Pathophysiological Biomarkers Research Articles

Multiple pathophysiological biomarkers are associated with gray matter volume and cerebral glucose metabolism in the early preclinical Alzheimer's continuum

AbstractBackgroundThe pathophysiological events that occur early in the preclinical Alzheimer’s disease (AD) continuum are not fully understood. Here, we sought for associations, in cognitively unimpaired individuals, between cerebrospinal (CSF) biomarkers of the main pathophysiological events described in AD vs. patterns of gray matter volume (GMv) and cerebral glucose metabolism (rCMRGlu).MethodThe first consecutive 381 participants of the ALFA+ study with valid T1w MRI, [18F]FDG‐PET scans and CSF samples were included. CSF biomarkers were measured with the NeuroToolKit robust prototype assays and Elecsys® immunoassays (Roche Diagnostics) and related to amyloid (Aβ42, Aβ40) and tau (pTau) metabolism, neuronal and axonal damage (NfL), synaptic dysfunction (neurogranin), neuroinflammation (sTREM2, YKL40, GFAP, S100, IL6), and α‐synuclein. Individuals were staged using the A/T system and pre‐established cut‐offs for the Aβ42/40 ratio and pTau concentrations. Modulated GMv maps were obtained from T1w scans. [18F]FDG uptake was normalized to the pons. Exploratory voxelwise associations between maps of GMv and rCMRGlu vs. CSF biomarkers (and differences between A/T groups in the AD continuum) were assessed with SPM12 (p<0.005, k>50 voxels) after accounting for the effect of age, sex, education, and APOE‐ε4 carriership, as well as for the Total Intracranial Volume (TIV) in the GMv analysis.ResultDemographics are shown in Table 1. Figure 1 shows regional differences in GMv and rCMRGlu between A/T groups and Figure 2 associations with biomarkers. Compared to the A‐T‐ group, A+T‐ individuals presented a widespread pattern of higher GMv. Higher pTau levels were associated with an extensive pattern of higher GMv and rCMRGlu. Higher sTREM2 values were associated with higher GMv in the temporoparietal junction and posterior cingulate cortex overlapping pTau GMv effects (Figure 3). Lower Aβ42/40 values were also associated to lower rCMRGlu in bilateral hippocampus and anterior cingulate. Higher NfL levels were coupled with lower GMv in bilateral parietotemporal cortices.ConclusionResults suggest that pathogenic events in very early stages of the Alzheimer’s continuum are unexpectedly associated with higher GMv and rCMRGlu. The overlap of pTau and sTREM2 effects in GMv may point towards a TREM2‐mediated microglial reaction to initial tau pathology. Interactions between biomarkers and A/T groups will be presented.

Nanobiosensors for Non-Amyloidbeta-Tau Biomarkers as Advanced Reporters of Alzheimer's Disease.

Emerging nanomaterials providing benefits in sensitivity, specificity and cost-effectiveness are being widely investigated for biosensors in the application of Alzheimer’s disease (AD) diagnosis. Core biomarkers amyloid-beta (Aβ) and Tau have been considered as key neuropathological hallmarks of AD. However, they did not sufficiently reflect clinical severity and therapeutic response, proving the difficulty of the Aβ- and Tau-targeting therapies in clinical trials. In recent years, there has still been a shortage of sensors for non-Aβ-Tau pathophysiological biomarkers that serve as advanced reporters for the early diagnosis of AD, predict AD progression, and monitor the treatment response. Nanomaterial-based sensors measuring multiple non-Aβ-Tau biomarkers could improve the capacity of AD progression characterization and supervised treatment, facilitating the comprehensive management of AD. This is the first review to principally represent current nanobiosensors for non-Aβ-Tau biomarker and that strategically deliberates future perspectives on the merit of non-Aβ-Tau biomarkers, in combination with Aβ and Tau, for the accurate diagnosis and prognosis of AD.

Krebs von den Lungen-6 (KL-6) is a pathophysiological biomarker of early-stage acute hypersensitivity pneumonitis among pigeon fanciers.

Identifying early stages of hypersensitivity pneumonitis (HP) is hampered by variable presentation, heterogeneous or undetected causal antigens and lack of gold-standard biomarkers. Krebs von den Lungen (KL)-6 is pathophysiological biomarker of alveolar epithelial damage. Pigeon fanciers, susceptible to HP, provide a model to investigate early HP. To test the hypothesis that plasma concentrations of KL-6 are increased in early-stage acute HP. Clinical history, spirometry and blood samples were obtained from pigeon fanciers, 20 with intermittent acute symptoms indicative of developing HP, 27 with no symptoms and 10 healthy subjects with no avian exposure. Plasma KL-6 (units/mL) and pigeon antigen-specific IgG antibody were quantified by enzyme immunoassay. Blood lymphocytes were quantified by flow cytometry and antigen specificity by in vitro cytokine production. KL-6 was higher in fanciers than controls, median (IQR) 452 (244, 632) vs 274 (151, 377), P=.01. Although fanciers with symptoms had similar antigen exposure and lung function, they had higher KL-6 than those without, 632 (468, 1314) vs 320 (200, 480), P<.001. KL-6 correlated with IgG antibody titre in those with symptoms, r=.591, P=.006. High KL-6, irrespective of symptom category, was associated with higher antibody (P=.006) and lymphocyte proliferation (P=.041), and lower CD4+ T lymphocyte proportion (P=.032). Raised KL-6 is associated with acute symptoms of early-stage HP, and its correlation with antibody may support therapeutic strategies when HP is suspected. KL-6 may act as a mechanistic biomarker of early pathogenesis by linking lung pathophysiological changes with an endotype of immune hypersensitivity.

Increased peptidergic fibers as a potential cutaneous marker of pain in diabetic small fiber neuropathy.

Diabetic polyneuropathy (DPN) is a common complication of diabetes and is often associated with neuropathic pain. The mechanisms underlying development and maintenance of painful DPN are largely unknown, and quantification of intraepidermal nerve fiber density from skin biopsy, one of the neuropathological gold standard when diagnosing DPN, does not differentiate between patients with and without pain. Identification of possible pain pathophysiological biomarkers in patients with painful DPN may increase our knowledge of mechanisms behind neuropathic pain. Animal models of painful DPN have been shown to have an increased density of peptidergic nerve fibers (substance P and calcitonin gene-related peptide). In this study, we performed a detailed skin biopsy analysis in a well-characterized group of DPN patients with primarily small fiber involvement, with and without pain, and in healthy controls and test for correlation between skin biopsy findings and pain intensity and quantitative sensory testing. We found that although there was no difference in intraepidermal nerve fiber density using protein gene product 9.5 between patients with and without pain, patients with pain had increased density of dermal peptidergic fibers containing substance P and calcitonin gene-related peptide compared with patients with painless DPN and healthy controls. Peptidergic nerve fiber density correlated with pain ratings in patients with pain (R = 0.33; P = 0.019), but not with quantitative sensory testing results. In this article, we show, for the first time in humans, an increased density of dermal peptidergic fibers in painful DPN. These findings provide new insight in the pathophysiological mechanisms of pain in diabetes and open the research towards new therapeutic targets.

Different Clinical Contexts of Use of Blood Neurofilament Light Chain Protein in the Spectrum of Neurodegenerative Diseases.

One of the most pressing challenges in the clinical research of neurodegenerative diseases (NDDs) is the validation and standardization of pathophysiological biomarkers for different contexts of use (CoUs), such as early detection, diagnosis, prognosis, and prediction of treatment response. Neurofilament light chain (NFL) concentration is a particularly promising candidate, an indicator of axonal degeneration, which can be analyzed in peripheral blood with advanced ultrasensitive methods. Serum/plasma NFL concentration is closely correlated with cerebrospinal fluid NFL and directly reflects neurodegeneration within the central nervous system. Here, we provide an update on the feasible CoU of blood NFL in NDDs and translate recent findings to potentially valuable clinical practice applications. As NFL is not a disease-specific biomarker, however, blood NFL is an easily accessible biomarker with promising different clinical applications for several NDDs: (1) early detection and diagnosis (i.e., amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, atypical parkinsonisms, sporadic late-onset ataxias), (2) prognosis (Huntington's disease and Parkinson's disease), and (3) prediction of time to symptom onset (presymptomatic mutation carriers in genetic Alzheimer's disease and spinocerebellar ataxia type 3).

Fluid Biomarkers for Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neuropathological condition that has been described in individuals who have been exposed to repetitive head impacts, including concussions and subconcussive trauma. Currently, there is no fluid or imaging biomarker for diagnosing CTE during life. Based on retrospective clinical data, symptoms of CTE include changes in behavior, cognition, and mood, and may develop after a latency phase following the injuries. However, these symptoms are often nonspecific, making differential diagnosis based solely on clinical symptoms unreliable. Thus, objective biomarkers for CTE pathophysiology would be helpful in understanding the course of the disease as well as in the development of preventive and therapeutic measures. Herein, we review the literature regarding fluid biomarkers for repetitive concussive and subconcussive head trauma, postconcussive syndrome, as well as potential candidate biomarkers for CTE. We also discuss technical challenges with regard to the current fluid biomarkers and potential pathways to advance the most promising biomarker candidates into clinical routine.

Identification of a Rare PSEN1 Mutation (Thr119Ile) in Late-Onset Alzheimer's Disease With Early Presentation of Behavioral Disturbance.

Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. In this study, whole genome sequencing identifies one rare and likely pathogenic mutation in the presenilin 1 (PSEN1) gene (c.356C > T, p.T119I) associated with a frontal variant of AD. Affected individuals in the kindred developed late-onset cognitive decline accompanied with early presentation of psychiatric symptoms. Positive amyloid PiB PET tracing suggested presence of pathophysiological biomarker for AD. Whole genome sequencing analysis evaluated rare coding mutations in susceptible genes for various types of dementia and supported the role of PSEN1 as a causal gene. Identification of this T119I variant in PSEN1 might broaden the spectrum of genetic basis and clinical diversity of familial AD.

Diabetic Nephropathy: A Review of Pathophysiological mechanisms, Therapeutic interventions and Biomarkers

Diabetic Nephropathy: A Review of Pathophysiological mechanisms, Therapeutic interventions and Biomarkers

Refinement of metabolite detection in cystic fibrosis sputum reveals heme correlates with lung function decline.

The bacterial growth environment within cystic fibrosis (CF) sputum is complex, dynamic, and shaped by both host and microbial processes. Characterization of the chemical parameters within sputum that stimulate the in vivo growth of airway pathogens (e.g. Pseudomonas aeruginosa) and their associated virulence factors may lead to improved CF treatment strategies. Motivated by conflicting reports of the prevalence and abundance of P. aeruginosa-derived metabolites known as phenazines within CF airway secretions, we sought to quantify these metabolites in sputum using quadrupole time-of-flight mass spectrometry. In contrast to our previous work, all phenazines tested (pyocyanin (PYO), phenazine-1-carboxylic acid (PCA), phenazine-1-carboxamide, and 1-hydroxyphenazine) were below detection limits of the instrument (0.1 μM). Instead, we identified a late-eluting compound that shared retention time and absorbance characteristics with PCA, yet generated mass spectra and a fragmentation pattern consistent with ferriprotoporphyrin IX, otherwise known as heme B. These data suggested that UV-vis chromatographic peaks previously attributed to PCA and PYO in sputum were mis-assigned. Indeed, retrospective analysis of raw data from our prior study found that the heme B peak closely matched the peaks assigned to PCA, indicating that the previous study likely uncovered a positive correlation between pulmonary function (percent predicted forced expiratory volume in 1 second, or ppFEV1) and heme B, not PCA or any other phenazine. To independently test this observation, we performed a new tandem mass-spectrometry analysis of 71 additional samples provided by the Mountain West CF Consortium Sputum Biomarker study and revealed a positive correlation (ρ = −0.47, p<0.001) between sputum heme concentrations and ppFEV1. Given that hemoptysis is strongly associated with airway inflammation, pulmonary exacerbations and impaired lung function, these new data suggest that heme B may be a useful biomarker of CF pathophysiology.

Sensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review

ObjectiveSystematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations). MethodsPubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards. ResultsERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients. ConclusionsWhile there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms. SignificanceThe review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.

Self-Care and Pathophysiological Function in Patients with Chronic Heart Failure

BackgroundSelf-care is assumed to benefit physiological function associated with prognosis in patients with chronic HF, but studies examining these relations are lacking. This study aims to prospectively examine the association of self-reported HF self-care with HF-associated pathophysiological markers, including renal, hematological, and immune function.MethodPatients with chronic HF (n = 460, 66.2 ± 9.6 years, 75% men) completed questionnaires and provided blood samples at baseline and 12-month follow-up. Linear mixed models examined random intercept and fixed between- and within-subjects effects of global self-care and the individual self-care behaviors on log-transformed TNF-α, IL-6, and IL-10, the glomerular filtration rate of creatinine (GFRcreat), and hemoglobin (Hb), controlling for sociodemographic and clinical covariates.ResultsSelf-care was independently associated with lower GFRcreat levels (β = − .14, P = .023) and improvement in self-care with a reduction in GFRcreat (β = − .03, P = .042). Individual self-care behaviors were differentially associated with renal, inflammatory, and hematological markers. Regular exercise was associated with level differences in IL-6 (P < .001), and improvement in exercise was associated with increasing GFRcreat (P = .002) and increasing Hb (P = .010). Fluid restriction was associated with lower overall GFRcreat (P = .006), and improvement in fluid restriction was associated with decreasing GFRcreat (P = .014). Low-sodium intake was associated with lower levels of Hb (P = .027), lower TNF-alpha (P = .011), and lower IL-10 (P = .029). Higher levels of medication adherence were associated with reduced pro-inflammatory activation (P < .007).ConclusionOur findings suggest that better global self-care was associated with poorer renal function. Performing self-care behaviors such as regular exercise and medication adherence was associated with improved physiological functioning, while restriction of fluid and sodium, and the associated daily weight monitoring were associated with adverse levels of pathophysiological biomarkers.

Diabetic Nephropathy: A Review of Pathophysiological mechanisms, Therapeutic interventions and Biomarkers

Diabetic Nephropathy: A Review of Pathophysiological mechanisms, Therapeutic interventions and Biomarkers

Selective serotonin reuptake inhibitors and Alzheimer's disease.

Given the failure to develop disease-modifying therapies for Alzheimer’s disease (AD), strategies aiming at preventing or delaying the onset of the disease are being prioritized. While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on, a key determining factor may be the timing of depression onset in older adults. There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline. Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden, tau deposits and neurogenesis. In humans, studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors. Paroxetine, which has strong anticholinergic properties, was associated with increased mortality and mixed effects on amyloid and tau deposits in mice, as well as increased odds of developing AD in humans. Although most of the data regarding selective serotonin reuptake inhibitors is promising, findings should be interpreted cautiously because of notable methodological heterogeneity between studies. There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.

Biomarker-Based Signature of Alzheimer's Disease in Pre-MCI Individuals.

Alzheimer’s disease (AD) pathology begins decades before the onset of clinical symptoms. It is recognized as a clinicobiological entity, being detectable in vivo independently of the clinical stage by means of pathophysiological biomarkers. Accordingly, neuropathological studies that were carried out on healthy elderly subjects, with or without subjective experience of cognitive decline, reported evidence of AD pathology in a high proportion of cases. At present, mild cognitive impairment (MCI) represents the only clinically diagnosed pre-dementia stage. Several attempts have been carried out to detect AD as early as possible, when subtle cognitive alterations, still not fulfilling MCI criteria, appear. Importantly, pre-MCI individuals showing the positivity of pathophysiological AD biomarkers show a risk of progression similar to MCI patients. In view of successful treatment with disease modifying agents, in a clinical setting, a timely diagnosis is mandatory. In clinical routine, biomarkers assessment should be taken into consideration whenever a subject with subtle cognitive deficits (pre-MCI), who is aware of his/her decline, requests to know the cause of such disturbances. In this review, we report the available neuropsychological and biomarkers data that characterize the pre-MCI patients, thus proposing pre-MCI as the first clinical manifestation of AD.

Cooling Treatment Induces Changes in Aquaporins Expression as a Protective Mechanism for Exertional Heat Stroke

Xiuzhen Liu1, Bing Zhang1, Yuanlong Liu2, Liye Zou3. 1Tsinghua University, Beijing, China.2Western Michigan University, Michigan, MI.3The Chinese University of Hong Kong, Hong Kong, China. (Sponsor: Yuanlong Liu, FACSM) ABSTRACT: Cooling treatment is important to ensure the survival of patients with Exertional Heat Stroke(EHS); however, the protective mechanism of aquaporins in the cooling treatment of EHS is not very clear. Cooling treatment induces changes in renal aquaporins and regulates homeostasis of water metabolism,which mechanism involves aquaporin gene expression. PURPOSE: To determine the role of AQP2 mRNA expression and AQP2 protein expression in kidney in the homeostasis of water metabolism when EHS rats were treated with cooling. METHODS: In this study, there were 4 groups of male SD rats, including normal control group(NC,n=8), EHS onset group(EHSO,n=9), EHS rest group(EHSR n=9) and EHS cooling group(EHSC,n = 8). We established the rat model of EHS by exercising to exhaustion in the environment of 36°C temperature and 75% humidity until rectal temperature reaching about 42°C. The cooling treatment for EHS was to immerse in cold water for 5 minutes at 19°C. Blood and kidney were taken. Hct in serum was measured by automatic blood cell analyzer. PCR and WB were used to detect AQP2 mRNA expression and AQP2 protein expression respectively. Data were analyzed with Mann-Whitney U in nonparametric test. RESULTS: When EHS occurs, Hct increased significantly(EHSO: 0.43±0.29 vs. 0.40±0.04L/L,p<0.05). To fit for water metabolism, AQP2 mRNA expression and AQP2 protein expression were up-regulated significantly (EHSO vs. NC)(mRNA: 3.45±0.95 vs. 1.19±0.37, p<0.01; Protein: 2.76±1.01 vs. 1.00±0.00g/L, p<0.01). After cold water immersion, No significant change of Hct was found, AQP2 mRNA expression and AQP2 protein expression were significantly down-regulated(EHSC vs. EHSO)(mRNA: 1.66±0.33 vs. 3.45±0.95, p<0.01; Protein: 1.52±0.85 vs. 2.76±1.01g/L, p<0.05). CONCLUSIONS: Hct, AQP2 mRNA expression and AQP2 protein expression are pathophysiological biomarkers of EHS. Cooling treatment restrain water reabsorption by down-regulating the expression of AQP2 mRNA and AQP2 protein in kidney.

Inflammation and Peripheral Arterial Disease

Peripheral arterial disease (PAD) is an atherosclerotic disease closely associated with high morbidity and mortality in cardiac events. Inflammation is crucial in atherosclerosis both at triggering and in progression. Numerous inflammatory biomarkers (cytokines, matrix metalloproteinases (MMPs), selectin, intracellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM) C-reactive protein (CRP), fibrinogen) have been measured in atherosclerotic diseases including PAD. This paper summarizes the data on the inflammatory biomarkers for PAD pathophysiology and highlights the most useful markers in monitoring PAD outcomes.

Neural Correlates of Self-referential Processing and Their Clinical Implications in Social Anxiety Disorder.

Social anxiety disorder (SAD) is associated with aberrant self-referential processing (SRP) such as increased self-focused attention. Aberrant SRP is one of the core features of SAD and is also related to therapeutic interventions. Understanding of the underlying neural correlates of SRP in SAD is important for identifying specific brain regions as treatment targets. We reviewed functional magnetic resonance imaging (fMRI) studies to clarify the neural correlates of SRP and their clinical implications for SAD. Task-based and resting fMRI studies have reported the cortical midline structures including the default mode network, theory of mind-related regions of the temporo-parietal junction and temporal pole, and the insula as significant neural correlates of aberrant SRP in SAD patients. Also, these neural correlates are related to clinical improvement on pharmacological and cognitive-behavioral treatments. Furthermore, these could be candidates for the development of novel SAD treatments. This review supports that neural correlates of SAD may be significant biomarkers for future pathophysiology based treatment.

Prevalence and risk of progression of preclinical Alzheimer\u2019s disease stages: a systematic review and meta-analysis

BackgroundAlzheimer’s disease (AD) pathology begins several years before the clinical onset. The long preclinical phase is composed of three stages according to the 2011National Institute on Aging and Alzheimer’s Association (NIA-AA) criteria, followed by mild cognitive impairment (MCI), a featured clinical entity defined as “due to AD”, or “prodromal AD”, when pathophysiological biomarkers (i.e., cerebrospinal fluid or positron emission tomography with amyloid tracer) are positive. In the clinical setting, there is a clear need to detect the earliest symptoms not yet fulfilling MCI criteria, in order to proceed to biomarker assessment for diagnostic definition, thus offering treatment with disease-modifying drugs to patients as early as possible. According to the available evidence, we thus estimated the prevalence and risk of progression at each preclinical AD stage, with special interest in Stage 3.MethodsCross-sectional and longitudinal studies published from April 2008 to May 2018 were obtained through MEDLINE-PubMed, screened, and systematically reviewed by four independent reviewers. Data from included studies were meta-analyzed using random-effects models. Heterogeneity was assessed by I2 statistics.ResultsEstimated overall prevalence of preclinical AD was 22% (95% CI = 18–26%). Rate of biomarker positivity overlapped in cognitively normal individuals and people with subjective cognitive decline. The risk of progression increases across preclinical AD stages, with individuals classified as NIA-AA Stage 3 showing the highest risk (73%, 95% CI = 40–92%) compared to those in Stage 2 (38%, 95% CI = 21–59%) and Stage 1 (20%, 95% CI = 10–34%).ConclusionAvailable data consistently show that risk of progression increases across the preclinical AD stages, where Stage 3 shows a risk of progression comparable to MCI due to AD. Accordingly, an effort should be made to also operationalize the diagnostic work-up in subjects with subtle cognitive deficits not yet fulfilling MCI criteria. The possibility to define, in the clinical routine, a patient as “pre-MCI due to AD” could offer these subjects the opportunity to use disease-modifying drugs at best.

Antemortem CSF Aβ42/Aβ40 ratio predicts Alzheimer's disease pathology better than Aβ42 in rapidly progressive dementias.

ObjectiveDespite the critical importance of pathologically confirmed samples for biomarker validation, only a few studies have correlated CSF Aβ42 values in vivo with postmortem Alzheimer's disease (AD) pathology, while none evaluated the CSF Aβ42/Aβ40 ratio. We compared CSF Aβ42 and Aβ42/Aβ40 ratio as biomarkers predicting AD neuropathological changes in patients with a short interval between lumbar puncture and death.MethodsWe measured CSF Aβ40 and Aβ42 and assessed AD pathology in 211 subjects with rapidly progressive dementia (RPD) and a definite postmortem diagnosis of Creutzfeldt‐Jakob disease (n = 159), AD (n = 12), dementia with Lewy bodies (DLB, n = 4), AD/DLB mixed pathologies (n = 5), and various other pathologies (n = 31).ResultsThe score reflecting the severity of Aβ pathology showed a better correlation with ln(Aβ42/Aβ40) (R 2 = 0.506, β = −0.713, P < 0.001) than with ln(Aβ42) (R 2 = 0.206, β = −0.458, P < 0.001), which was confirmed after adjusting for covariates. Aβ42/Aβ40 ratio showed significantly higher accuracy than Aβ42 in the distinction between cases with or without AD pathology (AUC 0.818 ± 0.028 vs. 0.643 ± 0.039), especially in patients with Aβ42 levels ≤495 pg/mL (AUC 0.888 ± 0.032 vs. 0.518 ± 0.064). Using a cut‐off value of 0.810, the analysis of Aβ42/Aβ40 ratio yielded 87.0% sensitivity, 88.2% specificity in the distinction between cases with an intermediate‐high level of AD pathology and those with low level or no AD pathology.InterpretationThe present data support the use of CSF Aβ42/Aβ40 ratio as a biomarker of AD pathophysiology and noninvasive screener for Aβ pathology burden, and its introduction in the research diagnostic criteria for AD.

Sickle Cell Subjects Have a Stronger and Faster Neurally Mediated Vasoconstriction Response to Cold Pain That Correlates with Anxiety Scores

Introduction: Vaso-occlusive pain crisis (VOC) is a significant contributor to the morbidity of Sickle Cell Disease (SCD) and cold exposure has long been associated with increased frequency and intensity of VOC. However, the mechanism by which cold exposure causes the transition from steady state to vaso-occlusion has not been well elucidated. Decreased regional blood flow results in red blood cells spending a longer period of time in the deoxygenated state in the capillaries, increasing the likelihood of hemoglobin S polymerization in the microvasculature and subsequent vaso-occlusion. Regional blood flow is primarily regulated by the autonomic nervous system (ANS) and recent literature shows evidence of cardiovascular autonomic dysfunction in SCD and of its role as a disease modulating factor. We hypothesized that cold exposure triggers a central autonomic response leading to vasoconstriction in the microvasculature and that SCD subjects will have a stronger response when compared to controls.Methods: 17 SCD and 16 control (healthy or sickle trait) subjects aged 13 to 39 years were exposed to thermal stimuli via a computer-controlled thermode (TSA-II) placed on the thenar eminence of the right hand. Predetermined individual threshold temperatures for heat detection, cold detection, heat pain and cold pain were applied, and changes in the microvascular blood flow (MBF) were measured at a sub-second sampling rate on the contralateral thumb using photo-plethysmography (PPG). Mean MBF was derived from the amplitude of the PPG signal, a greater decrease in mean MBF from baseline signifies stronger vasoconstriction. The vasoconstriction response within the PPG signal, and the time (in sec) to vasoconstriction were determined from the cross-correlation function of the pain stimulus signal and the vascular response.The R-to-R interval (RRI) derived from electrocardiogram was used to evaluate cardiac autonomic balance. Standard deviation of RRI represents total heart rate variability, Spectral indices of the RRI represent parasympathetic activity (high frequency power; HFP) and sympatho-vagal balance (Low to high Ratio; LHR = low frequency power(LFP)/HFP).Prior to the study, subjects were administered measures of current anxiety and general level of anxiety (STAI Y1 and Y2, respectively) as well as a measure of pain related anxiety (PASS).Results: All the thermal stimulation tasks caused a significant decrease in MBF from baseline (p values for cold detection, heat detection, heat pain and cold pain=0.027, <0.001, <0.001, <0.001 respectively), with cold pain task causing the greatest decrease in MBF. Compared to controls, SCD subjects had significantly higher pain anxiety (PASS) score (p=0.013). After controlling for PASS scores, SCD subjects still had significantly stronger vasoconstriction responses compared to controls (p =0.029)(Figure 1). The time to vasoconstriction was significantly shorter in SCD subjects (p=0.032), indicating a quicker vasoconstriction response (Figure 2). Individuals with greater anxiety state (STAI Y1) scores also showed a shorter time to vasoconstriction (p=0.034).At baseline and across all tasks, SCD subjects showed a significantly lower heart rate variability suggestive of autonomic dysfunction (standard deviation of RRI- 41.2 Vs 50 msec, p=0.007). Both cold and heat pain caused a significant increase in the mean LFP and LHR from baseline with no significant differences in HFP thus suggesting an overall increase in the cardiac sympathetic output with thermal pain.Conclusion: Using MBF as an objective marker of pain responses, cold pain causes significant decrease in MBF followed by other thermal stimuli. The rapid vasoconstriction responses to the thermal stimuli occurred in the contralateral hand, suggesting a neural mechanism. SCD subjects demonstrated an augmented peripheral vasoconstriction response with evidence of cardiac autonomic imbalance. Our findings imply that global autonomic mediated vasoconstriction and subsequent vaso-occlusion is the likely mechanistic link between cold exposure and VOC in SCD. Thus, vascular autonomic reactivity is a biomarker of basic SCD pathophysiology and serves as a potential target for prevention and treatment of pain in SCD. DisclosuresCoates:ApoPharma: Consultancy, Honoraria; Sangamo: Consultancy, Honoraria; Vifor Pharma: Consultancy; Celgene Corp.: Consultancy.