Association of Carotid Intima Media Thickening with Future Brain Region Specific Amyloid-β Burden.

BACKGROUND: Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid-β (Aβ) burden. OBJECTIVE: We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aβ on 11C-Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aβ burden. METHODS: We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5±5.7 years) and an average of 9.6 years later, and PiB imaging measuring Aβ on average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow-up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aβ in brain regions associated with Alzheimers disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors. RESULTS: Participants with higher mean ICA IMT had more Aβ in the precuneus (beta±standard error [β±SE]: 0.466±0.171 mm, p = 0.01) and the frontal, lateral, and retrosplenial regions (β±SE: 0.392±0.164 mm, p = 0.022) after adjusting for age, sex, vascular risk factors, and medication use. We did not find an association between any CCA IMT measures and Aβ or progression of ICA or CCA IMT and Aβ. CONCLUSION: Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aβ burden later in life. These findings support a link between vascular disease and AD/ADRD pathophysiology

Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-β and Tau Pathology in Middle-Aged Adults: The Framingham Study.

BACKGROUND: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimers disease pathology is unclear. OBJECTIVE: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-β (Aβ) and tau pathology. METHODS: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aβ, adjusting for potential confounders and multiple comparisons. RESULTS: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 > 1.3). Prevalent NAFLD was not associated with Aβ or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (β= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (β= 2.01±0.47, p < 0.001; β= 1.60±0.53, p = 0.007, and β= 1.59±0.47, p = 0.003 and β= 1.60±0.42, p = 0.001, respectively) and to Aβ deposition overall and in the inferior temporal and parahippocampal regions (β= 1.93±0.47, p < 0.001; β= 1.59±0.38, p < 0.001, and β= 1.52±0.54, p = 0.008, respectively). CONCLUSION: This study suggests a possible association between liver fibrosis and early Alzheimers disease pathology, independently of cardio-metabolic risk factors

Changes in prevalence and incidence of dementia and risk factors for dementia:an analysis from cohort studies

Background: Some cohort studies have reported a decline in dementia prevalence and incidence over time, although these findings have not been consistent across studies. We reviewed evidence on changes in dementia prevalence and incidence over time using published population-based cohort studies that had used consistent methods with each wave and aimed to quantify associated changes in risk factors over time using population attributable fractions (PAFs). Methods: We searched for systematic reviews of cohort studies examining changes in dementia prevalence or incidence over time. We searched PubMed for publications from database inception up to Jan 12, 2023, using the search terms “systematic review” AND “dementia” AND (“prevalence” OR “incidence”), with no language restrictions. We repeated this search on March 28, 2024. From eligible systematic reviews, we searched the references and selected peer-reviewed publications about cohort studies where dementia prevalence or incidence was measured in the same geographical location, at a minimum of two timepoints, and that reported age-standardised prevalence or incidence of dementia. Additionally, data had to be from population-based samples, in which participants’ cognitive status was assessed and where validated criteria were used to diagnose dementia. We extracted summary-level data from each paper about dementia risk factors, contacting authors when such data were not available in the published paper, and calculated PAFs for each risk factor at all available timepoints. Where possible, we linked changes in dementia prevalence or incidence with changes in the prevalence of risk factors. Findings: We identified 1925 records in our initial search, of which five eligible systematic reviews were identified. Within these systematic reviews, we identified 71 potentially eligible primary papers, of which 27 were included in our analysis. 13 (48%) of 27 primary papers reported change in prevalence of dementia, ten (37%) reported change in incidence of dementia, and four (15%) reported change in both incidence and prevalence of dementia. Studies reporting change in dementia incidence over time in Europe (n=5) and the USA (n=5) consistently reported a declining incidence in dementia. One study from Japan reported an increase in dementia prevalence and incidence and a stable incidence was reported in one study from Nigeria. Overall, across studies, the PAFs for less education or smoking, or both, generally declined over time, whereas PAFs for obesity, hypertension, and diabetes generally increased. The decrease in PAFs for less education and smoking was associated with a decline in the incidence of dementia in the Framingham study (Framingham, MA, USA, 1997–2013), the only study with sufficient data to allow analysis. Interpretation: Our findings suggest that lifestyle interventions such as compulsory education and reducing rates of smoking through country-level policy changes could be associated with an observed reduction, and therefore future reduction, in the incidence of dementia. More studies are needed in low-income and middle-income countries, where the burden of dementia is highest, and continues to increase. </p

Changes in prevalence and incidence of dementia and risk factors for dementia: an analysis from cohort studies

Background: Some cohort studies have reported a decline in dementia prevalence and incidence over time, although these findings have not been consistent across studies. We reviewed evidence on changes in dementia prevalence and incidence over time using published population-based cohort studies that had used consistent methods with each wave and aimed to quantify associated changes in risk factors over time using population attributable fractions (PAFs). Methods: We searched for systematic reviews of cohort studies examining changes in dementia prevalence or incidence over time. We searched PubMed for publications from database inception up to Jan 12, 2023, using the search terms “systematic review” AND “dementia” AND (“prevalence” OR “incidence”), with no language restrictions. We repeated this search on March 28, 2024. From eligible systematic reviews, we searched the references and selected peer-reviewed publications about cohort studies where dementia prevalence or incidence was measured in the same geographical location, at a minimum of two timepoints, and that reported age-standardised prevalence or incidence of dementia. Additionally, data had to be from population-based samples, in which participants’ cognitive status was assessed and where validated criteria were used to diagnose dementia. We extracted summary-level data from each paper about dementia risk factors, contacting authors when such data were not available in the published paper, and calculated PAFs for each risk factor at all available timepoints. Where possible, we linked changes in dementia prevalence or incidence with changes in the prevalence of risk factors. Findings: We identified 1925 records in our initial search, of which five eligible systematic reviews were identified. Within these systematic reviews, we identified 71 potentially eligible primary papers, of which 27 were included in our analysis. 13 (48%) of 27 primary papers reported change in prevalence of dementia, ten (37%) reported change in incidence of dementia, and four (15%) reported change in both incidence and prevalence of dementia. Studies reporting change in dementia incidence over time in Europe (n=5) and the USA (n=5) consistently reported a declining incidence in dementia. One study from Japan reported an increase in dementia prevalence and incidence and a stable incidence was reported in one study from Nigeria. Overall, across studies, the PAFs for less education or smoking, or both, generally declined over time, whereas PAFs for obesity, hypertension, and diabetes generally increased. The decrease in PAFs for less education and smoking was associated with a decline in the incidence of dementia in the Framingham study (Framingham, MA, USA, 1997–2013), the only study with sufficient data to allow analysis. Interpretation: Our findings suggest that lifestyle interventions such as compulsory education and reducing rates of smoking through country-level policy changes could be associated with an observed reduction, and therefore future reduction, in the incidence of dementia. More studies are needed in low-income and middle-income countries, where the burden of dementia is highest, and continues to increase. Funding: National Institute for Health and Care Research Three Schools’ Dementia Research Programme

A population-based meta-analysis of circulating GFAP for cognition and dementia risk

Funding Information: The authors thank the study participants, the study teams, and the investigators and staff of the cohort studies. Dr. Pase is supported by a Heart Foundation Future Leader Fellowship (GNT102052). Dr DeCarli is supported by the UCD ADRC P30 AG 010129. Dr Aparicio is supported by an American Academy of Neurology Career Development Award, Alzheimer's Association (AARGD‐20‐685362), and National Institutes of Health (L30 NS093634). Funding was provided by the CHARGE infrastructure grant (HL105756). Funding Information: This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC15103, 75N92021D00006, and grants R01AG15928, R01AG20098, U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG053325, K24AG065525, and R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS‐NHLBI.org. Funding Information: This work was made possible by grants from the Alzheimer's Drug Discovery Foundation (GDAPB‐202010‐2020940), National Institutes of Health (N01‐HC‐25195, HHSN268201500001I, 75N92019D00031) and the National Institute on Aging (AG059421, AG054076, AG049607, AG033090, AG066524, NS017950, P30AG066546, UF1NS125513). Funding Information: The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contract Nos. HHSN26820180003I, HHSN26820180004I, HHSN26820180005I, HHSN26820180006I, and HHSN26820180007I from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra‐agency agreement between NIA and NHLBI (No. AG0005) . Funding Information: The Age, Gene/Environment Susceptibility‐Reykjavik Study was supported by NIH contracts N01‐AG‐1‐2100 and HHSN27120120022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Funding Information: Dr. Pase is supported by a Heart Foundation Future Leader Fellowship (GNT102052). Dr DeCarli is supported by the UCD ADRC P30 AG 010129. Dr Aparicio is supported by an American Academy of Neurology Career Development Award, Alzheimer's Association (AARGD‐20‐685362), and National Institutes of Health (L30 NS093634). Funding was provided by the CHARGE infrastructure grant (HL105756). Funding Information Publisher Copyright: © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.Objective: Expression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population-based level are necessary to broaden generalizability to community settings. Methods: Circulating GFAP levels were assayed using a Simoa HD-1 analyzer in 4338 adults without prevalent dementia from four longitudinal community-based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all-cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta-analysis was performed on the estimates derived from each cohort using random-effects models. Results: Meta-analyses indicated that higher circulating GFAP associated with lower general cognition (ß = −0.09, [95% confidence interval [CI]: −0.15 to −0.03], p = 0.005), but not with total brain or hippocampal volume (p > 0.05). However, each standard deviation unit increase in log-transformed GFAP levels was significantly associated with a 2.5-fold higher risk of incident all-cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52–4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42–4.53]) over up to 15-years of follow-up. Interpretation: Results support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.Peer reviewe

Associations of Pulmonary Function with MRI Brain Volumes : A Coordinated Multi-Study Analysis

This study was supported by National Institute of Health (NIH) grant AG059421. Additional study-specific acknowledgements can be found in the Supplementary Material.BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent. OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables. METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses. RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume. CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.Peer reviewe

Ellipticine binds to a human telomere sequence: an additional mode of action as a putative anticancer agent?

Polyguanine sequences fold into G-quadruplex structures in the presence of monovalent cations. It is accepted that the telomeric DNA region consists of G-quadruplex structure. There are reports that potential G-quadruplex forming motifs are also present in the promoter region of some proto-oncogenes such as c-myc, c-kit, KRAS, etc. Small molecules with the potential to stabilize the telomeric DNA quadruplex have emerged as potential anticancer agents. We have studied the interaction of ellipticine, a putative anticancer agent from a plant source, with a human telomeric DNA sequence (H24). Spectroscopic and calorimetric studies indicate that the association of ellipticine with H24 is an entropically driven phenomenon with a 2:3 (H24:ellipticine) stoichiometry. Though ellipticine binding does not induce any major structural perturbation in H24, the association leads to formation of a complex with enhanced thermal stability. An assay with the telomerase repeat amplification protocol shows that ellipticine inhibits telomerase activity in MDAMB-231 breast cancer cell line extracts. This is the first report of the quadruplex binding ability of ellipticine. Using the results, we propose that along with DNA intercalation and/or topoisomerase II inhibition, interaction with the telomeric DNA region and the resultant inhibition of telomerase activity might be an additional mode of action for its anticancer property

Molecular basis of recognition of quadruplexes human telomere and c-myc promoter by the putative anticancer agent sanguinarine

Background: Interaction of putative anticancer agent sanguinarine with two quadruplex forming sequences, human telomeric DNA (H24) and NHE III1 upstream of the P1 promoter of c-myc (Pu27), has been studied to understand the structural basis of the recognition. Methods: Absorption, fluorescence and circular dichroism spectroscopy have been employed to characterize the association. Energetics of the interaction was studied by isothermal titration and differential scanning calorimetry. TRAP assay was done to assess the inhibitory potential of sanguinarine. Results: Absorption and fluorescence studies show that sanguinarine has high binding affinity of ~105 M-1 for both sequences. Binding stoichiometry is 2:1 for H24 and 3:1 for Pu27. Results suggest stacking interaction between planar sanguinarine moiety and G-quartets. Circular dichroism spectra show that sanguinarine does not cause structural perturbation in the all-parallel Pu27 but causes a structural transition from mixed hybrid to basket form at higher sanguinarine concentration in case of H24. The interaction is characterized by total enthalpy–entropy compensation and high heat capacity values. Differential scanning calorimetry studies suggest that sanguinarine binding increases the melting temperature and also the total enthalpy of transition of both quadruplexes. TRAP results show that sanguinarine effectively blocks telomerase activity in a concentration dependent manner in cell extracts from MDAMB-231 breast cancer cell lines. Conclusion: These results suggest that there is a difference in the structural modes of association of sanguinarine to the quadruplexes

Fusion with Anticodon Binding Domain of GluRS is Not Sufficient to Alter the Substrate Specificity of a Chimeric Glu-Q-RS

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Ellipticine Binds to a Human Telomere Sequence: An Additional Mode of Action as a Putative Anticancer Agent?

Polyguanine sequences fold into G-quadruplex structures in the presence of monovalent cations. It is accepted that the telomeric DNA region consists of G-quadruplex structure. There are reports that potential G-quadruplex forming motifs are also present in the promoter region of some proto-oncogenes such as c-myc, c-kit, KRAS, etc. Small molecules with the potential to stabilize the telomeric DNA quadruplex have emerged as potential anticancer agents. We have studied the interaction of ellipticine, a putative anticancer agent from a plant source, with a human telomeric DNA sequence (H24). Spectroscopic and calorimetric studies indicate that the association of ellipticine with H24 is an entropically driven phenomenon with a 2:3 (H24:ellipticine) stoichiometry. Though ellipticine binding does not induce any major structural perturbation in H24, the association leads to formation of a complex with enhanced thermal stability. An assay with the telomerase repeat amplification protocol shows that ellipticine inhibits telomerase activity in MDAMB-231 breast cancer cell line extracts. This is the first report of the quadruplex binding ability of ellipticine. Using the results, we propose that along with DNA intercalation and/or topoisomerase II inhibition, interaction with the telomeric DNA region and the resultant inhibition of telomerase activity might be an additional mode of action for its anticancer property