Citations

Abstract Alzheimer’s disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer’s disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer’s disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer’s disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer’s disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer’s disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0–16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer’s disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer’s disease and primary age-related tauopathy.

ABSTRACTFollowing intracerebral infection with Theiler’s murine encephalomyelitis virus (TMEV), susceptible strains of mice (SJL and PLJ) develop virus persistence and demyelination similar to that found in human multiple sclerosis. Resistant strains of mice (C57BL/6) clear virus and do not develop demyelination. To resolve the controversy about the role of CD4+and CD8+T cells in the development of demyelination and neurologic deficits in diseases of the central nervous system, we analyzed TMEV infection in CD4- and CD8-deficient B6, PLJ, and SJL mice. Genetic deletion of either CD4 or CD8 from resistant B6 mice resulted in viral persistence and demyelination during the chronic stage of disease. Viral persistence and demyelination were detected in all strains of susceptible background. Although genetic deletion of CD8 had no effect on the extent of demyelination in susceptible strains, deletion of CD4 dramatically increased the degree of demyelination observed. Whereas strains with deletions of CD4 showed severe neurologic deficits, mice with deletions of CD8 showed minimal or no deficits despite demyelination. In all strains, deletion of CD4 but not CD8 resulted in a decreased delayed-type hypersensitivity response to viral antigen. We conclude that each T-cell subset makes a discrete and nonredundant contribution to protection from viral persistence and demyelination in resistant strains. In contrast, in susceptible strains, CD8+T cells do not provide protection against chronic demyelinating disease. Furthermore, in persistent TMEV infection of the central nervous system, neurologic deficits appear to result either from the absence of a protective class II-restricted immune response or from the presence of a pathogenic class I-restricted response.

Background: Black-white gaps in high-quality hospital use are documented, but the relative contributions of various factors are unclear. The objective of this study was to quantify the contributions of differences in geographic and nongeographic factors to the gap, using decomposition methods and data for coronary heart disease. Research Design: We identified white and black fee-for-service beneficiaries aged 65 or older who were hospitalized for acute myocardial infarction (AMI) or coronary artery bypass grafting (CABG) surgery during 2009–2011. We categorized hospitals with AMI mortality rates in the lowest quintile as high-quality hospitals. We first decomposed the white-black gap in high-quality hospital use into a component due to racial differences in region of residence and a within-region component. We then decomposed the within-region differences into contributions due to racial differences in geographic proximity to high-quality hospitals and due to nongeographic factors. Results: The white-black gap in high-quality hospital use was smaller for AMI than for CABG (1.7 percentage points vs. 7.5 percentage points). For AMI, region of residence contributed more to the gap than within-region differences (1.0 percentage point vs. 0.6 percentage points), while for CABG, within-region differences prevailed (2.0 percentage points vs. 5.4 percentage points). For both conditions, the within-region white-black difference in high-quality hospital use was mainly driven by nongeographic factors. Conclusions: Decomposition methods are a useful tool in quantifying the contributions of various factors to the white-black gap in high-quality hospital use and could inform local policy aimed at reducing disparities in hospital quality.

Abstract White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Autonomic support of blood pressure increases with age in humans. Large differences exist in the dose of trimethaphan (TMP) required for ganglionic blockade in young and older women. We asked whether differences in the dose of TMP required to achieve ganglionic blockade are because of differences in the relative contributions of the sympathetic and parasympathetic nervous system in control of blood pressure with age. Muscle sympathetic nerve activity (microneurography, peroneal nerve), heart rate (HR), and blood pressure were recorded before and during incremental doses of TMP camsylate until ganglionic blockade was achieved (absence of muscle sympathetic nerve activity and <5-bpm increase in HR during a valsalva maneuver; final TMP dose, 1–7 mg/min). HR variability was analyzed from the ECG waveform (WinCPRS). The dose of TMP required to achieve ganglionic blockade is positively related to basal HR variability, where women with high HR variability require a higher dose of TMP to achieve ganglionic blockade. In contrast, baseline muscle sympathetic nerve activity is inversely related with the dose of TMP required to achieve ganglionic blockade, such that women with high basal muscle sympathetic nerve activity required a lower dose of TMP. As such, the change in HR with ganglionic blockade was positively related, and the change in mean arterial pressure was inversely related, with the dose of TMP required to achieve ganglionic blockade. These data suggest loss of parasympathetic tone and increased sympathetic tone with aging contribute to the increase in blood pressure with age in women and dictate the dose of TMP that is necessary to achieve ganglionic blockade.

The contributions of acetylcholine and/or nitric oxide (NO) to the rapid changes in human forearm blood flow (FBF) at the onset and recovery from mild exercise were studied in eight subjects. Rhythmic handgrip contractions were performed during brachial artery infusions of saline (2 ml/min; control), atropine (0.2 mg over 3 min), to block acetylcholine binding to muscarinic receptors, or atropine + N G-monomethyl-l-arginine (l-NMMA; 4 mg/min for 4 min), to additionally inhibit NO synthase. Brachial artery mean blood velocity (MBV; pulsed Doppler ultrasound) and diameter (echo Doppler) were measured continuously, and FBF was calculated. Atropine reduced acetylcholine-induced increases in FBF by ∼71% ( P < 0.05). FBF at rest was reduced by atropine and further reduced with atropine +l-NMMA. Both drug conditions reduced FBF during exercise by ∼10% compared with control, with no difference between drug treatments. Brachial artery diameter was unchanged from rest by exercise, recovery, and drug treatments. Neither drug treatment altered the rate or magnitude of the increase in FBF above rest. Peak FBF after exercise was reduced by atropine and atropine + l-NMMA. Total FBF during 5 min of recovery was reduced with atropine +l-NMMA compared with control and atropine. The results suggest that 1) acetylcholine and NO mechanisms additively contribute to FBF levels at rest, 2) a cholinergic mechanism adjusts the absolute FBF levels during exercise, 3) neither acetylcholine nor NO is essential to observe the normal time course or magnitude of the exercise response, and 4) NO contributes to the FBF response during recovery from exercise.

Abstract Aims Patients with heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction demonstrate an increased ventilatory equivalent for carbon dioxide (V̇E/V̇CO2) slope. The physiological correlates of the V̇E/V̇CO2 slope remain unclear in the two HF phenotypes. We hypothesized that changes in the physiological dead space to tidal volume ratio (VD/VT) and arterial CO2 tension (PaCO2) differentially contribute to the V̇E/V̇CO2 slope in HFrEF vs. HFpEF. Methods and results Adults with HFrEF (n = 32) and HFpEF (n = 27) [mean ± standard deviation (SD) left ventricular ejection fraction: 22 ± 7% and 61 ± 9%, respectively; mean ± SD body mass index: 28 ± 4 kg/m2 and 33 ± 6 kg/m2, respectively; P &lt; 0.01] performed cardiopulmonary exercise testing with breath-by-breath ventilation and gas exchange measurements. PaCO2 was measured via radial arterial catheterization. We calculated the V̇E/V̇CO2 slope via linear regression, and VD/VT = 1 − [(863 × V̇CO2)/(V̇E × PaCO2)]. Resting VD/VT (0.48 ± 0.08 vs. 0.41 ± 0.11; P = 0.04), but not PaCO2 (38 ± 5 mmHg vs. 40 ± 3 mmHg; P = 0.21) differed between HFrEF and HFpEF. Peak exercise VD/VT (0.39 ± 0.08 vs. 0.32 ± 0.12; P = 0.02) and PaCO2 (33 ± 6 mmHg vs. 38 ± 4 mmHg; P &lt; 0.01) differed between HFrEF and HFpEF. The V̇E/V̇CO2 slope was higher in HFrEF compared with HFpEF (44 ± 11 vs. 35 ± 8; P &lt; 0.01). Variance associated with the V̇E/V̇CO2 slope in HFrEF and HFpEF was explained by peak exercise VD/VT (R2 = 0.30 and R2 = 0.50, respectively) and PaCO2 (R2 = 0.64 and R2 = 0.28, respectively), but the relative contributions of each differed (all P &lt; 0.01). Conclusions Relationships between the V̇E/V̇CO2 slope and both VD/VT and PaCO2 are robust, but differ between HFpEF and HFrEF. Increasing V̇E/V̇CO2 slope appears to be strongly explained by mechanisms influential in regulating PaCO2 in HFrEF, which contrasts with the strong role of increased VD/VT in HFpEF.