Cerebrospinal fluid amyloid-ß and cerebral microbleed are associated with distinct neuropsychiatric sub-syndromes in cognitively impaired patients.

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent in cognitively impaired individuals including Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Whereas several studies have reported the associations between NPS with AD pathologic biomarkers and cerebral small vessel disease (SVD), but it remains unknown whether AD pathology and SVD contribute to different sub-syndromes independently or aggravate same symptoms synergistically. METHOD: We included 445 cognitively impaired individuals (including 316 MCI and 129 AD) with neuropsychiatric, cerebrospinal fluid (CSF) biomarkers (Aß42, p-tau, and t-tau) and multi-model MRI data. Psychiatric symptoms were accessed by using the Neuropsychiatric Inventory (NPI). Visual assessment of SVD (white matter hyperintensity, microbleed, perivascular space, lacune) on MRI images was performed by experienced radiologist. Linear regression analyses were conducted to test the association between neuropsychiatric symptoms with AD pathology and CSVD burden after adjustment for age, sex, education, apolipoprotein E (APOE) ε4 carrier status, and clinical diagnosis. RESULTS: The NPI total scores were related to microbleed (estimate 2.424; 95% CI [0.749, 4.099]; P =0.005). Considering the sub-syndromes, the hyperactivity was associated with microbleed (estimate 0.925; 95% CI [0.115, 1.735]; P =0.025), whereas the affective symptoms were correlated to CSF level of Aß42 (estimate -0.006; 95% CI [-0.011, -0.002]; P =0.005). Furthermore, we found the apathy sub-syndrome was associated with CSF t-tau/Aß42 (estimate 0.636; 95% CI [0.078, 1.194]; P =0.041) and microbleed (estimate 0.693; 95% CI [0.046, 1.340]; P =0.036). In addition, we found a significant interactive effect between CSF t-tau/Aß42 and microbleed (estimate 0.993; 95% CI [0.360, 1.626]; P =0.019) on severity of apathy sub-syndrome. CONCLUSION: Our study showed that CSF Aß42 was associated with affective symptoms, but microbleed was correlated with hyperactivity and apathy, suggesting the effect of AD pathology and SVD on different neuropsychiatric sub-syndromes.

The potential of phosphorylated α-synuclein as a biomarker for the diagnosis and monitoring of multiple system atrophy.

INTRODUCTION: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by the presence of glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-Syn). Accurate diagnosis and monitoring of MSA present significant challenges, which can lead to potential misdiagnosis and inappropriate treatment. Biomarkers play a crucial role in improving the accuracy of MSA diagnosis, and phosphorylated α-synuclein (p-syn) has emerged as a promising biomarker for aiding in diagnosis and disease monitoring. METHODS: A literature search was conducted on PubMed, Scopus, and Google Scholar using specific keywords and MeSH terms without imposing a time limit. Inclusion criteria comprised various study designs including experimental studies, case-control studies, and cohort studies published only in English, while conference abstracts and unpublished sources were excluded. RESULTS: Increased levels of p-syn have been observed in various samples from MSA patients, such as red blood cells, cerebrospinal fluid, oral mucosal cells, skin, and colon biopsies, highlighting their diagnostic potential. The α-Syn RT-QuIC assay has shown sensitivity in diagnosing MSA and tracking its progression. Meta-analyses and multicenter investigations have confirmed the diagnostic value of p-syn in cerebrospinal fluid, demonstrating high specificity and sensitivity in distinguishing MSA from other neurodegenerative diseases. Moreover, combining p-syn with other biomarkers has further improved the diagnostic accuracy of MSA. CONCLUSION: The p-syn stands out as a promising biomarker for MSA. It is found in oligodendrocytes and shows a correlation with disease severity and progression. However, further research and validation studies are necessary to establish p-syn as a reliable biomarker for MSA. If proven, p-syn could significantly contribute to early diagnosis, disease monitoring, and assessing treatment response.

A critical appraisal of blood-based biomarkers for Alzheimer's disease.

Biomarkers that predict the clinical onset of Alzheimer's disease (AD) enable the identification of individuals in the early, preclinical stages of the disease. Detecting AD at this point may allow for more effective therapeutic interventions and optimized enrollment for clinical trials of novel drugs. The current biological diagnosis of AD is based on the AT(N) classification system with the measurement of brain deposition of amyloid-ß (Aß) ("A"), tau pathology ("T"), and neurodegeneration ("N"). Diagnostic cut-offs for Aß1-42, the Aß1-42/Aß1-40 ratio, tau and hyperphosphorylated-tau concentrations in cerebrospinal fluid have been defined and may support AD clinical diagnosis. Blood-based biomarkers of the AT(N) categories have been described in the AD continuum. Cross-sectional and longitudinal studies have shown that the combination of blood biomarkers tracking neuroaxonal injury (neurofilament light chain) and neuroinflammatory pathways (glial fibrillary acidic protein) enhance sensitivity and specificity of AD clinical diagnosis and improve the prediction of AD onset. However, no international accepted cut-offs have been identified for these blood biomarkers. A kit for blood Aß1-42/Aß1-40 is commercially available in the U.S.; however, it does not provide a diagnosis, but simply estimates the risk of developing AD. Although blood-based AD biomarkers have a great potential in the diagnostic work-up of AD, they are not ready for the routine clinical use.

Impact of amyloid and tau positivity on longitudinal brain atrophy in cognitively normal individuals.

BACKGROUND: Individuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods. METHODS: This study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models. RESULTS: A total of 367 participants (48 A + T + , 86 A + T - , 63 A - T + , and 170 A - T - ; mean age 73.8 years, mean follow-up 5.1 years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T - and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A - T - group (lateral ventricle: ß = 0.757 cm3/year [95% confidence interval 0.463 to 1.050], P < .001 for A + T - , and ß = 0.889 cm3/year [0.523 to 1.255], P < .001 for A + T + ; PACC: ß = - 0.19 /year [- 0.36 to - 0.02], P = .029 for A + T - , and ß = - 0.59 /year [- 0.80 to - 0.37], P < .001 for A + T +). Notably, the A + T + group exhibited additional brain atrophy including the whole brain (ß = - 2.782 cm3/year [- 4.060 to - 1.504], P < .001), hippocampus (ß = - 0.057 cm3/year [- 0.085 to - 0.029], P < .001), and AD-signature regions (ß = - 0.02 mm/year [- 0.03 to - 0.01], P < .001). Cox proportional hazards models suggested an increased risk of progressing to MCI or dementia in the A + T + group versus the A - T - group (adjusted hazard ratio = 3.35 [1.76 to 6.39]). CONCLUSIONS: In cognitively normal individuals, A + T + compounds brain atrophy and cognitive deterioration, amplifying the likelihood of disease progression. Therapeutic interventions targeting A + T + individuals could be pivotal in curbing brain atrophy, cognitive decline, and disease progression.

Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer's disease.

Staging amyloid-beta (Aß) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aß pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aß ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aß-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aß therapies.

Total Tau Protein Mediates the Association of Ischemic Cerebrovascular Disease with Cognitive Decline.

Background: Patients with transient ischemic attack (TIA) or ischemic stroke demonstrate an increased risk of cognitive dysfunction. Accumulating evidence indicates that ischemic cerebrovascular disease (ICVD) may interact with the amyloid/tau/neurodegeneration (AT[N]) biomarkers to promote dementia. However, the precise pathological mechanisms remain to be fully characterized. Objective: To elucidate the interrelationships among ICVD, ATN biomarkers in cerebrospinal fluid (CSF), and cognition. Methods: A total of 2524 participants were recruited from the CABLE study. ICVD referred to TIA/ischemic stroke. Cognitive performance was assessed by China Modified Mini-Mental State Examination (CM-MMSE) and Montreal Cognitive Assessment-b (MoCA-b). Multivariate linear regression analyses were performed to evaluate the associations of ICVD with CSF ATN biomarkers and cognition. Causal mediation analyses were used to identify whether the association was mediated by ATN biomarkers. Results: ICVD was associated with higher total-tau (t-tau) (p = 2.828×10-2) and poorer cognition (CM-MMSE: p = 1.539×10-5, MoCA-b: p = 4.552×10-6). Additionally, no discernible correlation surfaced between ICVD and amyloid-ß (Aß) 42 (p = 6.910×10-1) or phosphorylated tau (p-tau) (p = 4.324×10-1). The influence of ICVD on cognitive function was partially mediated by CSF t-tau (CM-MMSE: proportion: 2.74%, MoCA-b: proportion: 2.51%). Subgroup analyses revealed the influences of t-tau were especially evident in male (CM-MMSE: proportion: 5.45%, MoCA-b: proportion: 5.38%) and mid-life group (CM-MMSE: proportion: 9.83%, MoCA-b: proportion: 5.31%). Conclusions: These results delineated t-tau as a potential mediator for the influence of ICVD on cognition. Targeting brain ischemia and alleviating neuronal injury induced by ischemia may be a promising approach for preventing cognitive decline.

Neuropathological changes associated with aberrant cerebrospinal fluid p-tau181 and Aß42 in Alzheimer's disease and other neurodegenerative diseases.

Recent studies suggest that increased cerebrospinal fluid (CSF) phospho-tau is associated with brain amyloid pathology rather than the tau pathology. However, confirmation using gold standard neuropathological assessments remains limited. This study aimed to determine background pathologies associated with aberrant CSF p-tau181 and amyloid-beta 1-42 (Aß42) in Alzheimer's disease (AD) and other neurodegenerative diseases. We retrospectively studied all patients with antemortem CSF and postmortem neuropathologic data at our institution. Comprehensive neuropathologic assessments were conducted for all patients, including Thal phase, Braak NFT stage, and CERAD score for AD. CSF concentrations of p-tau181 and Aß42 were compared between AD neuropathological scores at autopsy by one-way ANOVA stratified by other pathologies. A total of 127 patients with AD (n = 22), Lewy body disease (n = 26), primary tauopathies (n = 30), TDP-43 proteinopathy (n = 16), and other diseases (n = 33) were included. The age at lumbar puncture was 76.3 ± 9.1 years, 40.8% were female, and median time from lumbar puncture to autopsy was 637 (175-1625) days. While Braak NFT 0-II was prevalent without amyloid pathology, Braak NFT ≥IV was observed exclusively in patients with amyloid pathology. Stratified analyses showed that CSF p-tau181 was slightly but significantly higher in patients with high Thal phase or CERAD score even in those with Braak NFT 0-II at autopsy. In patients with amyloid pathology, CSF p-tau181 was significantly and more profoundly elevated in those with Braak NFT ≥III at autopsy. CSF Aß42 was lower in patients with high amyloid pathological scores. However, 34% with Thal ≤ 2 and 38% with CERAD ≤ sparse also showed decreased Aß42. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were overrepresented in this group. These results neuropathologically confirmed previous studies that CSF p-tau181 levels were slightly elevated with amyloid pathology alone and were even higher with tau pathology, and that CSFAß42 can be decreased in PSP/CBD.

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.

Profiling Human Cerebrospinal Fluid (CSF) Endogenous Peptidome in Alzheimer's Disease.

Human cerebrospinal fluid (CSF) is a rich source for central nervous system (CNS)-related disease biomarker discovery due to its direct interchange with the extracellular fluid of the CNS. Though extensive proteome-level profiling has been conducted for CSF, studies targeting at its endogenous peptidome is still limited. It is more difficult to include the post-translational modifications (PTMs) characterization of the peptidome in the mass spectrometry (MS) analysis because of their low abundance and the challenge of data interpretation. In this chapter, we present a peptidomic workflow that combines molecular weight cut-off (MWCO) separation, electron-transfer and higher-energy collision dissociation (EThcD) fragmentation, and a three-step database searching strategy for comprehensive PTM analysis of endogenous peptides including both N-glycosylation and O-glycosylation and other common peptide PTMs. The method has been successfully adopted to analyze CSF samples from healthy donors, mild cognitive impairment (MCI), and Alzheimer's disease (AD) patients to provide a landscape of peptidome in different disease states.

Evidence for cytokine dysregulation in schizophrenia spectrum disorders: A comparison of cerebrospinal fluid and blood samples.

Abnormalities in immune function have been described in schizophrenia but few studies have investigated cytokines in cerebrospinal fluid (CSF) and their correlation with blood levels. In this cross-sectional study, cytokines were measured in CSF and plasma of 30 subjects with schizophrenia spectrum disorder (SSD) diagnosis and 23 healthy volunteers (HV). Results showed that CSF TNFα was increased in SSD subjects compared to HV and there were no correlations between CSF and plasma cytokine levels. The present findings provide evidence of dysregulation of TNFα in CSF of schizophrenia. These results identify elevated CSF TNFα levels as a potential biomarker in schizophrenia.

CSF Biomarkers in Longitudinal Alzheimer Disease Cohorts: Pre-Analytic Challenges.

BACKGROUND: The sensitivity of amyloid to pre-analytic factors complicates cerebrospinal fluid (CSF) diagnostics for Alzheimer disease. We report reliability and validity evidence for automated immunoassays from frozen and fresh CSF samples in an ongoing, single-site research program. METHODS: CSF samples were obtained from 2 Wisconsin cohorts (1256 measurements; 727 participants). Levels of amyloid beta 1-42 (Aß42), phosphorylated tau 181 (pTau181), and total tau (tTau) were obtained using an Elecsys cobas e 601 platform. Repeatability and fixed effects of storage tube type, extraction method, and freezing were assessed via mixed models. Concordance with amyloid positron emission tomography (PET) was investigated with 238 participants having a temporally proximal PET scan. RESULTS: Repeatability was high with intraclass correlation (ICC) ≥0.9, but tube type strongly affected measurements. Discriminative accuracy for PET amyloid positivity was strong across tube types (area under the curve [AUC]: Aß42, 0.87; pTau181Aß42 , 0.96), although optimal thresholds differed. CONCLUSIONS: Under real-world conditions, the Elecsys platform had high repeatability. However, strong effects of pre-analytic factors suggest caution in drawing longitudinal inferences.

Circulating biomarkers of inflammaging and Alzheimer's disease to track age-related trajectories of dementia: Can we develop a clinically relevant composite combination?

Alzheimer's disease (AD) is a rapidly growing global concern due to a consistent rise of the prevalence of dementia which is mainly caused by the aging population worldwide. An early diagnosis of AD remains important as interventions are plausibly more effective when started at the earliest stages. Recent developments in clinical research have focused on the use of blood-based biomarkers for improve diagnosis/prognosis of neurodegenerative diseases, particularly AD. Unlike invasive cerebrospinal fluid tests, circulating biomarkers are less invasive and will become increasingly cheaper and simple to use in larger number of patients with mild symptoms or at risk of dementia. In addition to AD-specific markers, there is growing interest in biomarkers of inflammaging/neuro-inflammaging, an age-related chronic low-grade inflammatory condition increasingly recognized as one of the main risk factor for almost all age-related diseases, including AD. Several inflammatory markers have been associated with cognitive performance and AD development and progression. The presence of senescent cells, a key driver of inflammaging, has also been linked to AD pathogenesis, and senolytic therapy is emerging as a potential treatment strategy. Here, we describe blood-based biomarkers clinically relevant for AD diagnosis/prognosis and biomarkers of inflammaging associated with AD. Through a systematic review approach, we propose that a combination of circulating neurodegeneration and inflammatory biomarkers may contribute to improving early diagnosis and prognosis, as well as providing valuable insights into the trajectory of cognitive decline and dementia in the aging population.

Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson's disease.

Parkinson's disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research-L-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography-mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as L-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research.

Alteration of LARGE1 abundance in patients and a mouse model of 5q-associated spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by recessive pathogenic variants affecting the survival of motor neuron (SMN1) gene (localized on 5q). In consequence, cells lack expression of the corresponding protein. This pathophysiological condition is clinically associated with motor neuron (MN) degeneration leading to severe muscular atrophy. Additionally, vulnerability of other cellular populations and tissues including skeletal muscle has been demonstrated. Although the therapeutic options for SMA have considerably changed, treatment responses may differ thus underlining the persistent need for validated biomarkers. To address this need and to identify novel marker proteins for SMA, we performed unbiased proteomic profiling on cerebrospinal fluid derived (CSF) from genetically proven SMA type 1-3 cases and afterwards performed ELISA studies on CSF and serum samples to validate the potential of a novel biomarker candidates in both body fluids. To further decipher the pathophysiological impact of this biomarker, immunofluorescence studies were carried out on spinal cord and skeletal muscle derived from a 5q-SMA mouse model. Proteomics revealed increase of LARGE1 in CSF derived from adult patients showing a clinical response upon treatment with nusinersen. Moreover, LARGE1 levels were validated in CSF samples of further SMA patients (type 1-3) by ELISA. These studies also unveiled a distinguishment between groups in improvement of motor skills: adult patients do present with lowered level per se at baseline visit while no elevation upon treatment in the pediatric cohort can be observed. ELISA-based studies of serum samples showed no changes in the pediatric cohort but unraveled elevated level in adult patients responding to future intervention with nusinersen, while non-responders did not show a significant increase. Additional immunofluorescence studies of LARGE1 in MN and skeletal muscle of a SMA type 3 mouse model revealed an increase of LARGE1 during disease progression. Our combined data unraveled LARGE1 as a protein dysregulated in serum and CSF of SMA-patients (and in MN and skeletal muscle of SMA mice) holding the potential to serve as a disease marker for SMA and enabling to differentiate between patients responding and non-responding to therapy with nusinersen.

ANU-ADRI scores, tau pathology, and cognition in non-demented adults: the CABLE study.

BACKGROUND: It has been reported that the risk of Alzheimer's disease (AD) could be predicted by the Australian National University Alzheimer Disease Risk Index (ANU-ADRI) scores. However, among non-demented Chinese adults, the correlations of ANU-ADRI scores with cerebrospinal fluid (CSF) core biomarkers and cognition remain unclear. METHODS: Individuals from the Chinese Alzheimer's Biomarker and LifestyLE (CABLE) study were grouped into three groups (low/intermediate/high risk groups) based on their ANU-ADRI scores. The multiple linear regression models were conducted to investigate the correlations of ANU-ADRI scores with several biomarkers of AD pathology. Mediation model and structural equation model (SEM) were conducted to investigate the mediators of the correlation between ANU-ADRI scores and cognition. RESULTS: A total of 1078 non-demented elders were included in our study, with a mean age of 62.58 (standard deviation [SD] 10.06) years as well as a female proportion of 44.16% (n = 476). ANU-ADRI scores were found to be significantly related with MMSE (ß = -0.264, P < 0.001) and MoCA (ß = -0.393, P < 0.001), as well as CSF t-tau (ß = 0.236, P < 0.001), p-tau (ß = 0.183, P < 0.001), and t-tau/Aß42 (ß = 0.094, P = 0.005). Mediation analyses indicated that the relationships of ANU-ADRI scores with cognitive scores were mediated by CSF t-tau or p-tau (mediating proportions ranging from 4.45% to 10.50%). SEM did not reveal that ANU-ADRI scores affected cognition by tau-related pathology and level of CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2). CONCLUSION: ANU-ADRI scores were associated with cognition and tau pathology. We also revealed a potential pathological mechanism underlying the impact of ANU-ADRI scores on cognition.

Exploring the potential of fully automated LUMIPULSE G plasma assays for detecting Alzheimer's disease pathology.

BACKGROUND: LUMIPULSE G-automated immunoassays represent a widely used method for the quantification of Alzheimer's disease (AD) biomarkers in the cerebrospinal fluid (CSF). Less invasive blood-based markers confer a promising tool for AD diagnosis at prodromal stages (mild cognitive impairment (MCI)). Highly sensitive assays for the quantification of amyloid-beta (Aß) and phosphorylated Tau-181 (p-Tau181) in the blood are showing promising results. In this study, we evaluated the clinical performance of the recently available fully automated LUMIPULSE plasma marker assays for detecting brain AD pathology and for predicting progression from MCI to AD dementia stage. METHODS: A retrospective exploratory cohort of 138 individuals (22 neurological controls [NC], 72 MCI, and 44 AD dementia patients) was included. Data regarding baseline CSF concentrations of Aß42, Aß40, t-Tau, and p-Tau181 was available and used to establish the presence of AD brain pathology. Baseline Aß42, Aß40, and p-Tau181 concentrations were determined in stored plasma samples using high-throughput fully automated LUMIPULSE assays. Progression from MCI to AD dementia was evaluated during follow-up (mean 6.4 ± 2.5 years). Moreover, a prospective validation cohort of 72 individuals with memory complaints underwent AD biomarker quantification, closely mirroring typical clinical practice. This cohort aimed to confirm the study's main findings. RESULTS: In the exploratory cohort, correlations between CSF and plasma were moderate for p-Tau181 (ρ = 0.61, p < 0.001) and weak for Aß42/Aß40 ratio (ρ = 0.39, p < 0.001). Plasma p-Tau181 and p-Tau181/Aß42 concentrations were significantly increased while Aß42/Aß40 was significantly decreased (p < 0.001) in patients with AD dementia and prodromal AD, as well as in individuals with CSF abnormal amyloid concentrations (A +). Plasma p-Tau181 showed a robust performance in differentiating patients clinically diagnosed as AD (AUC = 0.89; 95% CI 0.83-0.94); A + vs. A - (AUC = 0.84, 95% CI 0.77-0.91) and also in predicting conversion to AD dementia in MCI patients (AUC = 0.89, 95% CI 0.81-0.96). When tested in the validation cohort, plasma p-Tau181 displayed 83.3% of the overall percentage of agreement according to amyloid status. CONCLUSIONS: Our results show that the measurement of p-Tau181 in plasma has great potential as a non-invasive prognostic screening tool for implementation in a clinical setting.

Blood-Based Biomarkers for Early Alzheimer's Disease Diagnosis in Real-World Settings.

As our knowledge about the biology of Alzheimer's disease (AD) expands and we recognize the significance of early intervention for effective treatment, there is a shift in focus toward detecting the disease at an early stage. AD is characterized by the accumulation of misfolded amyloid-ß (Aß) and phosphorylated tau proteins in the brain, leading to the formation of senile plaques and neurofibrillary tangles. While a definitive diagnosis of AD can only be confirmed through autopsy by examining these pathological features, there are now reliable methods available for diagnosing the disease in living individuals. These methods involve analyzing cerebrospinal fluid and using positron emission tomography to accurately assess the presence of Aß and tau proteins. While these diagnostic markers have shown high accuracy in memory-clinic populations, they do have limitations such as the requirement for invasive lumbar puncture or exposure to ionizing radiation. Additionally, they are not easily accessible outside of specialized healthcare settings. Blood-based biomarkers of the core pathological features of AD are being developed, showing promise for less invasive, scalable identification of AD cases in the community. The advantages for the healthcare systems of this development are obvious, but the diagnostic performance of blood-based biomarkers in broader, non-selected populations outside of retrospective analyses and research cohorts still requires further investigation, including the combination with more effective neuropsychological assessments such as digital cognitive test solutions.

Optimized Pre-analytical Handling Protocol for Blood-Based Biomarkers of Alzheimer's Disease.

The therapeutic management of patients with Alzheimer's disease (AD) has been hindered by poor diagnostic accuracy. As such, there is an unmet clinical need for tools that can detect and diagnose the disease in its early stages. Compared with cerebrospinal fluid (CSF)-based biomarkers or positron emission tomography (PET), the use of reliable blood-based biomarkers could offer an accessible and minimally invasive method of streamlining diagnosis in the clinical setting. However, the influence of pre-analytical processing and sample handling parameters on the accurate measurement of protein biomarkers is well established, especially for AD CSF-based biomarkers. In this chapter, we provide recommendations for an optimal sample handling protocol for the analysis of blood-based biomarkers specifically for amyloid pathology in AD.

Neuroimaging Methods for MRI Analysis in CSF Biomarkers Studies.

Among others, the existence of pathophysiological biomarkers such as cerebrospinal fluid (CSF) Aß-42, t-tau, and p-tau preceding the onset of Alzheimer's disease (AD) symptomatology has shifted the conceptualization of AD as a continuum. In addition, magnetic resonance imaging (MRI) enables the study of structural and functional cross-sectional correlates and longitudinal changes in vivo, and therefore, the combination of CSF data and imaging analyses emerges as a synergistic approach to understand the structural correlates related with specific AD-related biomarkers. In this chapter, we describe the methods used in neuroimaging that will allow researchers to combine data on CSF metabolites with imaging analyses.

Nanoscale imaging of pT217-tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early-stage neurodegeneration.

INTRODUCTION: Tau phosphorylated at threonine-217 (pT217-tau) is a novel fluid-based biomarker that predicts onset of Alzheimer's disease (AD) symptoms, but little is known about how pT217-tau arises in the brain, as soluble pT217-tau is dephosphorylated post mortem in humans. METHODS: We used multilabel immunofluorescence and immunoelectron microscopy to examine the subcellular localization of early-stage pT217-tau in entorhinal and prefrontal cortices of aged macaques with naturally occurring tau pathology and assayed pT217-tau levels in plasma. RESULTS: pT217-tau was aggregated on microtubules within dendrites exhibiting early signs of degeneration, including autophagic vacuoles. It was also seen trafficking between excitatory neurons within synapses on spines, where it was exposed to the extracellular space, and thus accessible to cerebrospinal fluid (CSF)/blood. Plasma pT217-tau levels increased across the age span and thus can serve as a biomarker in macaques. DISCUSSION: These data help to explain why pT217-tau predicts degeneration in AD and how it gains access to CSF and plasma to serve as a fluid biomarker.