Hippocampal subfield volumes and pre-clinical Alzheimer's disease in 408 cognitively normal adults born in 1946

BACKGROUND: The human hippocampus comprises a number of interconnected histologically and functionally distinct subfields, which may be differentially influenced by cerebral pathology. Automated techniques are now available that estimate hippocampal subfield volumes using in vivo structural MRI data. To date, research investigating the influence of cerebral β-amyloid deposition-one of the earliest hypothesised changes in the pathophysiological continuum of Alzheimer's disease-on hippocampal subfield volumes in cognitively normal older individuals, has been limited. METHODS: Using cross-sectional data from 408 cognitively normal individuals born in mainland Britain (age range at time of assessment = 69.2-71.9 years) who underwent cognitive assessment, 18F-Florbetapir PET and structural MRI on the same 3 Tesla PET/MR unit (spatial resolution 1.1 x 1.1 x 1.1. mm), we investigated the influences of β-amyloid status, age at scan, and global white matter hyperintensity volume on: CA1, CA2/3, CA4, dentate gyrus, presubiculum and subiculum volumes, adjusting for sex and total intracranial volume. RESULTS: Compared to β-amyloid negative participants (n = 334), β-amyloid positive participants (n = 74) had lower volume of the presubiculum (3.4% smaller, p = 0.012). Despite an age range at scanning of just 2.7 years, older age at time of scanning was associated with lower CA1 (p = 0.007), CA4 (p = 0.004), dentate gyrus (p = 0.002), and subiculum (p = 0.035) volumes. There was no evidence that white matter hyperintensity volume was associated with any subfield volumes. CONCLUSION: These data provide evidence of differential associations in cognitively normal older adults between hippocampal subfield volumes and β-amyloid deposition and, increasing age at time of scan. The relatively selective effect of lower presubiculum volume in the β-amyloid positive group potentially suggest that the presubiculum may be an area of early and relatively specific volume loss in the pathophysiological continuum of Alzheimer's disease. Future work using higher resolution imaging will be key to exploring these findings further

Cognition at age 70: Life course predictors and associations with brain pathologies

Objective: To investigate predictors of performance on a range of cognitive measures including the Preclinical Alzheimer Cognitive Composite (PACC) and test for associations between cognition and dementia biomarkers in Insight 46, a substudy of the Medical Research Council National Survey of Health and Development. // Methods: A total of 502 individuals born in the same week in 1946 underwent cognitive assessment at age 69–71 years, including an adapted version of the PACC and a test of nonverbal reasoning. Performance was characterized with respect to sex, childhood cognitive ability, education, and socioeconomic position (SEP). In a subsample of 406 cognitively normal participants, associations were investigated between cognition and β-amyloid (Aβ) positivity (determined from Aβ-PET imaging), whole brain volumes, white matter hyperintensity volumes (WMHV), and APOE ε4. // Results: Childhood cognitive ability was strongly associated with cognitive scores including the PACC more than 60 years later, and there were independent effects of education and SEP. Sex differences were observed on every PACC subtest. In cognitively normal participants, Aβ positivity and WMHV were independently associated with lower PACC scores, and Aβ positivity was associated with poorer nonverbal reasoning. Aβ positivity and WMHV were not associated with sex, childhood cognitive ability, education, or SEP. Normative data for 339 cognitively normal Aβ-negative participants are provided. // Conclusions: This study adds to emerging evidence that subtle cognitive differences associated with Aβ deposition are detectable in older adults, at an age when dementia prevalence is very low. The independent associations of childhood cognitive ability, education, and SEP with cognitive performance at age 70 have implications for interpretation of cognitive data in later life

Associations Between Vascular Risk Across Adulthood and Brain Pathology in Late Life: Evidence From a British Birth Cohort

IMPORTANCE: Midlife vascular risk burden is associated with late-life dementia. Less is known about if and how risk exposure in early adulthood influences late-life brain health. OBJECTIVE: To determine the associations between vascular risk in early adulthood, midlife, and late life with late-life brain structure and pathology using measures of white matter–hyperintensity volume, β-amyloid load, and whole-brain and hippocampal volumes. DESIGN, SETTING, AND PARTICIPANTS: This prospective longitudinal cohort study, Insight 46, is part of the Medical Research Council National Survey of Health and Development, which commenced in 1946. Participants had vascular risk factors evaluated at ages 36 years (early adulthood), 53 years (midlife), and 69 years (early late life). Participants were assessed with multimodal magnetic resonance imaging and florbetapir-amyloid positron emission tomography scans between May 2015 and January 2018 at University College London. Participants with at least 1 available imaging measure, vascular risk measurements at 1 or more points, and no dementia were included in analyses. EXPOSURES: Office-based Framingham Heart study–cardiovascular risk scores (FHS-CVS) were derived at ages 36, 53, and 69 years using systolic blood pressure, antihypertensive medication usage, smoking, diabetic status, and body mass index. Analysis models adjusted for age at imaging, sex, APOE genotype, socioeconomic position, and, where appropriate, total intracranial volume. MAIN OUTCOMES AND MEASURES: White matter–hyperintensity volume was generated from T1/fluid-attenuated inversion recovery scans using an automated technique and whole-brain volume and hippocampal volume were generated from automated in-house pipelines; β-amyloid status was determined using a gray matter/eroded subcortical white matter standardized uptake value ratio threshold of 0.61. RESULTS: A total of 502 participants were assessed as part of Insight 46, and 463 participants (236 male [51.0%]) with at least 1 available imaging measure (mean [SD] age at imaging, 70.7 [0.7] years; 83 β-amyloid positive [18.2%]) who fulfilled eligibility criteria were included. Among them, FHS-CVS increased with age (36 years: median [interquartile range], 2.7% [1.5%-3.6%]; 53 years: 10.9% [6.7%-15.6%]; 69 years: 24.3% [14.9%-34.9%]). At all points, these scores were associated with smaller whole-brain volumes (36 years: β coefficient per 1% increase, −3.6 [95% CI, −7.0 to −0.3]; 53 years: −0.8 [95% CI, −1.5 to −0.08]; 69 years: −0.6 [95% CI, −1.1 to −0.2]) and higher white matter–hyperintensity volume (exponentiated coefficient: 36 years, 1.09 [95% CI, 1.01-1.18]; 53 years, 1.02 [95% CI, 1.00-1.04]; 69 years, 1.01 [95% CI, 1.00-1.02]), with largest effect sizes at age 36 years. At no point were FHS-CVS results associated with β-amyloid status. CONCLUSIONS AND RELEVANCE: A total of 502 participants were assessed as part of Insight 46, and 463 participants (236 male [51.0%]) with at least 1 available imaging measure (mean [SD] age at imaging, 70.7 [0.7] years; 83 β-amyloid positive [18.2%]) who fulfilled eligibility criteria were included. Among them, FHS-CVS increased with age (36 years: median [interquartile range], 2.7% [1.5%-3.6%]; 53 years: 10.9% [6.7%-15.6%]; 69 years: 24.3% [14.9%-34.9%]). At all points, these scores were associated with smaller whole-brain volumes (36 years: β coefficient per 1% increase, −3.6 [95% CI, −7.0 to −0.3]; 53 years: −0.8 [95% CI, −1.5 to −0.08]; 69 years: −0.6 [95% CI, −1.1 to −0.2]) and higher white matter–hyperintensity volume (exponentiated coefficient: 36 years, 1.09 [95% CI, 1.01-1.18]; 53 years, 1.02 [95% CI, 1.00-1.04]; 69 years, 1.01 [95% CI, 1.00-1.02]), with largest effect sizes at age 36 years. At no point were FHS-CVS results associated with β-amyloid status

Dissociable effects of APOE ε4 and β-amyloid pathology on visual working memory

Although APOE ε4 carriers are at substantially higher risk of developing Alzheimer’s disease than noncarriers, controversial evidence suggests that APOE ε4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy). In a population-based cohort born in one week in 1946 (assessed aged 69–71 years), we assessed differential effects of APOE ε4 and β-amyloid pathology (quantified using 18F-Florbetapir-PET) on visual working memory (object–location binding). In 398 cognitively normal participants, APOE ε4 and β-amyloid had opposing effects on object identification, predicting better and poorer recall, respectively. ε4 carriers also recalled locations more precisely, with a greater advantage at higher β-amyloid burden. These results provide evidence of superior visual working memory in ε4 carriers, showing that some benefits of this genotype are demonstrable in older age, even in the preclinical stages of Alzheimer’s disease

A population‐based study of head injury, cognitive function and pathological markers

OBJECTIVE: To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later-life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia-free individuals. METHODS: Participants (n = 502, age = 69-71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18 F-florbetapir Aβ-PET and MR imaging. Measures include Aβ-PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer's disease (AD)-related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15 years prior to the scan (ii) anytime up to age 71. RESULTS: Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15 years prior (16%, n = 80) performed worse on cognitive tests at age 69-71, taking into account premorbid cognition, particularly on the digit-symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD-related cortical thickness or NFL (all p > 0.01). INTERPRETATION: Having a LOC HI aged 50's and younger was linked with lower later-life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL)

Anti-angiogenic effects of pterogynidine alkaloid isolated from Alchornea glandulosa

<p>Abstract</p> <p>Background</p> <p>Angiogenesis, a complex multistep process that comprehends proliferation, migration and anastomosis of endothelial cells (EC), has a major role in the development of pathologic conditions such as inflammatory diseases, tumor growth and metastasis. Brazilian flora, the most diverse in the world, is an interesting spot to prospect for new chemical leads, being an important source of new anticancer drugs. Plant-derived alkaloids have traditionally been of interest due to their pronounced physiological activities. We investigated the anti-angiogenic potential of the naturally occurring guanidine alkaloid pterogynidine (Pt) isolated from the Brazilian plant <it>Alchornea glandulosa</it>. The purpose of this study was to examine which features of the angiogenic process could be disturbed by Pt.</p> <p>Methods</p> <p>Human umbilical vein endothelial cells (HUVEC) were incubated with 8 μM Pt and cell viability, proliferation, apoptosis, invasion and capillary-like structures formation were addressed. Nuclear factor κB (NFκB), a transcription factor implicated in these processes, was also evaluated in HUVEC incubated with Pt. Quantifications were expressed as mean ± SD of five independent experiments and one-way analysis of variance (ANOVA) followed by the Dunnet test was used.</p> <p>Results</p> <p>A significant decrease in proliferation and invasion capacity and an effective increase in apoptosis as assessed by bromodeoxyuridine (BrdU), double-chamber and terminal transferase dUTP nick end labeling (TUNEL) assay, respectively, have been found. Pt also led to a drastic reduction in the number of capillary-like structures formation when HUVEC were cultured on growth factor reduced-Matrigel (GFR-Matrigel) coated plates. In addition, incubation of HUVEC with Pt resulted in reduced NFκB activity.</p> <p>Conclusion</p> <p>These findings emphasize the potential use of Pt against pathological situations where angiogenesis is stimulated as tumor development.</p

Incidental findings on brain imaging and blood tests: results from the first phase of Insight 46, a prospective observational substudy of the 1946 British birth cohort

Objective To summarise the incidental findings detected on brain imaging and blood tests during the first wave of data collection for the Insight 46 study. Design Prospective observational sub-study of a birth cohort. Setting Single-day assessment at a research centre in London, UK. Participants 502 individuals were recruited from the MRC National Survey of Health and Development (NSHD), the 1946 British birth cohort, based on pre-specified eligibility criteria; mean age was 70.7 (SD: 0.7) and 49% were female. Outcome measures Data regarding the number and types of incidental findings were summarised as counts and percentages, and 95% confidence intervals were calculated. Results 93.8% of participants completed a brain scan (n=471); 4.5% of scanned participants had a pre-defined reportable abnormality on brain MRI (n=21); suspected vascular malformations and suspected intracranial mass lesions were present in 1.9% (n=9) and 1.5% (n=7) respectively; suspected cerebral aneurysms were the single most common vascular abnormality, affecting 1.1% of participants (n=5), and suspected meningiomas were the most common intracranial lesion, affecting 0.6% of participants (n=3); 34.6% of participants had at least one abnormality on clinical blood tests (n=169), but few reached the prespecified threshold for urgent action (n=11). Conclusions In older adults, aged 69-71 years, potentially serious brain MRI findings were detected in around 5% of participants, and clinical blood test abnormalities were present in around one third of participants. Knowledge of the expected prevalence of incidental findings in the general population at this age is useful in both research and clinical settings

Androgen receptor expresion in breast cancer: Relationship with clinicopathological characteristics of the tumors, prognosis, and expression of metalloproteases and their inhibitors

<p>Abstract</p> <p>Background</p> <p>In the present study we analyze, in patients with breast cancer, the tumor expression of androgen receptors (AR), its relationship with clinicopathological characteristics and with the expression of several matrix metalloproteases (MMPs) and their inhibitors (TIMPs), as well as with prognosis.</p> <p>Methods</p> <p>An immunohistochemical study was performed using tissue microarrays and specific antibodies against AR, MMPs -1, -2, -7, -9, -11, -13, -14, and TIMPs -1, -2 and -3. More than 2,800 determinations on tumor specimens from 111 patients with primary invasive ductal carcinoma of the breast (52 with axillary lymph node metastases and 59 without them) and controls were performed. Staining results were categorized using a score based on the intensity of the staining and a specific software program calculated the percentage of immunostained cells automatically.</p> <p>Results</p> <p>A total of 83 cases (74.8%) showed a positive immunostaining for AR, but with a wide variation in the staining score values. There were no significant associations between the total immunostaining scores for AR and any clinicopathological parameters. However, score values for MMP-1, -7 and -13, were significantly higher in AR-positive tumors than in AR-negative tumors. Likewise, when we considered the cellular type expressing each factor, we found that AR-positive tumors had a higher percentage of cases positive for MMP-1, -7, -11, and TIMP-2 in their malignant cells, as well as for MMP-1 in intratumoral fibroblasts. On the other hand, multivariate analysis demonstrated that patients with AR-positive tumors have a significant longer overall survival than those with AR-negative breast carcinomas (<it>p </it>= 0.03).</p> <p>Conclusion</p> <p>Our results confirm that AR are commonly expressed in breast cancer, and are correlated with the expression of some MMPs and TIMP-2. Although we found a specific value of AR expression to be a prognostic indicator in breast cancer, the functional role of AR in these neoplasms is still unclear and further data are needed in order to clarify their biological signification in breast cancer.</p

Associations between blood pressure across adulthood and late-life brain structure and pathology in the neuroscience substudy of the 1946 British birth cohort (Insight 46): an epidemiological study

BACKGROUND: Midlife hypertension confers increased risk for cognitive impairment in late life. The sensitive period for risk exposure and extent that risk is mediated through amyloid or vascular-related mechanisms are poorly understood. We aimed to identify if, and when, blood pressure or change in blood pressure during adulthood were associated with late-life brain structure, pathology, and cognition. METHODS: Participants were from Insight 46, a neuroscience substudy of the ongoing longitudinal Medical Research Council National Survey of Health and Development, a birth cohort that initially comprised 5362 individuals born throughout mainland Britain in one week in 1946. Participants aged 69-71 years received T1 and FLAIR volumetric MRI, florbetapir amyloid-PET imaging, and cognitive assessment at University College London (London, UK); all participants were dementia-free. Blood pressure measurements had been collected at ages 36, 43, 53, 60-64, and 69 years. We also calculated blood pressure change variables between ages. Primary outcome measures were white matter hyperintensity volume (WMHV) quantified from multimodal MRI using an automated method, amyloid-β positivity or negativity using a standardised uptake value ratio approach, whole-brain and hippocampal volumes quantified from 3D-T1 MRI, and a composite cognitive score-the Preclinical Alzheimer Cognitive Composite (PACC). We investigated associations between blood pressure and blood pressure changes at and between 36, 43, 53, 60-64, and 69 years of age with WMHV using generalised linear models with a gamma distribution and log link function, amyloid-β status using logistic regression, whole-brain volume and hippocampal volumes using linear regression, and PACC score using linear regression, with adjustment for potential confounders. FINDINGS: Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. 465 participants (238 [51%] men; mean age 70·7 years [SD 0·7]; 83 [18%] amyloid-β-positive) were included in imaging analyses. Higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) at age 53 years and greater increases in SBP and DBP between 43 and 53 years were positively associated with WMHV at 69-71 years of age (increase in mean WMHV per 10 mm Hg greater SBP 7%, 95% CI 1-14, p=0·024; increase in mean WMHV per 10 mm Hg greater DBP 15%, 4-27, p=0·0057; increase in mean WMHV per one SD change in SBP 15%, 3-29, p=0·012; increase in mean WMHV per 1 SD change in DBP 15%, 3-30, p=0·017). Higher DBP at 43 years of age was associated with smaller whole-brain volume at 69-71 years of age (-6·9 mL per 10 mm Hg greater DBP, -11·9 to -1·9, p=0·0068), as were greater increases in DBP between 36 and 43 years of age (-6·5 mL per 1 SD change, -11·1 to -1·9, p=0·0054). Greater increases in SBP between 36 and 43 years of age were associated with smaller hippocampal volumes at 69-71 years of age (-0·03 mL per 1 SD change, -0·06 to -0·001, p=0·043). Neither absolute blood pressure nor change in blood pressure predicted amyloid-β status or PACC score at 69-71 years of age. INTERPRETATION: High and increasing blood pressure from early adulthood into midlife seems to be associated with increased WMHV and smaller brain volumes at 69-71 years of age. We found no evidence that blood pressure affected cognition or cerebral amyloid-β load at this age. Blood pressure monitoring and interventions might need to start around 40 years of age to maximise late-life brain health. FUNDING: Alzheimer's Research UK, Medical Research Council, Dementias Platform UK, Wellcome Trust, Brain Research UK, Wolfson Foundation, Weston Brain Institute, Avid Radiopharmaceuticals

The Twin-Arginine Translocation Pathway in α-Proteobacteria Is Functionally Preserved Irrespective of Genomic and Regulatory Divergence

The twin-arginine translocation (Tat) pathway exports fully folded proteins out of the cytoplasm of Gram-negative and Gram-positive bacteria. Although much progress has been made in unraveling the molecular mechanism and biochemical characterization of the Tat system, little is known concerning its functionality and biological role to confer adaptive skills, symbiosis or pathogenesis in the α-proteobacteria class. A comparative genomic analysis in the α-proteobacteria class confirmed the presence of tatA, tatB, and tatC genes in almost all genomes, but significant variations in gene synteny and rearrangements were found in the order Rickettsiales with respect to the typically described operon organization. Transcription of tat genes was confirmed for Anaplasma marginale str. St. Maries and Brucella abortus 2308, two α-proteobacteria with full and partial intracellular lifestyles, respectively. The tat genes of A. marginale are scattered throughout the genome, in contrast to the more generalized operon organization. Particularly, tatA showed an approximately 20-fold increase in mRNA levels relative to tatB and tatC. We showed Tat functionality in B. abortus 2308 for the first time, and confirmed conservation of functionality in A. marginale. We present the first experimental description of the Tat system in the Anaplasmataceae and Brucellaceae families. In particular, in A. marginale Tat functionality is conserved despite operon splitting as a consequence of genome rearrangements. Further studies will be required to understand how the proper stoichiometry of the Tat protein complex and its biological role are achieved. In addition, the predicted substrates might be the evidence of role of the Tat translocation system in the transition process from a free-living to a parasitic lifestyle in these α-proteobacteria