Biomarkers Of Neurodegeneration Research Articles

Alzheimer's Disease and Cognitive Decline in Patients with Cardiovascular Diseases Along the Heart-Brain Axis.

We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-β42/40 (Aβ42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. Among patients, Aβ42/40 was not associated with cognitive performance at baseline. However, lower Aβ42/40 was associated with steeper decline in global cognition (β±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (-0.14±0.04) and memory (-0.31±0.09) and with steeper decline in global cognition (-0.07±0.02), memory (-0.09±0.04), attention (-0.05±0.02), and language (-0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (-0.22±0.05), memory (-0.43±0.10), attention (-0.14±0.06), language (-0.15±0.05), and executive functioning (-0.15±0.05) and steeper decline in global cognition (-0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (-0.16±0.04), memory (-0.28±0.09), attention (-0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases.

Disentangling sex-dependent effects of APOE on diverse trajectories of cognitive decline in Alzheimer's disease

Current diagnostic systems for Alzheimer's disease (AD) rely upon clinical signs and symptoms, despite the fact that the multiplicity of clinical symptoms renders various neuropsychological assessments inadequate to reflect the underlying pathophysiological mechanisms. Since putative neuroimaging biomarkers play a crucial role in understanding the etiology of AD, we sought to stratify the diverse relationships between AD biomarkers and cognitive decline in the aging population and uncover risk factors contributing to the diversities in AD. To do so, we capitalized on a large amount of neuroimaging data from the ADNI study to examine the inflection points along the dynamic relationship between cognitive decline trajectories and whole-brain neuroimaging biomarkers, using a state-of-the-art statistical model of change point detection. Our findings indicated that the temporal relationship between AD biomarkers and cognitive decline may differ depending on the synergistic effect of genetic risk and biological sex. Specifically, tauopathy-PET biomarkers exhibit a more dynamic and age-dependent association with Mini-Mental State Examination scores (p<0.05), with inflection points at 72, 78, and 83 years old, compared with amyloid-PET and neurodegeneration (cortical thickness from MRI) biomarkers. In the landscape of health disparities in AD, our analysis indicated that biological sex moderates the rate of cognitive decline associated with APOE4 genotype. Meanwhile, we found that higher education levels may moderate the effect of APOE4, acting as a marker of cognitive reserve.

Sociodemographic patterns in biomarkers of aging in the Add Health cohort

ABSTRACT Biomarkers in population health research serve as indicators of incremental physiological deterioration and contribute to our understanding of mechanisms through which social disparities in health unfold over time. Yet, few population-based studies incorporate biomarkers of aging in early midlife, when disease risks may emerge and progress across the life course. We describe the distributions of several biomarkers of inflammation and neurodegeneration and their variation by sociodemographic characteristics using blood samples collected during Wave V of the National Longitudinal Study of Adolescent to Adult Health (ages 33–44 years). Higher mean levels of inflammatory and neurodegenerative biomarkers were associated with greater socioeconomic disadvantage. For example, the neurodegenerative markers, Neurofilament Light Chain and total Tau proteins were higher among lower income groups, though the relationship was not statistically significant. Similarly, proinflammatory marker Tumor Necrosis Factor-α (TNF-α) levels were higher among those with lower education. Significant differences in the mean levels of other proinflammatory markers were observed by race/ethnicity, sex, census region, BMI, and smoking status. These descriptive findings indicate that disparities in biomarkers associated with aging are already evident among young adults in their 30s and attention should focus on age-related disease risk earlier in the life course.

Neurodegeneration Biomarkers in Adult Spinal Muscular Atrophy (SMA) Patients Treated with Nusinersen.

The objective of this study is to evaluate biomarkers for neurodegenerative disorders in adult SMA patients and their potential for monitoring the response to nusinersen. Biomarkers for neurodegenerative disorders were assessed in plasma and CSF samples obtained from a total of 30 healthy older adult controls and 31 patients with adult SMA type 2 and 3. The samples were collected before and during nusinersen treatment at various time points, approximately at 2, 6, 10, and 22 months. Using ELISA technology, the levels of total tau, pNF-H, NF-L, sAPPβ, Aβ40, Aβ42, and YKL-40 were evaluated in CSF samples. Additionally, plasma samples were used to measure NF-L and total tau levels using SIMOA technology. SMA patients showed improvements in clinical outcomes after nusinersen treatment, which were statistically significant only in walkers, in RULM (p = 0.04) and HFMSE (p = 0.05) at 24 months. A reduction in sAPPβ levels was found after nusinersen treatment, but these levels did not correlate with clinical outcomes. Other neurodegeneration biomarkers (NF-L, pNF-H, total tau, YKL-40, Aβ40, and Aβ42) were not found consistently changed with nusinersen treatment. The slow progression rate and mild treatment response of adult SMA types 2 and 3 may not lead to detectable changes in common markers of axonal degradation, inflammation, or neurodegeneration, since it does not involve large pools of damaged neurons as observed in pediatric forms. However, changes in biomarkers associated with the APP processing pathway might be linked to treatment administration. Further studies are warranted to better understand these findings.

Cellular Organelle-Related Transcriptomic Profile Abnormalities in Neuronopathic Types of Mucopolysaccharidosis: A Comparison with Other Neurodegenerative Diseases.

Mucopolysaccharidoses (MPS) are a group of diseases caused by mutations in genes encoding lysosomal enzymes that catalyze reactions of glycosaminoglycan (GAG) degradation. As a result, GAGs accumulate in lysosomes, impairing the proper functioning of entire cells and tissues. There are 14 types/subtypes of MPS, which are differentiated by the kind(s) of accumulated GAG(s) and the type of a non-functional lysosomal enzyme. Some of these types (severe forms of MPS types I and II, MPS III, and MPS VII) are characterized by extensive central nervous system disorders. The aim of this work was to identify, using transcriptomic methods, organelle-related genes whose expression levels are changed in neuronopathic types of MPS compared to healthy cells while remaining unchanged in non-neuronopathic types of MPS. The study was conducted with fibroblast lines derived from patients with neuronopathic and non-neuronopathic types of MPS and control (healthy) fibroblasts. Transcriptomic analysis has identified genes related to cellular organelles whose expression is altered. Then, using fluorescence and electron microscopy, we assessed the morphology of selected structures. Our analyses indicated that the genes whose expression is affected in neuronopathic MPS are often associated with the structures or functions of the cell nucleus, endoplasmic reticulum, or Golgi apparatus. Electron microscopic studies confirmed disruptions in the structures of these organelles. Special attention was paid to up-regulated genes, such as PDIA3 and MFGE8, and down-regulated genes, such as ARL6IP6, ABHD5, PDE4DIP, YIPF5, and CLDN11. Of particular interest is also the GM130 (GOLGA2) gene, which encodes golgin A2, which revealed an increased expression in neuronopathic MPS types. We propose to consider the levels of mRNAs of these genes as candidates for biomarkers of neurodegeneration in MPS. These genes may also become potential targets for therapies under development for neurological disorders associated with MPS and candidates for markers of the effectiveness of these therapies. Although fibroblasts rather than nerve cells were used in this study, it is worth noting that potential genetic markers characteristic solely of neurons would be impractical in testing patients, contrary to somatic cells that can be relatively easily obtained from assessed persons.

The Contribution of Functional Near-Infrared Spectroscopy (fNIRS) to the Study of Neurodegenerative Disorders: A Narrative Review.

Functional near-infrared spectroscopy (fNIRS) is an innovative neuroimaging method that offers several advantages over other commonly used modalities. This narrative review investigated the potential contribution of this method to the study of neurodegenerative disorders. Thirty-four studies involving patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), frontotemporal dementia (FTD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) and healthy controls were reviewed. Overall, it was revealed that the prefrontal cortex of individuals with MCI may engage compensatory mechanisms to support declining brain functions. A rightward shift was suggested to compensate for the loss of the left prefrontal capacity in the course of cognitive decline. In parallel, some studies reported the failure of compensatory mechanisms in MCI and early AD; this lack of appropriate hemodynamic responses may serve as an early biomarker of neurodegeneration. One article assessing FTD demonstrated a heterogeneous cortical activation pattern compared to AD, indicating that fNIRS may contribute to the challenging distinction of these conditions. Regarding PD, there was evidence that cognitive resources (especially executive function) were recruited to compensate for locomotor impairments. As for ALS, fNIRS data support the involvement of extra-motor networks in ALS, even in the absence of measurable cognitive impairment.

Highly sensitive detection of the neurodegenerative biomarker Tau by using the concentration effect of the pyro-electrohydrodynamic jetting

It is largely documented that neurodegenerative diseases can be effectively treated only if early diagnosed. In this context, the structural changes of some biomolecules such as Tau, seem to play a key role in neurodegeneration mechanism becoming eligible targets for an early diagnosis. Post-translational modifications are responsible to drive the Tau protein towards a transition phase from a native disorder conformation into a preaggregation state, which then straight recruits the final fibrillization process. Here, we show for the first time the detection of pre-aggregated Tau in artificial urine at femto-molar level, through the concentration effect of the pyro-electrohydrodynamic jet (p-jet) technique. An excellent linear calibration curve is demonstrated at the femto-molar level with a limit of detection (LOD) of 130 fM. Moreover, for the first time we show here the structure stability of the protein after p-jet application through a deep spectroscopic investigation. Thanks to the small volumes required and the relatively compact and cost-effective characteristics, this technique represents an innovative breakthrough in monitoring the early stage associated to neurodegeneration syndromes in different scenarios of point of care (POC) and such as for example in long-term human space exploration missions.

Abstract P335: Predictors of Cognitive Resilience in Those With and Without High White Matter Hyperintensity Burden: A Post-Hoc Analysis of Systolic Blood Pressure Intervention Trial Memory &amp; Cognition in Decreased Hypertension (SPRINT MIND)

Introduction: Little is known if predictors of cognitive resilience (CR) differ between adults with or without large white matter hyperintensity burdens. In the current analysis of cross-sectional baseline SPRINT MIND data, we a) determined bivariate associations of sociodemographic, vascular-metabolic, and neurodegenerative biomarkers with CR and b) delineated variables that maximized predictive fit of CR among participants with the highest and lowest white matter hyperintensity volumes (WMHv). Methods: We included SPRINT MIND participants with baseline available plasma biomarker concentrations &amp; Montreal Cognitive Assessment (MoCA) scores. We then created two analytic samples: those with the highest tertile of WMHv (N = 186) and those with the lowest tertile (N=134). We defined CR two ways: as a MoCA score a) &gt;25 or b) &gt;22. We determined the association between sociodemographic, vascular-metabolic, and serum neurodegenerative variables, as well as WMHv with CR using logistic regressions to generate unadjusted odds ratios (OR) &amp; 95% confidence intervals (CI). Multivariate lasso regressions were then used to determine which variables optimized predictive fit of CR, and R 2 values were calculated. Results: In participants with the lowest tertile of WMHv , the median age was 66 years, 45.5% were female and 63% were Non-Hispanic white. In participants with the highest tertile of WMHv, the median age was 73 years, 45.7% were female and 66% were Non-Hispanic white. . CR defined as MoCA scores &gt; 25 &amp; &gt;22 was present in 37.3% and 64.9% in those with the lowest tertile of WMHv and 28.5% &amp; 56.5% in those with the highest tertile, respectively. Higher education and self-reported race generally had the strongest ORs in all analyses (Table 1 excerpt). Only age and education level were included in all four predictive models after lasso shrinkage. The R 2 values for all lasso regressions were &lt;0.25. Conclusion: Education level may be associated with CR irrespective of WMHv. However, a large variation of CR remains unaccounted for.

NeuroGenetics of Alzheimer’s Disease: Crosslinking SIRT1 Gene in the Genetic Nexus of Type II Diabetes and Dementia

Background: Background: Type II Diabetes Mellitus (DM) is a chronic condition that not only affects organ function but also contributes to the development of dementia. SIRT1, a gene implicated in the pathophysiology of Type II DM, has been associated with neurodegenerative processes and cognitive decline. Objective: This study aimed to evaluate the expression of the SIRT1 gene in patients with Type II DM and dementia, elucidating its potential role as a biomarker for cognitive impairment and neurodegeneration in this population. Methods: A cohort of 88 diabetic patients with dementia and 12 healthy controls were recruited, and EDTA blood samples were collected. SIRT1 serum levels were quantified using chemiluminescent immunoassay (CLIA). Genomic DNA was extracted and assessed for quality before bisulfite DNA modification and Methylation Specific PCR (MSP) to profile SIRT1 gene methylation. Real-time PCR was conducted to determine SIRT1 gene expression levels. Cognitive function was assessed using Mini-Mental State Examination (MMSE) scores. Results: The average SIRT1 serum levels in diabetic dementia patients (4.98 ± 1.38 µg/mL) were significantly lower than those in healthy controls (14.21 ± 3.64 µg/mL). MMSE scores mirrored this trend, with patients scoring 12.26 ± 4.56, indicating more considerable cognitive impairment compared to healthy controls' score of 24.1 ± 3.12. SIRT1 gene expression was found to be underexpressed with a fold decrease of approximately 4.1 in dementia cases. Conclusion: The study's findings highlight the downregulated expression of the SIRT1 gene in diabetic patients with dementia, confirming its potential as a biomarker for cognitive decline. Identifying SIRT1 alterations may provide a non-invasive approach for early diagnosis and management of dementia in the diabetic population.

Association between Mediterranean-dietary approaches to stop hypertension intervention for neurodegenerative delay diet and biomarkers of oxidative stress, metabolic factors, disease severity, and odds of disease in rheumatoid arthritis patients.

This research aimed to examine the association between the following Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) dietary pattern and oxidative stress indicators, metabolic factors, disease activity, and the odds of disease in patients with rheumatoid arthritis (RA). In this cross-sectional study, we included 101 patients with RA and 101 healthy individuals. The MIND diet score was measured using a semi-quantitative Food Frequency Questionnaire (FFQ) with 147 food items. Total capacity antioxidant (TCA), superoxide dismutase (SOD), glutathione peroxidase (GPX), and malondialdehyde (MDA) serum concentrations were evaluated by ELISA, and the disease severity was measured regarding the disease activity score 28 (DAS-28) criteria. The average score of the MIND diet was substantially lower in the RA subjects than in the healthy people (p < .001). Individuals with a higher MIND diet score had lower odds of RA than those with a low score (p < .001). There was no remarkable link between the MIND diet and oxidative stress factors (p > .05). A reverse association was found between the MIND diet score and disease activity (p < .05). The MIND diet was significantly and negatively correlated with triglycerides, low-density lipoprotein cholesterol, total cholesterol, fasting blood glucose, and hemoglobin A1C. There was a positive association between the diet and high-density lipoprotein cholesterol. The findings indicate that following the MIND diet may decrease disease activity and the odds of RA. Also, high adherence to the MIND diet may improve the lipid profile and blood glucose status in RA patients.

Biomarkers of neurodegeneration in isolated and antidepressant-related rapid eye movement sleep behavior disorder.

This study compared the features of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and antidepressant-related REM sleep behaviour disorder (RBD) with the aim of highlighting markers that might distinguish the two entities. The observational cohort study included RBD patients with and without antidepressant use (antiD+ and antiD- patients, respectively), without cognitive impairment and parkinsonism. Clinical features of RBD, subtle motor and non-motor symptoms of parkinsonism, sleep architecture, REM atonia index, dopamine transporter-single photon emission computed tomography (DAT-SPECT) and skin biopsies for the intraneuronal alpha-synuclein (α-syn), were evaluated in the baseline work-up. Thirty-nine patients, 10 antiD+ and 29 antiD-, were included. AntiD+ patients (more frequently female) reported more psychiatric symptoms, less violent dream enactment, and less frequent hyposmia. Dermal α-syn was detected in 93.1% of antiD- versus 30% of antiD+ patients (p = 0.00024). No differences appeared in other motor and non-motor symptoms, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score, DAT-SPECT, or polysomnographic features. Patients with antidepressant-related RBD have clinical and neuropathological features suggesting a lower risk of evolution than those with iRBD.

Protocol for a randomized, placebo-controlled, double-blind phase IIa study of the safety, tolerability, and symptomatic efficacy of the ROCK-inhibitor Fasudil in patients with Parkinson's disease (ROCK-PD).

The Rho-kinase (ROCK) inhibitor Fasudil has shown symptomatic and disease-modifying effects in Parkinson's disease (PD) models in vitro and in vivo. In Japan, Fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995 and shows a favourable safety profile. To investigate the safety, tolerability, and symptomatic efficacy of ROCK-inhibitor Fasudil in comparison to placebo in a randomized, national, multicenter, double-blind phase IIa study in patients with PD. We plan to include 75 patients with at least 'probable' PD (MDS criteria), Hoehn and Yahr stages 1-3, and age 30-80 years in 13 German study sites. Patients must be non-fluctuating and their response to PD medication must have been stable for 6 weeks. Patients will be randomly allocated to treatment with the oral investigational medicinal product (IMP) containing either Fasudil in two dosages, or placebo, for a total of 22 days. As primary analysis, non-inferiority of low/high dose of Fasudil on the combined endpoint consisting of occurrence of intolerance and/or treatment-related serious adverse events (SAEs) over 22 days will be assessed in a sequential order, starting with the lower dose. Secondary endpoints will include tolerability alone over 22 days and occurrence of treatment-related SAEs (SARs) over 22 and 50 days and will be compared on group level. Additional secondary endpoints include efficacy on motor and non-motor symptoms, measured on established scales, and will be assessed at several timepoints. Biomaterial will be collected to determine pharmacokinetics of Fasudil and its active metabolite, and to evaluate biomarkers of neurodegeneration. After positive evaluation by the competent authority and the ethics committee, patient recruitment started in the 3rd quarter of 2023. ROCK-PD is registered with Eudra-CT (2021-003879-34) and clinicaltrials.gov (NCT05931575). Results of this trial can pave way for conducting extended-duration studies assessing both symptomatic efficacy and disease-modifying properties of Fasudil.

Which Are the Most Reliable Sleep Parameters that Predict Cognitive Decline and Alzheimer's Disease?

Sleep disorders can represent an independent risk factor for cognitive decline and Alzheimer's disease (AD). It remains to be clarified if specific sleep parameters could be considered biomarkers of AD-related neurodegeneration. Several studies solely investigated the results of cross-sectional research, without providing conclusive evidence. Few longitudinal studies showed some inconsistencies in macrostructural and microstructural sleep findings. Methodological heterogeneity among studies can explain the discrepancies in the results. Moreover, the polysomnographic findings are usually related to only one-night recording. The combination of actigraphic recordings with sleep EEG monitoring for some consecutive days should be considered in future research.

Effects of obstructive sleep apnea treatment on neurodegenerative biomarker neurofilament light chain and cognitive performance.

Obstructive sleep apnea is associated with cognitive impairment and increased risk for neurodegenerative diseases. Obstructive sleep apnea treatment with positive airway pressure therapy helps to improve cognitive symptoms and reduces long-term dementia risk. To test whether these treatment effects are due to a reduction in neuronal damage, we examined longitudinal changes in the neurodegenerative serum neurofilament light chain and cognitive performance of patients with obstructive sleep apnea. In this study, 17 patients with obstructive sleep apnea completed baseline and follow-up (9 month after starting PAP treatment) investigation of sleep, daytime symptoms, cognitive testing and serum neurofilament light chain measurements. Depending on treatment adherence and efficacy, participants were assigned either to the effective treatment (n = 10) or non-effective treatment group (n = 7). As results at baseline lower mean oxygen saturation during sleep was associated with higher serum neurofilament light chain. Patients in the non-effective treatment group showed a significant increase of age-adjusted percentile of serum neurofilament light chain levels at follow-up, whereas serum neurofilament light chain values remained constant in the effective treatment group. At a functional level, effective treatment leads to an improvement in processing speed, which was not the case in the non-effective treatment group. Longitudinal changes of age-adjusted serum neurofilament light chain levels were associated with changes in cognitive performance. To conclude, this longitudinal observational study showed that effective obstructive sleep apnea treatment positively affects the amount of neuronal damage as well as working memory performance. As cognitive symptoms might not only be attributed to obstructive sleep apnea-related sleep deficiency, but also neurodegeneration, our results underline the importance of treatment adherence and efficacy for the prevention of neuronal damage and cognitive consequences.

ATH-1105, a small-molecule positive modulator of the neurotrophic HGF system, is neuroprotective, preserves neuromotor function, and extends survival in preclinical models of ALS.

Amyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder, primarily affects the motor neurons of the brain and spinal cord. Like other neurodegenerative conditions, ongoing pathological processes such as increased inflammation, excitotoxicity, and protein accumulation contribute to neuronal death. Hepatocyte growth factor (HGF) signaling through the MET receptor promotes pro-survival, anti-apoptotic, and anti-inflammatory effects in multiple cell types, including the neurons and support cells of the nervous system. This pleiotropic system is therefore a potential therapeutic target for treatment of neurodegenerative disorders such as ALS. Here, we test the effects of ATH-1105, a small-molecule positive modulator of the HGF signaling system, in preclinical models of ALS. In vitro, the impact of ATH-1105 on HGF-mediated signaling was assessed via phosphorylation assays for MET, extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Neuroprotective effects of ATH-1105 were evaluated in rat primary neuron models including spinal motor neurons, motor neuron-astrocyte cocultures, and motor neuron-human muscle cocultures. The anti-inflammatory effects of ATH-1105 were evaluated in microglia- and macrophage-like cell systems exposed to lipopolysaccharide (LPS). In vivo, the impact of daily oral treatment with ATH-1105 was evaluated in Prp-TDP43A315T hemizygous transgenic ALS mice. In vitro, ATH-1105 augmented phosphorylation of MET, ERK, and AKT. ATH-1105 attenuated glutamate-mediated excitotoxicity in primary motor neurons and motor neuron- astrocyte cocultures, and had protective effects on motor neurons and neuromuscular junctions in motor neuron-muscle cocultures. ATH-1105 mitigated LPS-induced inflammation in microglia- and macrophage-like cell systems. In vivo, ATH-1105 treatment resulted in improved motor and nerve function, sciatic nerve axon and myelin integrity, and survival in ALS mice. Treatment with ATH-1105 also led to reductions in levels of plasma biomarkers of inflammation and neurodegeneration, along with decreased pathological protein accumulation (phospho-TDP-43) in the sciatic nerve. Additionally, both early intervention (treatment initiation at 1 month of age) and delayed intervention (treatment initiation at 2 months of age) with ATH-1105 produced benefits in this preclinical model of ALS. The consistent neuroprotective and anti-inflammatory effects demonstrated by ATH-1105 preclinically provide a compelling rationale for therapeutic interventions that leverage the positive modulation of the HGF pathway as a treatment for ALS.

Prior infections are associated with smaller hippocampal volume in older women.

Accumulating evidence suggests that infections may play a major role in Alzheimer's disease (AD), however, mechanism is unclear, as multiple pathways may be involved. One possibility is that infections could contribute to neurodegeneration directly by promoting neuronal death. We explored relationships between history of infections and brain hippocampal volume (HV), a major biomarker of neurodegeneration, in a subsample of the UK Biobank (UKB) participants. Infectious disease diagnoses were based on ICD10 codes. The left/right HV was measured by the magnetic resonance imaging (MRI) in cubic millimeters and normalized. Analysis of variance (ANOVA), Welch test, and regression were used to examine statistical significance. We found that HV was significantly lower in women aged 60-75, as well as 65-80, years, with history of infections, compared to same age women without such history. The effect size increased with age faster for the left vs. right HV. Results for males didn't reach statistical significance. Results of our study support a major role of adult infections in neurodegeneration in women. The detrimental effect of infections on HV became stronger with age, in line with declining resilience and increasing brain vulnerability to stressors due to aging. The faster increase in the effect size observed for the left vs. right HV may indicate that female verbal memory degrades faster over time than visual-spatial memory. The observed sex difference may reflect a higher vulnerability of female brain to infection-related factors, which in turn may contribute to a higher risk of AD in women compared to men.

Association of cigarette smoking with cerebrospinal fluid biomarkers of insulin sensitivity and neurodegeneration.

Cigarette smoking increases both the risk for insulin resistance and amyloid-β (Aβ) aggregation, and impaired brain insulin/insulin-like growth factor 1 (IGF1) signaling might increase risk factors for Alzheimer's disease (AD). We aimed to investigate the association among cerebrospinal fluid (CSF) insulin sensitivity/IGF1, glucose/lactate, and Aβ42 and further explore whether insulin sensitivity contributed to the risk for AD in active smokers. In this cross-sectional study, levels of insulin, IGF1, and lactate/glucose of 75 active smokers and 78 nonsmokers in CSF were measured. Three polymorphisms regulating IGF1 were genotyped. Analysis of variance was used to compare differences of variables between groups. Partial correlation was performed to test the relationship between CSF biomarkers and smoking status. General linear models were applied to test the interaction of the effect of single nucleotide polymorphisms and cigarette smoking on CSF IGF1 levels. In the CSF from active smokers, IGF1 and lactate levels were significantly lower (p=.016 and p=.010, respectively), whereas Aβ42 (derived from our earlier research) and insulin levels were significantly higher (p<.001 and p=.022, respectively) as compared to the CSF from nonsmokers. The AG+GG genotype of rs6218 in active smokers had a significant effect on lower CSF IGF1 levels (p=.004) and lower CSF insulin levels in nonsmokers (p=.016). Cigarette smoking as the "at-risk" factor for AD might be due to lower cerebral insulin sensitivity in CSF, and the subjects with rs6218G allele seem to be more susceptible to the neurodegenerative risks for cigarette smoking.

Abstract TP29: Neurodegenerative Plasma Biomarker Associations With Cognitive Resilience in Adults With High White Matter Hyperintensity Volume: A Post-Hoc Analysis of Systolic Blood Pressure Intervention Trial Memory &amp; Cognition in Decreased Hypertension (SPRINT MIND)

Introduction: Although high cerebral white matter hyperintensity volume (WMHv) is associated with cognitive decline, many adults with high WMHv show no cognitive deficits. Neurodegenerative plasma biomarkers may be associated with cognitive decline via vascular processes causing higher WMHv such as cerebral amyloid angiopathy &amp; inflammatory small vessel disease. We determined associations of plasma amyloid β 42 (AB42), amyloid β 40 (AB40), AB42/AB40, total tau, &amp; neurofilament light chain (NfL) with cognitive resilience (CR) in adults with high WMHv using baseline MRIs &amp; measurements from SPRINT MIND. Methods: This study included baseline data from 186 SPRINT MIND participants who were in the highest WMHv tertile &amp; had available plasma biomarker concentrations &amp; Montreal Cognitive Assessment (MoCA) scores. We defined CR two ways: A) MoCA score &gt;25 or B) MoCA score &gt;22. We determined univariate &amp; adjusted odds ratios (OR) &amp; 90% confidence intervals (CI) for each aforementioned plasma biomarker with CR. Confounders in adjusted models were: age, sex, race-ethnicity (Non-Hispanic white, Non-Hispanic Black, Hispanic, or other) education (no college education, college education, or post-graduate education), smoking history (never smoker, prior smoker, or current smoker) physical activity (0, 1-4, or ≥ 5 days of vigorous physical activity), diabetes, having insurance, &amp; average systolic blood pressure. Residual confounding and effect modification by WMHv were tested in sensitivity analyses. Results: In our sample, the mean age was 72.6 years, 45.7% were female &amp; 66% were Non-Hispanic white. The median WMHv was 10.0 cm 3 (25%-75% range: 6.3 - 16.9 cm 3 ). . CR defined as MoCA scores &gt; 25 &amp; &gt;22 was present in 28.5% &amp; 56.5% of participants respectively. Lower plasma AB40 was marginally associated with CR using a MoCa cutoff of &gt;25 (OR 1.003, 90% CI: 1.001-1.006) in univariate analyses. There were no other significant (P&gt;0.1) univariate or adjusted associations between plasma biomarkers with CR using either MoCa cutoff, nor significant confounding or effect modification by WMHv (P&gt; 0.1). Conclusion: There were no significant adjusted associations between any plasma biomarker with CR. Future work should identify factors associated with CR in adults with high WMHv.

Abstract WP275: Longitudinal Biomarker Analysis in Patients With Ischemic Stroke: Exploratory Targeted and Omics Assessments From a Phase 2a Clinical Trial

Introduction: Elezanumab (EZB), a monoclonal antibody specific to repulsive guidance molecule A (RGMa), is under investigation to treat acute ischemic stroke. Biomarker evidence in ischemic stroke and for the RGMa pathway is limited. Methods: This blinded, in-study analysis from a 52-week phase 2a, multicenter, randomized (1:1; EZB:placebo) clinical trial (NCT04309474) included patients aged 30-90 years with an acute ischemic stroke (onset ≤ 24 hours before baseline), and a NIHSS score of 7-21. Blinded analyses did not distinguish between treatment arms. Healthy adult controls were procured outside this trial. Blood samples were taken post-stroke across 52 weeks, or 1 time (baseline) for healthy adults. Plasma concentrations of neurodegenerative markers neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) were measured (validated Simoa Human Neurology 4-Plex A assay; Quanterix). Protein, mRNA, and miRNA were assessed with omics approaches. Results: This preliminary analysis included 34 patients with stroke (mean [SD] age 67.1 [12.3] years, 58.8% male) and 31 healthy adults (61.8 [8.0] years, 71.0% male). The mean (SD) baseline NIHSS total score was 10.9 (4.3). NfL and GFAP concentrations were elevated on day 1 in patients with stroke vs healthy adults (healthy adults are included for reference only). Mean concentrations of NfL were 48.7 pg/mL vs 13.9 pg/mL, respectively; mean concentrations of GFAP were 746.0 pg/mL vs 137.2 pg/mL, respectively. In patients with stroke, agnostic to treatment, peak NfL and GFAP elevations occurred at day 28 and days 2-4, respectively; NfL and GFAP concentrations were lower at week 52 than day 1. Conclusions: Preliminary blinded analysis of plasma markers of neurodegeneration confirm increased NfL and GFAP levels during acute stroke, which diminish over time with different temporal patterns. Final unblinded results will provide a robust natural time course of specific biomarkers of neurodegeneration including GAP43. Forthcoming analyses evaluate broad panels of proteins, mRNA, and miRNA markers. Identifying relevant post stroke biomarkers with directed and exploratory omics may allow development of validated assays to assess efficacy and support decision making in clinical trials.

The Return of Biomarker Results in Research: Balancing Complexity, Precision, and Ethical Responsibility.

Recent research aimed at the discovery, integration, and communication of health outcome measures (or "biomarkers") in Alzheimer's disease has raised challenging questions related to whether, how and when results from these investigations should be disclosed to research participants. Reflecting the apparent heterogeneity of many neurodegenerative diseases, biomarker or other risk factor results are often probabilistic, interactive, multi-modal, and selective. Such characteristics make it very complex to summarize and communicate to clinicians, researchers, and research participants. Whereas the format and content of academic literature is well-managed by the peer-review process, reporting individualized results to participants involves complex, sensitive, and ethical considerations. This paper describes three key factors to consider in decisions about the return of results to research participants: complexity, precision, and responsibility. The paper also presents six practical recommendations for implementing meaningful and ethical communication with research participants.