Citations

Abstract Introduction We have previously shown that older adults with excessive daytime sleepiness (EDS) appear to be more vulnerable to longitudinal amyloid PET accumulation before the onset of the dementia. It remains unclear whether this vulnerability is specific to amyloid or extends to other biomarkers of Alzheimer’s disease pathology, or axonal integrity and inflammation, which can also contribute to neurodegeneration and cognitive changes. Methods For this cross-sectional analysis, we identified 260 cognitively unimpaired adults (>60 years old) without neurologic disorder who underwent CSF quantification of AD biomarkers (CSF Aβ-42, p-tau181, p-tau217) along with at least one other biomarker of interest (neurofilament light chain [NfL], IL-6, IL-10, and TNF-α) from the Mayo Clinic Study of Aging – a longitudinal population-based cohort in Olmsted County, Minnesota. CSF biomarkers were available in 251-260 individuals, depending on the biomarker. We fit linear regression models to assess whether the CSF biomarkers were associated with sleepiness as measured by the Epworth Sleepiness Scale (ESS), after controlling for age, sex, APOE4 genotype, BMI, hypertension, dyslipidemia, and OSA diagnosis (by chart review). Results Higher ESS scores were independently associated with higher CSF IL-6 and NfL, but not with the other biomarkers in the whole sample. For every single-point increase in the ESS score, there was a .008 ([95% CI .001-.016], p=0.033) increase in the log of IL-6 and .01 ([95% CI .002-.018], p=0.016) increase in the log of NfL. A sensitivity analysis showed a correlation between ESS scores and log of p-tau/Aβ-42 ratio only in participants with abnormal ratio (>0.023), after controlling for APOE4 (partial r=.27, p=039). Conclusion Our results corroborate previous literature suggesting that higher inflammatory milieu reflected by increased CSF IL-6 is associated with sleepiness. The association between NfL and sleepiness suggests that sleepiness may be related to disturbed connectivity due to axonal damage. Alternatively, NfL may be a surrogate of active axonal injury associated with more disrupted sleep. A correlation between sleepiness and CSF p-tau/ab-42 ratio was only seen in patients with abnormal ratio, suggesting a stronger association between sleepiness and AD pathology as the disease progresses, possibly because AD pathology worsens sleep quality and/or vice-versa. Support (If Any) NIH/NIA

AbstractBackgroundPhysical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty.MethodsAtherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline.ResultsIn the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk.ConclusionThe current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.

AbstractThe extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of ‘sporadic’ late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease.We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer’s Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset.Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants.These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.

AbstractBackgroundPYRAMID was an international post‐marketing registry that aimed to collect data on the long‐term safety and effectiveness of adalimumab treatment per local standard of care in patients with moderately to severely active Crohn's disease (CD). Here, we present post hoc analyses of observational data from patients who became pregnant while participating in this registry and receiving adalimumab.MethodsFrom the subpopulation of patients receiving adalimumab who became pregnant while taking part in PYRAMID, data on patient characteristics, pregnancy outcomes, and complications of pregnancy were analysed retrospectively.ResultsAcross the PYRAMID registry, 293 pregnancies occurred in patients who had gestational adalimumab exposure (average disease duration at last menstrual period: 8.6 years), resulting in 300 pregnancy outcomes. A total of 197 pregnancies (67.2%) were exposed to adalimumab in all trimesters per physician's decision. Of the known reported outcomes (96.3%), 81.7% (236/289) were live births, 10.4% (30/289) were spontaneous abortions, 4.8% (14/289) elective terminations, 2.8% (8/289) ectopic pregnancies, and 0.3% (1/289) was a stillbirth. Congenital malformations (pulmonary valve stenosis and tricuspid valve incompetence) were reported in one infant. In addition to the pregnancy outcomes described above, 23 complications of pregnancy were reported in 20 patients.ConclusionsThis analysis showed that adalimumab treatment in patients with CD, who became pregnant whilst participating in the PYRAMID registry, contributed no additional adverse effects during the pregnancy course or on pregnancy outcomes.

Background: Cerebral microbleeds (CMBs) are a common vascular pathology associated with future intracerebral hemorrhage. Plasma biomarkers of amyloid, tau, and neurodegeneration may provide a screening avenue to identify those with CMBs, but evidence is conflicting. Objective: To determine the association between plasma biomarkers (Aβ40, Aβ42, t-tau, p-tau181, p-tau217, neurofilament light chain (NfL)) and CMBs in a population-based study of aging and whether these biomarkers predict higher signal on Aβ-PET imaging in patients with multiple CMBs. Methods: 712 participants from the Mayo Clinic Study of Aging with T2* GRE MRI and plasma biomarkers were included. Biomarkers were analyzed utilizing Simoa (Aβ40, Aβ42, t-tau, NfL) or Meso Scale Discovery (p-tau181, p-tau217) platforms. Cross-sectional associations between CMBs, plasma biomarkers and Aβ-PET were evaluated using hurdle models and multivariable regression models. Results: Among the 188 (26%) individuals with≥1 CMB, a lower plasma Aβ42/Aβ40 ratio was associated with more CMBs after adjusting for covariables (IRR 568.5 95% CI 2.8–116,127). No other biomarkers were associated with risk or number CMBs. In 81 individuals with≥2 CMBs, higher plasma t-tau, p-tau181, and p-tau217 all were associated with higher Aβ-PET signal, with plasma p-tau217 having the strongest predictive value (r2 0.603, AIC –53.0). Conclusion: Lower plasma Aβ42/Aβ40 ratio and higher plasma p-tau217 were associated with brain amyloidosis in individuals with CMBs from the general population. Our results suggest that in individuals with multiple CMBs and/or lobar intracranial hemorrhage that a lower plasma Aβ42/Aβ40 ratio or elevated p-tau217 may indicate underlying cerebral amyloid angiopathy.

Objective Hypercapnia, an elevated concentration of carbon dioxide (CO2) in the blood, is known to promote acute increases in cerebral blood flow (CBF). This pilot study aimed to investigate whether a novel training method involving repeated bouts of hypercapnia, would influence cerebrovascular reactivity response in healthy adults. Hypothesis Repeated bouts of hypercapnia (as interval training) may promote beneficial adaptation to increase cerebrovascular reactivity. Methods Adults over 40yrs old without known disease or cardiovascular risk factors, were recruited for a non‐randomized cross‐over design pilot study. Subjects completed a 2‐week control period followed by a 2‐week intervention. The intervention involved a progressive hypercapnia training program of six sessions, whereby subjects completed 4‐6 intervals of rebreathing oxygen until a target end‐tidal CO2 (up to 25mmHg above resting) was reached, separated by recovery intervals breathing room air. Cerebrovascular reactivity was measured during study testing visits at baseline, 2‐weeks (between control and intervention) and 4‐weeks (after intervention). During study visits subjects underwent a stepped CO2 protocol, involving 5‐min stages of inspired room air, 2% CO2, 4% CO2, and 6% CO2, while measuring middle cerebral artery velocity (CBFv) using transcranial doppler ultrasound, mean arterial pressure (MAP) by finger plethysmography, ventilation, and end‐tidal CO2. Cerebrovascular conductance (CVCi) was calculated as CBFv/MAP. The reactivity of CBFv (in cm/s/mmHg), CVCi (in cm/s/mmHg2), and MAP (in mmHg/mmHg) were calculated as the linear regression slope against end‐tidal CO2 during the stepped CO2 protocol. Chemosensitivity (in L/min/mmHg) is the linear regression slope of VE vs end‐tidal CO2. Results Six healthy adults (age: 56 ± 10; 2 females) completed the study. Study visit data are displayed in Table 1. Individual training data are presented in Table 2. Following the control period there was a large reduction from baseline in CBFv reactivity [2.81 ± 1.50 to 2.03 ± 1.03; effect size 0.9], CVCi reactivity [0.020 ± 0.015 to 0.015 ± 0.010; effect size 0.7], and MAP reactivity [0.95 ± 0.63 to 0.62 ± 0.42; effect size 0.6] with no change in chemosensitivity [0.99 ± 0.68 to 0.98 ± 0.51; effect size 0.0]. Following the intervention there was no change from the 2‐week study visit in CBFv reactivity [2.03 ± 1.03 to 2.01 ± 1.09; effect size 0.0], CVCi reactivity [0.015 ± 0.010 to 0.014 ± 0.010; effect size 0.1], and MAP reactivity [0.62 ± 0.42 to 0.72 ± 0.44; effect size 0.1] with a small increase in chemosensitivity [0.98 ± 0.51 to 1.04 ± 0.53; effect size 0.3]. Conclusion Preliminary findings suggest a very brief progressive hypercapnia training program does not increase or desensitize cerebrovascular reactivity in healthy adults. These data also suggest an exaggerated cerebrovascular reactivity response may occur to an initial exposure of a stepped CO2 protocol (without familiarization), which appears to be driven by blood pressure response not chemosensitivity. Further research, particularly in populations with impaired cerebrovascular reactivity, is of interest for CBF regulation.

Abstract Primary four-repeat tauopathies are characterized by depositions of the four-repeat isoform of the microtubule binding protein, tau. The two most common sporadic four-repeat tauopathies are progressive supranuclear palsy and corticobasal degeneration. Because tau PET tracers exhibit poor binding affinity to four-repeat pathology, determining how well in vivo MRI findings relate to underlying pathology is critical to evaluating their utility as surrogate markers to aid in diagnosis and as outcome measures for clinical trials. We studied the relationship of cross-sectional imaging findings, such as MRI volume loss and diffusion tensor imaging white matter tract abnormalities, to tau histopathology in four-repeat tauopathies. Forty-seven patients with antemortem 3 T MRI volumetric and diffusion tensor imaging scans plus post-mortem pathological diagnosis of a four-repeat tauopathy (28 progressive supranuclear palsy; 19 corticobasal degeneration) were included in the study. Tau lesion types (pretangles/neurofibrillary tangles, neuropil threads, coiled bodies, astrocytic lesions) were semiquantitatively graded in disease-specific cortical, subcortical and brainstem regions. Antemortem regional volumes, fractional anisotropy and mean diffusivity were modelled using linear regression with post-mortem tau lesion scores considered separately, based on cellular type (neuronal versus glial), or summed (total tau). Results showed that greater total tau burden was associated with volume loss in the subthalamic nucleus (P = 0.001), midbrain (P < 0.001), substantia nigra (P = 0.03) and red nucleus (P = 0.004), with glial lesions substantially driving the associations. Decreased fractional anisotropy and increased mean diffusivity in the superior cerebellar peduncle correlated with glial tau in the cerebellar dentate (P = 0.04 and P = 0.02, respectively) and red nucleus (P < 0.001 for both). Total tau and glial pathology also correlated with increased mean diffusivity in the midbrain (P = 0.02 and P < 0.001, respectively). Finally, increased subcortical white matter mean diffusivity was associated with total tau in superior frontal and precentral cortices (each, P = 0.02). Overall, results showed clear relationships between antemortem MRI changes and pathology in four-repeat tauopathies. Our findings show that brain volume could be a useful surrogate marker of tau pathology in subcortical and brainstem regions, whereas white matter integrity could be a useful marker of tau pathology in cortical regions. Our findings also suggested an important role of glial tau lesions in the pathogenesis of neurodegeneration in four-repeat tauopathies. Thus, development of tau PET tracers selectively binding to glial tau lesions could potentially uncover mechanisms of disease progression.

Objective The objective of this study was to determine whether a triple therapy regimen incorporating twice-daily saquinavir is as effective as a three-times daily regimen. Methods This was an open-label, Phase III, multicentre, 48-week study involving 837 HIV-1-infected patients randomised to one of the following: saquinavir soft gel capsule (SGC) 1200 mg three-times daily, plus two nucleoside reverse transcriptase inhibitors (NRTIs) (arm A); saquinavir SGC 1600 mg twice-daily, plus two NRTIs (arm B); saquinavir SGC 1200 mg twice-daily and nelfinavir 1250 mg twice-daily, plus a single NRTI (arm C). The primary outcome measure was the virological response in arm A versus B and in arm A versus C with respect to the percentage of patients whose plasma HIV-1 RNA levels fell below the level of quantification for the Amplicor assay (<400 copies/ml) at weeks 24 and 48. Results At 48 weeks, the percentage of patients with plasma HIV-1 RNA levels <400 copies/ml was 47.1% (arm A), 45.3% (arm B) and 42.7% (arm C) in the intention-to-treat analysis. The treatment difference between arm B–arm A was -1.8% (95% confidence intervals -10.1, 6.5) and for arm C–arm A was -4.5% (95% confidence intervals -12.7, 3.7) in the intention-to-treat analysis. These differences fell within the maximum allowable difference (±12%) for arm B compared with arm A. At week 24, the percentage of patients with HIV-1 RNA levels <400 copies/ml was 59.6% (arm A), 57.6% (arm B) and 51.3% (arm C). Conclusions A twice-daily triple therapy regimen incorporating saquinavir SGC plus two NRTIs was of equivalent efficacy to the three-times daily regimen studied. All regimens were generally well tolerated.