rate-of-change in plasma can predict AIS clinical and neuroimaging outcome after successful recanalization. Such dynamic measures match and anticipate neuroimaging predictive capacity, potentially improving AIS patient stratification for treatment, and targeting individualized stroke care.

Associations of amyloid and neurodegeneration plasma biomarkers with comorbidities.

INTRODUCTION: Blood-based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect the levels of these markers. METHODS: Plasma markers (Aß42, Aß40, NfL, T-tau, Aß42/40 ratio) were measured on the Quanterix Simoa HD-1 analyzer for 996 Mayo Clinic Study of Aging (MCSA) participants, aged 51 to 95 years. All other data were collected during in-person MCSA visits or abstracted from the medical record. RESULTS: Among cognitively unimpaired (CU) participants, all plasma markers correlated with age. Linear regression models revealed multiple relationships. For example, higher Charlson Comorbidity Index and chronic kidney disease were associated with higher levels of all biomarkers. Some relationships differed between mild cognitive impairment and dementia participants. DISCUSSION: Multiple variables affect plasma biomarkers of amyloid pathology and neurodegeneration among CU in the general population. Incorporating this information is critical for accurate interpretation of the biomarker levels and for the development of reference ranges.

Biomarkers for central nervous system injury in cerebrospinal fluid are elevated in COVID-19 and associated with neurological symptoms and disease severity.

BACKGROUND AND PURPOSE: Neurological symptoms have been frequently reported in hospitalized patients with coronavirus disease 2019 (COVID-19), and biomarkers of central nervous system (CNS) injury are reported to be increased in plasma but not extensively studied in cerebrospinal fluid (CSF). This study examined CSF for biomarkers of CNS injury and other pathology in relation to neurological symptoms and disease severity in patients with neurological manifestations of COVID-19. METHODS: Nineteen patients with neurological symptoms and mild to critical COVID-19 were prospectively included. Extensive analysis of CSF, including measurement of biomarkers of CNS injury (neurofilament light chain [NfL] protein, glial fibrillary acidic protein [GFAp], and total tau), was performed and compared to neurological features and disease severity. RESULTS: Neurological symptoms included altered mental status (42%), headache (42%), and central (21%) and peripheral weakness (32%). Two patients demonstrated minor pleocytosis, and four patients had increased immunoglobulin G levels in CSF. Neuronal autoantibody testing using commercial tests was negative in all patients. Increased CSF levels of NfL protein, total tau, and GFAp were seen in 63%, 37%, and 16% of patients, respectively. Increased NfL protein correlated with disease severity, time in intensive care, and level of consciousness. NfL protein in CSF was higher in patients with central neurological symptoms. CONCLUSIONS: Although limited by the small sample size, our data suggest that levels of NfL protein, GFAp, and total tau in CSF are commonly elevated in patients with COVID-19 with neurological symptoms. This is in contrast to the standard CSF workup where pathological findings are scarce. NfL protein, in particular, is associated with central neurological symptoms and disease severity.

A preliminary study about neurofilament light chain and tau protein levels in psoriasis: Correlation with disease severity.

BACKGROUND: Studies investigating cognitive dysfunction in psoriatic patients remain inconclusive. OBJECTIVE: To investigate the risk of cognitive decline in plaque-type psoriasis patients. METHODS: Serum neurofilament light chain (NFL) and tau protein concentrations in 45 patients with plaque-type psoriasis and forty-five healthy controls were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Mean homeostasis model assessment (HOMA-IR) values (6.82 vs 3.25) and serum levels of insulin (28.19 vs 15.71), NFL (5.74 vs 1.98), and tau (348.17 vs 207.30) in patients with psoriasis were found to be significantly higher than those of in healthy controls. There was a significant positive correlation between NFL and tau (r = .257, P = .015). There was significant correlation between NFL, tau and PASI (r = .310, P = .040) and (r = .383, P = .010), respectively. Significant correlations between NFL and insulin, TC, HDL-C, TG, VLDL-C, and BMI were found. NFL (9.38 vs 3.08) and tau (439.28 vs 281.58) concentrations and PASI values (23.94 vs 14.18) in patients with disease onset before 40 years were significantly higher than that of the patients with disease onset after 40 years. C-reactive protein (CRP) was significantly correlated with BMI (r = .449, P < .001), LDL-C (r = .240, P = .026), TG (r = .244, P = .024), and VLDL-C (r = .241, P = .025) in patients with psoriasis. CONCLUSIONS: Increased serum NFL and tau protein levels and the presence of positive correlations between NFL, tau protein and PASI score show cognitive decline risk may be higher in moderate-to-severe psoriasis.

Comparison of CSF neurofilament light chain, neurogranin, and tau to MRI markers.

INTRODUCTION: We determined whether cerebrospinal fluid (CSF) neurofilament light (NfL), neurogranin (Ng), and total-tau (t-tau) differentially mapped to magnetic resonance imaging (MRI) measures of cortical thickness, microstructural integrity (corpus callosum and cingulum fractional anisotropy [FA]), and white matter hyperintensities (WMH). METHODS: Analyses included 536 non-demented Mayo Clinic Study of Aging participants with CSF NfL, Ng, t-tau, amyloid beta (Aß)42 and longitudinal MRI scans. Linear mixed models assessed longitudinal associations between CSF markers and MRI changes. RESULTS: Higher CSF NfL was associated with decreasing microstructural integrity and WMH. Higher t-tau was associated with decreasing temporal lobe and Alzheimer's disease (AD) meta region of interest (ROI) cortical thickness. There was no association between Ng and any MRI measure. CSF Aß42 interacted with Ng for declines in temporal lobe and AD meta ROI cortical thickness and cingulum FA. DISCUSSION: CSF NfL predicts changes in white matter integrity, t-tau reflects non-specific changes in cortical thickness, and Ng reflects AD-specific synaptic and neuronal degeneration.

ATN incorporating cerebrospinal fluid neurofilament light chain detects frontotemporal lobar degeneration.

INTRODUCTION: The ATN framework provides an in vivo diagnosis of Alzheimer's disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non-Alzheimer's pathophysiologies (SNAP), including frontotemporal lobar degeneration (FTLD), leads to misdiagnoses. We compared accuracy of ATN (ATNTAU ) using CSF total tau (t-tau) to a modified strategy (ATNNfL ) using CSF neurofilament light chain (NfL) in an autopsy cohort. METHODS: ATNTAU and ATNNfL were trained in an independent sample and validated in autopsy-confirmed AD (n = 67) and FTLD (n = 27). RESULTS: ATNNfL more accurately identified FTLD as SNAP (sensitivity = 0.93, specificity = 0.94) than ATNTAU (sensitivity = 0.44, specificity = 0.97), even in cases with co-occurring AD and FTLD. ATNNfL misclassified fewer AD and FTLD as "Normal" (2%) than ATNTAU (14%). DISCUSSION: ATNNfL is a promising diagnostic strategy that may accurately identify both AD and FTLD, even when pathologies co-occur.

Fingerprinting Alzheimer's Disease by 1H Nuclear Magnetic Resonance Spectroscopy of Cerebrospinal Fluid.

In this study, we sought for a cerebrospinal fluid (CSF) metabolomic fingerprint in Alzheimer's disease (AD) patients characterized, according to the clinical picture and CSF AD core biomarkers (Aß42, p-tau, and t-tau), both at pre-dementia (mild cognitive impairment due to AD, MCI-AD) and dementia stages (ADdem) and in a group of patients with a normal CSF biomarker profile (non-AD) using untargeted 1H nuclear magnetic resonance (NMR) spectroscopy-based metabolomics. This is a retrospective study based on two independent cohorts: a Dutch cohort, which comprises 20 ADdem, 20 MCI-AD, and 20 non-AD patients, and an Italian cohort, constituted by 14 ADdem and 12 non-AD patients. 1H NMR CSF spectra were analyzed using OPLS-DA. Metabolomic fingerprinting in the Dutch cohort provides a significant discrimination (86.1% accuracy) between ADdem and non-AD. MCI-AD patients show a good discrimination with respect to ADdem (70.0% accuracy) but only slight differences when compared with non-AD (59.6% accuracy). Acetate, valine, and 3-hydroxyisovalerate result to be altered in ADdem patients. Valine correlates with cognitive decline at follow-up (R = 0.53, P = 0.0011). The discrimination between ADdem and non-AD was confirmed in the Italian cohort. The CSF metabolomic fingerprinting shows a signature characteristic of ADdem patients with respect to MCI-AD and non-AD patients.

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease.

BACKGROUND: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. METHODS: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months. RESULTS: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. CONCLUSIONS: CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.