Search

Background and Purpose: Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-β, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure. Methods: Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE -ε4 positive, LV mass index 51.4±8.1 g/m 2 , NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE -ε 4 . In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations. Results: Among all participants, LV mass index was unrelated to CSF biomarkers ( P >0.33). LV mass index interacted with MCI ( P =0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE -ε4 carriers ( P =0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage. Conclusions: Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE -ε4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage.

It is well known that cardiovascular disease and related vascular risk factors are associated with cognitive decline and worse brain health outcomes among aging adults. Recently, subtle age-related changes in cardiac hemodynamics have been proposed as an emerging risk factor for abnormal brain aging, even in the absence of cardiovascular disease. Changes in cardiac function, vital for determining the total amount of blood available for perfusing the body, and arterial stiffness, important for regulating blood flow delivery, have been associated with compromised brain structure and function among older adults. Such alterations in cardiac output and arterial stiffening may directly affect brain health through blood-brain barrier breakdown or oligemia, or may interact with Alzheimer disease and concomitant pathologies common in aging adults to accelerate cognitive decline. This review examines how age-related alterations in cardiovascular integrity contribute to abnormal brain aging, emphasizing that changes in systemic hemodynamics may compromise brain health before or concurrently with the development of neurodegenerative processes that are common in aging.

ObjectiveHippocampal volume is a sensitive marker of neurodegeneration and a well-established predictor of age-related cognitive impairment. Recently, free-water (FW) magnetic resonance imaging (MRI) has shown associations with pathology in Alzheimer’s disease (AD), but it is still unclear whether these metrics are associated with measures of cognitive impairment. Here, we investigate whether FW and FW-corrected fractional anisotropy (FAT) within medial temporal lobe white matter tracts (cingulum, fornix, uncinate fasciculus, inferior longitudinal fasciculus, and tapetum) provides meaningful contribution to cognition and cognitive decline beyond hippocampal volume.Participants and MethodsVanderbilt Memory & Aging Project participants (n=319, 73±7 years, 59% male) with normal cognition and mild cognitive impairment (40% of cohort) underwent baseline brain MRI, including structural MRI to quantify hippocampal volume, diffusion MRI to quantify medial temporal lobe white matter tract FW and FAT, and longitudinal neuropsychological assessment with a mean follow-up of 3.5 years. Linear regressions were conducted to determine how hippocampal volume and white matter tract FW and FAT interact with baseline memory and executive function performances. Competitive model analyses determined the unique variance provided by white matter tract FW and FAT beyond that of hippocampal volume and other comorbidities. Linear mixed-effects models were conducted to determine how baseline hippocampal volume and white matter tract FW and FAT interact to explain longitudinal change in memory and executive function performances.ResultsFW in the inferior longitudinal fasciculus, tapetum, uncinate fasciculus, and cingulum were robustly associated with baseline memory and executive function. Further, competitive model analysis showed that tract FW contributed unique variance beyond other comorbidities and hippocampal volume for memory (ΔRadj2 range: 0.82-2.00%) and executive function (ΔRadj2 range: 0.88-1.87%). Longitudinal analyses demonstrated significant interactions of hippocampal volume and FAT in the inferior longitudinal fasciculus (p=0.02), tapetum (p=0.02), uncinate fasciculus (p=0.02), and cingulum (p=0.002) with decline in memory. For decline in executive function, we found significant interactions of hippocampal volume and FAT in inferior longitudinal fasciculus (p=0.03), tapetum (p=0.02), uncinate fasciculus (p=0.02), and fornix (p=0.02), as well as cingulum (p=0.02) and fornix (p=0.02) FW.ConclusionsOur results highlight novel associations between FW and FAT measures of medial temporal lobe tract microstructure and cognitive performance such that individuals with smaller hippocampal volumes and lower tract microstructure experience greater cognitive decline. These results suggest that white matter has a unique role in cognitive decline and, therefore, could be used to provide better disease staging, allowing for more precise disease monitoring in AD.

Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) are markers of cerebral oxygen homeostasis and metabolism that may offer insights into abnormal changes in brain aging. The present study cross-sectionally related OEF and CMRO2 to cognitive performance and structural neuroimaging variables among older adults (n = 246, 74 ± 7 years, 37% female) and tested whether apolipoprotein E ( APOE)-ε4 status modified these associations. Main effects of OEF and CMRO2 were null (p-values >0.06), and OEF interactions with APOE-ε4 status on cognitive and structural imaging outcomes were null (p-values >0.06). However, CMRO2 interacted with APOE-ε4 status on language (p = 0.002), executive function (p = 0.03), visuospatial (p = 0.005), and episodic memory performances (p = 0.03), and on hippocampal (p = 0.006) and inferior lateral ventricle volumes (p = 0.02). In stratified analyses, lower oxygen metabolism related to worse language (p = 0.02) and episodic memory performance (p = 0.03) among APOE-ε4 carriers only. Associations between CMRO2 and cognitive performance were primarily driven by APOE-ε4 carriers with existing cognitive impairment. Congruence across language and episodic memory results as well as hippocampal and inferior lateral ventricle volume findings suggest that APOE-ε4 may interact with cerebral oxygen metabolism in the pathogenesis of Alzheimer’s disease and related neurodegeneration.

Objective: To determine whether baseline aortic stiffness, measured by aortic pulse wave velocity (PWV), relates to longitudinal cerebral gray or white matter changes among older adults. Baseline cardiac magnetic resonance imaging will be used to assess aortic PWV while brain magnetic resonance imaging will be used to assess gray matter and white matter hyperintensity (WMH) volumes at baseline, 18 months, 3 years, 5 years, and 7 years. Approach and Results: Aortic PWV (m/s) was quantified from cardiac magnetic resonance. Multimodal 3T brain magnetic resonance imaging included T 1 -weighted imaging for quantifying gray matter volumes and T 2 -weighted fluid-attenuated inversion recovery imaging for quantifying WMHs. Mixed-effects regression models related baseline aortic PWV to longitudinal gray matter volumes (total, frontal, parietal, temporal, occipital, hippocampal, and inferior lateral ventricle) and WMH volumes (total, frontal, parietal, temporal, and occipital) adjusting for age, sex, race/ethnicity, education, cognitive diagnosis, Framingham stroke risk profile, APOE (apolipoprotein E)-ε4 carrier status, and intracranial volume. Two hundred seventy-eight participants (73±7 years, 58% male, 87% self-identified as non-Hispanic White, 159 with normal cognition, and 119 with mild cognitive impairment) from the Vanderbilt Memory & Aging Project (n=335) were followed on average for 4.9±1.6 years with PWV measurements occurring from September 2012 to November 2014 and longitudinal brain magnetic resonance imaging measurements occurring from September 2012 to June 2021. Higher baseline aortic PWV was related to greater decrease in hippocampal (β=−3.6 [mm 3 /y]/[m/s]; [95% CI, −7.2 to −0.02] P =0.049) and occipital lobe (β=−34.2 [mm 3 /y]/[m/s]; [95% CI, −67.8 to −0.55] P =0.046) gray matter volume over time. Higher baseline aortic PWV was related to greater increase in WMH volume over time in the temporal lobe (β=17.0 [mm 3 /y]/[m/s]; [95% CI, 7.2–26.9] P Conclusions: In older adults, higher baseline aortic PWV related to greater decrease in gray matter volume and greater increase in WMHs over time. Because of unmet cerebral metabolic demands and microvascular remodeling, arterial stiffening may preferentially affect certain highly active brain regions like the temporal lobes. These same regions are affected early in the course of Alzheimer disease.

Introduction Neuroaxonal damage may contribute to cognitive changes preceding clinical dementia. Accessible biomarkers are critical for detecting such damage. Methods Plasma and cerebrospinal fluid (CSF) neurofilament light (NFL) were related to neuropsychological performance among Vanderbilt Memory & Aging Project participants (plasma n = 333, 73 ± 7 years; CSF n = 149, 72 ± 6 years) ranging from normal cognition (NC) to mild cognitive impairment (MCI). Models adjusted for age, sex, race/ethnicity, education, apolipoprotein E ε4 carriership, and Framingham Stroke Risk Profile. Results Plasma NFL was related to all domains (P values ≤ .008) except processing speed (P values ≥ .09). CSF NFL was related to memory and language (P values ≤ .04). Interactions with cognitive diagnosis revealed widespread plasma associations, particularly in MCI participants, which were further supported in head-to-head comparison models. Discussion Plasma and CSF NFL (reflecting neuroaxonal injury) relate to cognition among non-demented older adults albeit with small to medium effects. Plasma NFL shows particular promise as an accessible biomarker with relevance to cognition in MCI., Highlights • Plasma and cerebrospinal fluid neurofilament light (NFL) were moderately correlated. • Cerebrospinal fluid NFL was related to language and memory functions. • Plasma NFL exhibited widespread cognitive associations. • Plasma NFL associations were particularly robust in mild cognitive impairment.

Background: Central retinal artery occlusion (CRAO) causes sudden, irreversible blindness and is a form of acute ischemic stroke. In this study, we sought to determine the proportion of patients in whom atrial fibrillation (AF) is detected by extended cardiac monitoring after CRAO. Methods: We performed a retrospective, observational cohort study using data from the Optum deidentified electronic health record of 30.8 million people cross-referenced with the Medtronic CareLink database of 2.7 million people with cardiac monitoring devices in situ. We enrolled patients in 3 groups: (1) CRAO, (2) cerebral ischemic stroke, and (3) age-, sex-, and comorbidity-matched controls. The primary end point was the detection of new AF (defined as ≥2 minutes of AF detected on a cardiac monitoring device). Results: We reviewed 884 431 patient records in common between the two databases to identify 100 patients with CRAO, 6559 with ischemic stroke, and 1000 matched controls. After CRAO, the cumulative incidence of new AF at 2 years was 49.6% (95% CI, 37.4%–61.7%). Patients with CRAO had a higher rate of AF than controls (hazard ratio, 1.64 [95% CI, 1.17–2.31]) and a comparable rate to patients with stroke (hazard ratio, 1.01 [95% CI, 0.75–1.36]). CRAO was associated with a higher incidence of new stroke compared with matched controls (hazard ratio, 2.85 [95% CI, 1.29–6.29]). Conclusions: The rate of AF detection after CRAO is higher than that seen in age-, sex-, and comorbidity-matched controls and comparable to that seen after ischemic cerebral stroke. Paroxysmal AF should be considered as part of the differential etiology of CRAO, and those patients may benefit from long-term cardiac monitoring.

Highlights • RDT within several white matter tracts is associated with SCD. • RDT contributes unique variance to SCD beyond that of CSF Aβ42. • Our findings suggest that RDT is a sensitive marker of SCD., Subjective cognitive decline (SCD) is a perceived cognitive change prior to objective cognitive deficits, and although it is associated with Alzheimer’s disease (AD) pathology, it likely results from multiple underlying pathologies. We investigated the association of white matter microstructure to SCD as a sensitive and early marker of cognitive decline and quantified the contribution of white matter microstructure separate from amyloidosis. Vanderbilt Memory & Aging Project participants with diffusion MRI data and a 45-item measure of SCD were included [n = 236, 137 cognitively unimpaired (CU), 99 with mild cognitive impairment (MCI), 73 ± 7 years, 37% female]. A subset of participants (64 CU, 40 MCI) underwent a fasting lumbar puncture for quantification of cerebrospinal fluid (CSF) amyloid-β(CSF Aβ42), total tau (CSF t-tau), and phosphorylated tau (CSF p-tau). Diffusion MRI data was post-processed using the free-water (FW) elimination technique, which allowed quantification of extracellular (FW) and intracellular compartment (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) microstructure. Microstructural values were quantified within 11 cognitive-related white matter tracts, including medial temporal lobe, frontal transcallosal, and fronto-parietal tracts using a region of interest approach. General linear modeling related each tract to SCD scores adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile scores, APOE ε4 carrier status, diagnosis, Geriatric Depression Scale scores, hippocampal volume, and total white matter volume. Competitive models were analyzed to determine if white matter microstructural values have a unique role in SCD scores separate from CSF Aβ42. FW-corrected radial diffusivity (RDT) was related to SCD scores in 8 tracts: cingulum bundle, inferior longitudinal fasciculus, as well as inferior frontal gyrus (IFG) pars opercularis, IFG orbitalis, IFG pars triangularis, tapetum, medial frontal gyrus, and middle frontal gyrus transcallosal tracts. While CSF Aβ42 was related to SCD scores in our cohort (Radj2 = 39.03%; β = −0.231; p = 0.020), competitive models revealed that fornix and IFG pars triangularis transcallosal tract RDT contributed unique variance to SCD scores beyond CSF Aβ42 (Radj2 = 44.35% and Radj2 = 43.09%, respectively), with several other tract measures demonstrating nominal significance. All tracts which demonstrated nominal significance (in addition to covariates) were input into a backwards stepwise regression analysis. ILF RDT, fornix RDT, and UF FW were best associated with SCD scores (Radj2 = 46.69%; p = 6.37 × 10-12). Ultimately, we found that medial temporal lobe and frontal transcallosal tract microstructure is an important driver of SCD scores independent of early amyloid deposition. Our results highlight the potential importance of abnormal white matter diffusivity as an early contributor to cognitive decline. These results also highlight the value of incorporating multiple biomarkers to help disentangle the mechanistic heterogeneity of SCD as an early stage of cognitive decline.

Central retinal artery occlusion (CRAO) is a form of acute ischemic stroke which affects the retina. Intravenous thrombolysis is emerging as a compelling therapeutic approach. However, it is not known which patients may benefit from this therapy because there are no imaging modalities that adequately distinguish viable retina from irreversibly infarcted retina. The inner retina receives arterial supply from the central retinal artery and there is robust collateralization between this circulation and the outer retinal circulation, provided by the posterior ciliary circulation. Fundus photography can show canonical changes associated with CRAO including a cherry-red spot, arteriolar boxcarring and retinal pallor. Fluorescein angiography provides 2-dimensional imaging of the retinal circulation and can distinguish a complete from a partial CRAO as well as central versus peripheral retinal non-perfusion. Transorbital ultrasonography may assay flow through the central retinal artery and is useful in the exclusion of other orbital pathology that can mimic CRAO. Optical coherence tomography provides structural information on the different layers of the retina and exploratory work has described its utility in determining the time since onset of ischemia. Two experimental techniques are discussed. 1) Retinal functional imaging permits generation of capillary perfusion maps and can assay retinal oxygenation and blood flow velocity. 2) Photoacoustic imaging combines the principles of optical excitation and ultrasonic detection and - in animal studies - has been used to determine the retinal oxygen metabolic rate. Future techniques to determine retinal viability in clinical practice will require rapid, easily used, and reproducible methods that can be deployed in the emergency setting.

Subclinical cardiac dysfunction is associated with smaller total brain volume on magnetic resonance imaging (MRI). To study whether cardiac output relates to regional measurements of grey and white matter structure, older adults (n=326) underwent echocardiogram to quantify cardiac output (L/min) and brain MRI. Linear regressions related cardiac output to grey matter volumes measured on T(1) and white matter hyperintensities assessed on T(2)-FLAIR. Voxelwise analyses related cardiac output to diffusion tensor imaging adjusting for demographic, genetic, and vascular risk factors. Follow-up models assessed a cardiac output x diagnosis interaction with stratification (normal cognition, mild cognitive impairment). Cardiac output interacted with diagnosis, such that lower cardiac output related to smaller total grey matter (p=0.01), frontal lobe (p=0.01), and occipital lobe volumes (p=0.01) among participants with normal cognition. When excluding participants with cardiovascular disease and atrial fibrillation, associations emerged with smaller parietal lobe (p=0.005) and hippocampal volume (p=0.05). Subtle age-related cardiac changes may contribute to disrupt neuronal homeostasis and impact grey matter integrity prior to cognitive impairment.

ObjectivesTo test the hypothesis that increased aortic stiffening is associated with greater CSF evidence of core Alzheimer disease pathology (β-amyloid [Aβ], phosphorylated tau [p-tau]), neurodegeneration (total tau [t-tau]), synaptic dysfunction (neurogranin), neuroaxonal injury (neurofilament light [NFL]), and neuroinflammation (YKL-40, soluble triggering receptor expressed on myeloid cells 2 [sTREM2]), we analyzed pulse wave velocity (PWV) data and CSF data among older adults.MethodsParticipants free of stroke and dementia from the Vanderbilt Memory and Aging Project, an observational community-based study, underwent cardiac magnetic resonance to assess aortic PWV (meters per second) and lumbar puncture to obtain CSF. Linear regressions related aortic PWV to CSF Aβ, p-tau, t-tau, neurogranin, NFL, YKL-40, and sTREM2 concentrations after adjustment for age, race/ethnicity, education, apolipoprotein (APOE) ε4 status, Framingham Stroke Risk Profile, and cognitive diagnosis. Models were repeated testing PWV interactions with age, diagnosis, APOE ε4, and hypertension on each biomarker.ResultsOne hundred forty-six participants were examined (age 72 ± 6 years). Aortic PWV interacted with age on p-tau (β = 0.31, p = 0.04), t-tau, (β = 2.67, p = 0.05), neurogranin (β = 0.94, p = 0.04), and sTREM2 (β = 20.4, p = 0.05). Among participants >73 years of age, higher aortic PWV related to higher p-tau (β = 2.4, p = 0.03), t-tau (β = 19.3, p = 0.05), neurogranin (β = 8.4, p = 0.01), and YKL-40 concentrations (β = 7,880, p = 0.005). Aortic PWV had modest interactions with diagnosis on neurogranin (β = −10.76, p = 0.03) and hypertension status on YKL-40 (β = 18,020, p < 0.001).ConclusionsAmong our oldest participants, ≥74 years of age, greater aortic stiffening is associated with in vivo biomarker evidence of neuroinflammation, tau phosphorylation, synaptic dysfunction, and neurodegeneration, but not amyloidosis. Central arterial stiffening may lead to cumulative cerebral microcirculatory damage and reduced blood flow delivery to tissue, resulting in neuroinflammation and neurodegeneration in more advanced age.

Cerebrospinal fluid (CSF) neurofilament light (NFL) is a protein biomarker of axonal injury. To study whether NFL is associated with diffusion tensor imaging (DTI) measurements of white matter (WM) microstructure, Vanderbilt Memory & Aging Project participants with normal cognition (NC, n=77), early mild cognitive impairment (eMCI, n=15), and MCI (n=55) underwent lumbar puncture to obtain CSF and 3T brain MRI. Voxel-wise analyses cross-sectionally related NFL to DTI metrics, adjusting for demographic and vascular risk factors. Increased NFL correlated with multiple DTI metrics (p-values

Arterial stiffening is associated with cognitive impairment and prodromal Alzheimer's disease. This study tested the interaction between arterial stiffening and an Alzheimer's disease genetic risk factor (apolipoprotein E [APOE] genotype) on cognition among older adults. Vanderbilt Memory & Aging Project participants with normal cognition (n = 162, 72 ± 7 years, 29% APOE-e4 carrier) and mild cognitive impairment (n = 121, 73 ± 8 years, 42% APOE-e4 carrier) completed neuropsychological assessment and cardiac MRI to assess aortic stiffening using pulse wave velocity (PWV, m/s). Linear regression models stratified by cognitive diagnosis related aortic PWV × APOE-e4 status to neuropsychological performances, adjusting for demographic and vascular risk factors. PWV × APOE-e4 related to poorer performance on measures of lexical retrieval (β = −0.29, p = 0.01), executive function (β = −0.44, p = 0.02), and episodic memory (β = −3.07, p = 0.02). Among participants with higher aortic PWV, APOE-e4 modified the association between central arterial stiffening and cognition, such that carriers had worse performances than noncarriers. Findings add to a growing body of evidence for APOE-vascular interactions on cognition in older adults and warrant further research into less heart-healthy cohorts where the association between PWV and cognition among older adults might be stronger.

Objective Cerebrospinal fluid (CSF) and plasma neurofilament light (NFL) concentrations were assessed in relation to longitudinal objective and subjective cognitive outcomes in older adults ranging from normal cognition to mild cognitive impairment. Interactive effects were assessed for apolipoprotein E ϵ4 (APOE4) carriership, a strong genetic risk factor for Alzheimer’s disease and molecular moderator of vascular disease. Method Vanderbilt Memory & Aging Project participants (CSF n = 149, 72 ± 6 years; plasma n = 333, 73 ± 7 years) underwent fasting blood draw and lumbar puncture at baseline for NFL quantification. Serial neuropsychological assessments and subjective cognitive decline (SCD) questionnaires were completed at 18-month increments. Linear mixed effects regression models adjusted for age, sex, race/ethnicity, education, APOE4 carriership (for main effect models), and depressed mood. NFL x APOE4 interaction terms were used as predictors in follow-up models. Results CSF NFL predicted steeper declines in an executive functioning composite score (β = −0.0001, p = 0.001) and WAIS-IV Coding (β = −0.001, p = 0.001). An APOE4 interaction was present for executive functioning (β = −0.0002, p = 0.005) such that CSF NFL associations with longitudinal decline were stronger among APOE4+ participants. Plasma NFL predicted worsening SCD (β = 0.27, p = 0.002) and objective cognitive decline across all domains (p-values Conclusions Both CSF and plasma NFL detect neuropathology associated with cognitive decline among non-demented older adults, especially among APOE4 carriers. Findings further support the value of SCD as reflecting neurodegenerative changes associated with accelerated cognitive aging.

Objective Subjective cognitive decline (SCD), a potential precursor to Alzheimer’s disease (ad), has been associated with increased neurodegeneration and cerebrovascular disease longitudinally. However, the impact of amyloid status, an early pathological marker of Alzheimer’s disease (ad) on these longitudinal associations is less clear. Here, we related baseline SCD to longitudinal biomarkers of brain health in the context of amyloid status. Method Participants included 139 non-demented older adults (72 ± 7 years) from the Vanderbilt Memory & Aging Project who completed a SCD questionnaire and fasting lumbar-puncture to quantify amyloid status (defined using published cutoffs of amyloid-beta42 levels) at baseline. 3 T brain-MRI to measure gray and white matter hyperintensity (WMH) volumes was collected at baseline, 18-months, 3-years, and 5-years. Linear mixed effects models assessed if baseline SCD X amyloid status was associated with longitudinal total and lobar grey and white matter volumes, covarying for baseline age, sex, race/ethnicity, education, diagnosis, mood, and apolipoprotein-Ee4 status. Models were also stratified by baseline amyloid status. Results Baseline SCD score and amyloid status interacted with total gray (p = 0.02) and WMH volume (p Conclusion In the presence of amyloid, the presence of SCD is predictive of neurodegeneration in ad-specific regions. Conversely, SCD without amyloidosis may reflect a cerebrovascular disease, indicated by WMHs. Results highlight how amyloid status may help delineate etiologies of SCD.

Objective Neurogranin is a postsynaptic protein associated with declining memory and executive functioning in Alzheimer’s disease (ad). While previous research suggests neurogranin concentrations in ad are higher in women, it is unclear whether sex differences exist in earlier disease stages or predict different cognitive outcomes. This study investigates cerebrospinal fluid (CSF) neurogranin in relation to longitudinal cognitive decline in older adults ranging from normal cognition to mild cognitive impairment, assessing for interactions by sex. Method Vanderbilt Memory & Aging Project participants completed baseline fasting lumbar puncture (n = 155, 73 ± 8 years) for neurogranin quantification and serial neuropsychological assessments at 18-month intervals. Linear mixed effect regression adjusting for age, sex (for main effect models), race/ethnicity, education, cognitive diagnosis, depressed mood, and APOE-ε4 carrier status. Results CSF neurogranin predicted worse cognitive decline across multiple domains (p-values Conclusion Results suggest that among nondemented older adults, CSF neurogranin predicts worse longitudinal cognitive decline in women but not in men. Further research is needed to elucidate underlying mechanisms that may account for these differences, such as possible sex hormone factors. These findings highlight the importance of pursuing individualized prevention and treatment approaches to combat accelerated cognitive aging that take into account the possibility of multiple, divergent disease pathways preceding ad and dementia among various demographic groups.

Introduction: Patterns of atrophy can distinguish normal cognition from Alzheimer's disease (AD), but neuropathological drivers of this pattern are unknown. This study examined associations between cerebrospinal fluid biomarkers of AD pathology, synaptic dysfunction, and neuroaxonal injury with two AD imaging signatures. Methods: Signatures were calculated using published guidelines. Linear regressions related each biomarker to both signatures, adjusting for demographic factors. Bootstrapped analyses tested if associations were stronger with one signature versus the other. Results: Increased phosphorylated tau (p-tau), total tau, and neurofilament light (P-values

Aim and objective To describe factors associated with father involvement in the neonatal intensive care unit using the Heuristic model of the dynamic of parental behaviour and influence on children over time. Background Research shows that infants with involved fathers have better cognitive development, fewer crying episodes after caesarean birth, improved breastfeeding exclusivity and duration, and more regular sleep patterns. Preterm infants with involved fathers have improved cognitive development. Design This cross-sectional exploratory study used survey methodology to explore factors associated with father involvement in the neonatal intensive care unit. Methods The STROBE checklist for cross-sectional studies was used (see Appendix S2). Biological fathers of infants in a 97-bed neonatal intensive care unit in the southern USA completed a survey which asked about their involvement with their hospitalised infants and factors which affected that involvement. Eighty fathers completed the survey. Results Age ranged between 20-53 with 43% first-time fathers. Compared to less involved fathers, fathers who were more involved were younger, married or living with the mother, performed kangaroo care or fathers of multiple gestation. Fathers who had attended the delivery were more likely to bathe their infants than those who had not attended the delivery and fathers who performed kangaroo care felt more confident than those who did not. Compared to fathers who visited less often, fathers who visited more often were younger, had infants with a shorter hospitalisation time and lower acuity, and had fewer children in the family. Conclusions Fathers are involved with their neonatal intensive care unit infants in many ways. Factors were identified that affect involvement in the neonatal intensive care unit. Relevance to clinical practice Results can help nurses in neonatal intensive care units worldwide facilitate father-infant interaction, identify fathers at risk for decreased involvement and advocate for institutional policy development for supporting neonatal intensive care unit father involvement.

The first step in NH 2 Cl oxidation of NO 2 - is the general acid-assisted formation of nitryl chloride, where k HA is 7.6×10 6 M -2 s -1 for HaO + and is 46 M -2 s -1 for H 2 PO 4 - (25.0 o C, μ=0.50 M). This is the rate-limiting step at very low [NH 3 ] and high [NO 2 - ] concentrations: HA+NH 2 Cl+ NO 2 - →A - +NH 3 +NO 2 Cl, where the subsequent reactions of NO 2 Cl are rapid

White matter hyperintensities (WMHs) are associated with poorer brain health, but their pathophysiological substrates remain elusive. To better understand the mechanistic underpinnings of WMHs among older adults, this study examined in vivo cerebrospinal fluid biomarkers of β-amyloid42 deposition (Aβ42), hyperphosphorylated tau pathology, neurodegeneration (total tau), and axonal injury (neurofilament light [NFL]) in relation to log-transformed WMHs volume. Participants free of clinical stroke and dementia were drawn from the Vanderbilt Memory & Aging Project (n = 148, 72 ± 6 years). Linear regression models adjusted for age, sex, race/ethnicity, education, intracranial volume, modified Framingham Stroke Risk Profile (excluding points assigned for age), cognitive diagnosis, and APOE-e4 carrier status. Aβ42 (β = −0.001, p = 0.007) and NFL (β = 0.0003, p = 0.01) concentrations related to WMHs but neither hyperphosphorylated tau nor total tau associations with WMHs reached statistical significance (p-values > 0.21). In a combined model, NFL accounted for 3.2% of unique variance in WMHs and Aβ42 accounted for an additional 4.3% beyond NFL, providing novel evidence of the co-occurrence of at least 2 distinct pathways for WMHs among older adults, including amyloid deposition and axonal injury.