Individual differences in brain aging: heterogeneity in cortico-hippocampal but not caudate atrophy rates.

It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.

Lung Function Trajectories and Associated Mortality among Adults with and without Airway Obstruction.

Rationale: Spirometry is essential for diagnosis and assessment of prognosis in patients with chronic obstructive pulmonary disease (COPD). Objectives: To identify FEV1 trajectories and their determinants on the basis of annual spirometry measurements among individuals with and without airway obstruction (AO) and to assess mortality in relation to trajectories. Methods: From 2002 through 2004, individuals with AO (FEV1/VC < 0.70, n = 993) and age- and sex-matched nonobstructive (NO) referents were recruited from population-based cohorts. Annual spirometry until 2014 was used in joint-survival latent-class mixed models to identify lung function trajectories. Mortality data were collected during 15 years of follow-up. Measurements and Main Results: Three trajectories were identified among the subjects with AO and two among the NO referents. Trajectory membership was driven by baseline FEV1% predicted (FEV1%pred) in both groups and also by pack-years in subjects with AO and current smoking in NO referents. Longitudinal FEV1%pred depended on baseline FEV1%pred, pack-years, and obesity. The trajectories were distributed as follows: among individuals with AO, 79.6% in AO trajectory 1 (FEV1 high with normal decline), 12.8% in AO trajectory 2 (FEV1 high with rapid decline), and 7.7% in AO trajectory 3 (FEV1 low with normal decline) (mean, 27, 72, and 26 ml/yr, respectively) and, among NO referents, 96.7% in NO trajectory 1 (FEV1 high with normal decline) and 3.3% in NO trajectory 2 (FEV1 high with rapid decline) (mean, 34 and 173 ml/yr, respectively). Hazard for death was increased for AO trajectories 2 (hazard ratio [HR], 1.56) and 3 (HR, 3.45) versus AO trajectory 1 and for NO trajectory 2 (HR, 2.99) versus NO trajectory 1. Conclusions: Three different FEV1 trajectories were identified among subjects with AO and two among NO referents, with different outcomes in terms of FEV1 decline and mortality. The FEV1 trajectories among subjects with AO and the relationship between low FVC and trajectory outcome are of particular clinical interest.

Educational attainment does not influence brain aging.

Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain aging.

Mapping quality of life after balloon dilatation in subglottic stenosis using Dyspnea index and Short Form Health Survey-36.

PURPOSE: An accurate diagnosis and proper treatment plan are required to restore an adequate patent airway in fibrotic subglottic stenosis (SGS). Currently, the definitive treatment entails single-stage balloon dilatation with steroid injections. The primary aim was to evaluate successful airway restoration and general quality of life in cases with SGS in northern Sweden using robust patient reported outcomes. METHODS: All participants with need of surgical treatment due to SGS that had been referred to the department of otorhinolaryngology, University Hospital of Umeå from September 2020 to August 2023 was included. Exclusion criteria included malignant, extrathoracic or cartilaginous cause, age < 18 years, or incompetent to sign consent documents. We assessed the patient-reported outcome measures pre- as well as 3 months postoperatively. RESULTS: Of the 40 cases fulfilling the eligibility criteria's, 33 cases completed the Dyspnea index (DI) and the short form health survey (SF-36) pre- as well as 3 months post-operatively. Receiver operating characteristics showed significant improvement in DI as well as in SF 36 scores post-operatively. CONCLUSIONS: Evaluation of balloon dilatation in SGS in this cohort follow-up analysis shows clear improvement in patient quality of life using robust PROM 3 months postoperatively, ensuring the use of a safe and well-tolerated procedure.

5-Year Associations among Cerebral Arterial Pulsatility, Perivascular Space Dilation, and White Matter Lesions.

OBJECTIVE: High cerebral arterial pulsatility index (PI), white matter lesions (WMLs), enlarged perivascular spaces (PVSs), and lacunar infarcts are common findings in the elderly population, and considered indicators of small vessel disease (SVD). Here, we investigate the potential temporal ordering among these variables, with emphasis on determining whether high PI is an early or delayed manifestation of SVD. METHODS: In a population-based cohort, 4D flow MRI data for cerebral arterial pulsatility was collected for 159 participants at baseline (age 64-68), and for 122 participants at follow-up 5 years later. Structural MRI was used for WML and PVS segmentation, and lacune identification. Linear mixed-effects (LME) models were used to model longitudinal changes testing for pairwise associations, and latent change score (LCS) models to model multiple relationships among variables simultaneously. RESULTS: Longitudinal 5-year increases were found for WML, PVS, and PI. Cerebral arterial PI at baseline did not predict changes in WML or PVS volume. However, WML and PVS volume at baseline predicted 5-year increases in PI. This was shown for PI increases in relation to baseline WML and PVS volumes using LME models (R  ≥  0.24; p < 0.02 and R  ≥  0.23; p < 0.03, respectively) and LCS models ( ß  = 0.28; p = 0.015 and ß  = 0.28; p = 0.009, respectively). Lacunes at baseline were unrelated to PI. INTERPRETATION: In healthy older adults, indicators of SVD are related in a lead-lag fashion, in which the expression of WML and PVS precedes increases in cerebral arterial PI. Hence, we propose that elevated PI is a relatively late manifestation, rather than a risk factor, for cerebral SVD. ANN NEUROL 2022;92:871-881.

On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis.

OBJECTIVE: Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA) patients display a unique feature defined by the abundant presence of N-linked glycans within the variable domains (V-domains). Recently, we showed that N-glycosylation sites, which are required for the incorporation of V-domain glycans, are introduced following somatic hypermutation. However, it is currently unclear when V-domain glycosylation occurs. Further, it is unknown which factors might trigger the generation of V-domain glycans and whether such glycans are relevant for the transition towards RA. Here, we determined the presence of ACPA-IgG V-domain glycans in paired samples of pre-symptomatic individuals and RA patients. METHODS: ACPA-IgG V-domain glycosylation was analysed using ultra-high performance liquid chromatography (UHPLC) in paired samples of pre-symptomatic individuals (median interquartile range (IQR) pre-dating time: 5.8 (5.9) years; n=201; 139 ACPA-positive and 62 ACPA-negative) and RA patients (n=99; 94 ACPA-positive and 5 ACPA-negative). RESULTS: V-domain glycans on ACPA-IgG were already present up to 15 years before disease in pre-symptomatic individuals and their abundance increased closer to symptom onset. Noteworthy, human leucocyte antigen class II shared epitope (HLA-SE) alleles associated with the presence of V-domain glycans on ACPA-IgG. CONCLUSION: Our observations indicate that somatic hypermutation of ACPA, which results in the incorporation of N-linked glycosylation sites and consequently V-domain glycans, occurs already years before symptom onset in individuals that will develop RA later in life. Moreover, our findings provide first evidence that HLA-SE alleles associate with ACPA-IgG V-domain glycosylation in the pre-disease phase and thereby further refine the connection between HLA-SE and the development of ACPA-positive RA.

Longitudinal Evidence for Dissociation of Anterior and Posterior MTL Resting-State Connectivity in Aging: Links to Perfusion and Memory.

Neuroimaging studies of spontaneous signal fluctuations as measured by resting-state functional magnetic resonance imaging have revealed age-related alterations in the functional architecture of brain networks. One such network is located in the medial temporal lobe (MTL), showing structural and functional variations along the anterior-posterior axis. Past cross-sectional studies of MTL functional connectivity (FC) have yielded discrepant findings, likely reflecting the fact that specific MTL subregions are differentially affected in aging. Here, using longitudinal resting-state data from 198 participants, we investigated 5-year changes in FC of the anterior and posterior MTL. We found an opposite pattern, such that the degree of FC within the anterior MTL declined after age 60, whereas elevated FC within the posterior MTL was observed along with attenuated posterior MTL-cortical connectivity. A significant negative change-change relation was observed between episodic-memory decline and elevated FC in the posterior MTL. Additional analyses revealed age-related cerebral blood flow (CBF) increases in posterior MTL at the follow-up session, along with a positive relation of elevated FC and CBF, suggesting that elevated FC is a metabolically demanding alteration. Collectively, our findings indicate that elevated FC in posterior MTL along with increased local perfusion is a sign of brain aging that underlie episodic-memory decline.

Age-related and genetic modulation of frontal cortex efficiency.

The dorsolateral pFC (DLPFC) is a key region for working memory. It has been proposed that the DLPFC is dynamically recruited depending on task demands. By this view, high DLPFC recruitment for low-demanding tasks along with weak DLPFC upregulation at higher task demands reflects low efficiency. Here, the fMRI BOLD signal during working memory maintenance and manipulation was examined in relation to aging and catechol-O-methyltransferase (COMT) Val(158)Met status in a large representative sample (n = 287). The efficiency hypothesis predicts a weaker DLPFC response during manipulation, along with a stronger response during maintenance for older adults and COMT Val carriers compared with younger adults and COMT Met carriers. Consistent with the hypothesis, younger adults and met carriers showed maximal DLPFC BOLD response during manipulation, whereas older adults and val carriers displayed elevated DLPFC responses during the less demanding maintenance condition. The observed inverted relations support a link between dopamine and DLPFC efficiency.

Community-dwelling older people with an injurious fall are likely to sustain new injurious falls within 5 years--a prospective long-term follow-up study.

BACKGROUND: Fall-related injuries in older people are a leading cause of morbidity and mortality. Self-reported fall events in the last year is often used to estimate fall risk in older people. However, it remains to be investigated if the fall frequency and the consequences of the falls have an impact on the risk for subsequent injurious falls in the long term. The objective of this study was to investigate if a history of one single non-injurious fall, at least two non-injurious falls, or at least one injurious fall within 12 months increases the risk of sustaining future injurious falls. METHODS: Community-dwelling individuals 75-93 years of age (n = 230) were initially followed prospectively with monthly calendars reporting falls over a period of 12 months. The participants were classified into four groups based on the number and type of falls (0, 1, ≥2 non-injurious falls, and ≥1 injurious fall severe enough to cause a visit to a hospital emergency department). The participants were then followed for several years (mean time 5.0 years ±1.1) regarding injurious falls requiring a visit to the emergency department. The Andersen-Gill method of Cox regression for multiple events was used to estimate the risk of injurious falls. RESULTS: During the long-term follow-up period, thirty per cent of the participants suffered from at least one injurious fall. Those with a self-reported history of at least one injurious fall during the initial 12 months follow-up period showed a significantly higher risk for sustaining subsequent injurious falls in the long term (hazard ratio 2.78; 95% CI, 1.40-5.50) compared to those with no falls. No other group showed an increased risk. CONCLUSIONS: In community-dwelling people over 75 years of age, a history of at least one self-reported injurious fall severe enough to cause a visit to the emergency department within a period of 12 months implies an increased risk of sustaining future injurious falls. Our results support the recommendations to offer a multifactorial fall-risk assessment coupled with adequate interventions to community-dwelling people over 75 years who present to the ED due to an injurious fall.

Incidence and predisposing factors of extra-articular manifestations in contemporary rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis [RA) is a chronic inflammatory disease, with potential for extra-articular manifestations (ExRA). The incidence and predisposing factors for ExRA and the mortality were evaluated in an early RA inception cohort. METHODS: Patients (n = 1468; 69 % females, mean age (SD) 57.3(16.3) years) were consecutively included at the date of diagnosis, between 1 January 1996 and 31 December 2016, and assessed prospectively. In December 2016 development of ExRA was evaluated by a patient questionnaire and a review of medical records. Cumulative incidence and incidence rates were compared between 5-year periods and between patients included before and after 1 January 2001. Cox proportional hazard regression models were used to identify predictors for ExRA, and models with ExRA as time-dependent variables to estimate the mortality. RESULTS: After a mean (SD) follow-up of 9.3(4.9) years, 238 cases (23.3 %) had ExRA and 151 (14.7 %) had ExRA without rheumatoid nodules. Most ExRA developed within 5 years from diagnosis. Rheumatoid nodules (10.5 %) and keratoconjunctivitis sicca (7.1 %) were the most frequent manifestations, followed by pulmonary fibrosis (6.1 %). The ExRA incidence among more recently diagnosed patients was similar as to the incidence among patients diagnosed before 2001. Seropositivity, smoking and early biological treatment were associated with development of ExRA. After 15 years 20 % had experienced ExRA. ExRA was associated with increased mortality, HR 3.029 (95 % CI 2.177-4.213). CONCLUSIONS: Early development of ExRA is frequent, particularly rheumatoid nodules. Predisposing factors were age, RF positivity, smoking and early biological treatment. The patients with ExRA had a 3-fold increase in mortality.

Longitudinal change-change associations of cognition with cortical thickness and surface area.

Age-related changes in cortical volumes are well established but relatively few studies probed its constituents, surface area (SA) and thickness (TH). Here we analyzed 10-year, 3-waves longitudinal data from a large sample of healthy individuals (baseline age = 55-80). The findings showed marked age-related changes of SA in frontal, temporal, and parietal association cortices, and Bivariate Latent Change Score models revealed significant SA-associations with changes in speed of processing in both the 5- and 10-year models. The corresponding results for TH revealed a late onset of thinning and significant associations with reduced cognition in the 10-year model only. Taken together, our findings suggest that cortical surface area shrinks and impacts information-processing capacity gradually in aging, whereas cortical thinning only manifests and impacts fluid cognition in advanced aging.

Protein Profiling in Presymptomatic Individuals Separates Myeloperoxidase-Antineutrophil Cytoplasmic Antibody and Proteinase 3-Antineutrophil Cytoplasmic Antibody Vasculitides.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a chronic relapsing condition with unknown etiology. To gain insight into the molecular processes underlying the disease, we examined biomarkers in blood samples collected prior to symptom onset. METHODS: The National Patient Register and Cause of Death register were searched for AAV-related International Classification of Diseases, Ninth Revision and Tenth Revision codes and linked to the registers from 5 biobanks. Eighty-five AAV patients with samples predating symptom onset of AAV were identified. For each case of AAV, 2 matched controls were included. Proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA expression levels were analyzed using enzyme-linked immunosorbent assays. Using an Olink Inflammation panel, 73 of 92 proteins were included after quality control. Data were replicated in a second cohort of 48 presymptomatic individuals and 96 controls. RESULTS: Of the 20 proteins with the lowest P values in the original cohort, 7 were replicated in the second cohort and 5 proteins were found to be significant between the groups in a meta-analysis. Eleven different pathways were identified in network enrichment analyses and were found to be significant in both cohorts. Stratification of samples obtained ≤5 years before symptom onset showed significant levels of CCL23, vascular endothelial growth factor A, and hepatocyte growth factor, which were also increased at borderline significant levels in the replication cohort (interleukin-6 was found to be significantly increased in the replication cohort). In presymptomatic AAV patients, 6 proteins were associated with MPO-ANCA positivity, and 7 proteins were associated with PR3-ANCA positivity. CONCLUSION: To our knowledge, this is the first study to identify protein markers preceding symptom onset in AAV patients. These findings set the stage for further research into the underlying cellular and molecular mechanisms in the pathogenesis of AAV and the diversification of patients into PR3-ANCA+ and MPO-ANCA+ subphenotypes.

Vaccination with Helicobacter pylori attachment proteins protects against gastric cancer.

Most cases of gastric cancer are caused by chronic Helicobacter pylori infection, but the lack of early onco-diagnostics and a high risk for antibiotic resistance hampers early intervention through eradication of H. pylori infection by antibiotics. We reported on a protective mechanism where H. pylori gastric mucosal attachment can be reduced by natural antibodies that block the binding of its attachment protein BabA. Here we show that challenge infection with H. pylori induced response of such blocking antibodies in both human volunteers and in rhesus macaques, that mucosal vaccination with BabA protein antigen induced blocking antibodies in rhesus macaques, and that vaccination in a mouse model induced blocking antibodies that reduced gastric mucosal inflammation, preserved the gastric juice acidity, and fully protected the mice from gastric cancer caused by H. pylori.

Helicobacter pylori attachment-blocking antibodies protect against duodenal ulcer disease.

The majority of the world population carry the gastric pathogen Helicobacter pylori. Fortunately, most individuals experience only low-grade or no symptoms, but in many cases the chronic inflammatory infection develops into severe gastric disease, including duodenal ulcer disease and gastric cancer. Here we report on a protective mechanism where H. pylori attachment and accompanying chronic mucosal inflammation can be reduced by antibodies that are present in a vast majority of H. pylori carriers. These antibodies block binding of the H. pylori attachment protein BabA by mimicking BabA's binding to the ABO blood group glycans in the gastric mucosa. However, many individuals demonstrate low titers of BabA blocking antibodies, which is associated with an increased risk for duodenal ulceration, suggesting a role for these antibodies in preventing gastric disease.

Polygenic Risk for Schizophrenia Has Sex-Specific Effects on Brain Activity during Memory Processing in Healthy Individuals.

Genetic risk for schizophrenia has a negative impact on memory and other cognitive abilities in unaffected individuals, and it was recently shown that this effect is specific to males. Using functional MRI, we investigated the effect of a polygenic risk score (PRS) for schizophrenia on brain activation during working memory and episodic memory in 351 unaffected participants (167 males and 184 females, 25-95 years), and specifically tested if any effect of PRS on brain activation is sex-specific. Schizophrenia PRS was significantly associated with decreased brain activation in the left dorsolateral prefrontal cortex (DLPFC) during working-memory manipulation and in the bilateral superior parietal lobule (SPL) during episodic-memory encoding and retrieval. A significant interaction effect between sex and PRS was seen in the bilateral SPL during episodic-memory encoding and retrieval, and sex-stratified analyses showed that the effect of PRS on SPL activation was male-specific. These results confirm previous findings of DLPFC inefficiency in schizophrenia, and highlight the SPL as another important genetic intermediate phenotype of the disease. The observed sex differences suggest that the previously shown male-specific effect of schizophrenia PRS on cognition translates into an additional corresponding effect on brain functioning.

Dopamine D2/3-receptor availability and its association with autonomous motivation to exercise in older adults: An exploratory [11C]-raclopride study.

Background: Autonomous motivation to exercise occurs when the activity is voluntary and with a perceived inherent satisfaction from the activity itself. It has been suggested that autonomous motivation is related to striatal dopamine D2/3-receptor (D2/3R) availability within the brain. In this study, we hypothesized that D2/3R availability in three striatal regions (nucleus accumbens, caudate nucleus, and putamen) would be positively associated with self-reported autonomous motivation to exercise. We also examined this relationship with additional exploratory analyses across a set of a priori extrastriatal regions of interest (ROI). Methods: Our sample comprised 49 older adults (28 females) between 64 and 78 years of age. The D2/3R availability was quantified from positron emission tomography using the non-displaceable binding potential of [11C]-raclopride ligand. The exercise-related autonomous motivation was assessed with the Swedish version of the Behavioral Regulations in Exercise Questionnaire-2. Results: No significant associations were observed between self-reported autonomous motivation to exercise and D2/3R availability within the striatum (nucleus accumbens, caudate nucleus, and putamen) using semi-partial correlations controlling for ROI volume on D2/3R availability. For exploratory analyses, positive associations were observed for the superior (r = 0.289, p = 0.023) and middle frontal gyrus (r = 0.330, p = 0.011), but not for the inferior frontal gyrus, orbitofrontal cortex, anterior cingulate cortex, or anterior insular cortex. Conclusion: This study could not confirm the suggested link between striatal D2/3R availability and subjective autonomous motivation to exercise among older adults. The exploratory findings, however, propose that frontal brain regions may be involved in the intrinsic regulation of exercise-related behaviors, though this has to be confirmed by future studies using a more suitable ligand and objective measures of physical activity levels.

Model of brain maintenance reveals specific change-change association between medial-temporal lobe integrity and episodic memory.

Brain maintenance has been identified as a major determinant of successful memory aging. However, the extent to which brain maintenance in support of successful memory aging is specific to memory-related brain regions or forms part of a brain-wide phenomenon is unresolved. Here, we used longitudinal brain-wide gray matter MRI volumes in 262 healthy participants aged 55 to 80 years at baseline to investigate separable dimensions of brain atrophy, and explored the links of these dimensions to different dimensions of cognitive change. We statistically adjusted for common causes of change in both brain and cognition to reveal a potentially unique signature of brain maintenance related to successful memory aging. Critically, medial temporal lobe (MTL)/hippocampal change and episodic memory change were characterized by unique, residual variance beyond general factors of change in brain and cognition, and a reliable association between these two residualized variables was established (r = 0.36, p < 0.01). The present study is the first to provide solid evidence for a specific association between changes in (MTL)/hippocampus and episodic memory in normal human aging. We conclude that hippocampus-specific brain maintenance relates to the specific preservation of episodic memory in old age, in line with the notion that brain maintenance operates at both general and domain-specific levels.

Association of APOE ɛ4 and Plasma p-tau181 with Preclinical Alzheimer's Disease and Longitudinal Change in Hippocampus Function.

BACKGROUND: The Apolipoprotein E (APOE) ɛ4 allele has been linked to increased tau phosphorylation and tangle formation. APOE ɛ4 carriers with elevated tau might be at the higher risk for Alzheimer's disease (AD) progression. Previous studies showed that tau pathology begins early in areas of the medial temporal lobe. Similarly, APOE ɛ4 carriers showed altered hippocampal functional integrity. However, it remains unknown whether the influence of elevated tau accumulation on hippocampal functional changes would be more pronounced for APOE ɛ4 carriers. OBJECTIVE: We related ɛ4 carriage to levels of plasma phosphorylated tau (p-tau181) up to 15 years prior to AD onset. Furthermore, elevated p-tau181 was explored in relation to longitudinal changes in hippocampal function and connectivity. METHODS: Plasma p-tau181 was analyzed in 142 clinically defined AD cases and 126 matched controls. The longitudinal analysis involved 87 non-demented individuals (from population-based study) with two waves of plasma samples and three waves of functional magnetic resonance imaging during rest and memory encoding. RESULTS: Increased p-tau181 was observed for both ɛ4 carriers and non-carriers close to AD onset, but exclusively for ɛ4 carriers in the early preclinical groups (7- and 13-years pre-AD). In ɛ4 carriers, longitudinal p-tau181 increase was paralleled by elevated local hippocampal connectivity at rest and subsequent reduction of hippocampus encoding-related activity. CONCLUSION: Our findings support an association of APOE ɛ4 and p-tau181 with preclinical AD and hippocampus functioning.