Cardiovascular health (CVH) has been associated with cognitive decline and dementia, but the extent to which CVH affects brain health remains unclear. We investigated the association of CVH, assessed using Life's Essential 8 (LE8), with neuroimaging-based brain age and brain-predicted age difference (brain-PAD).

This longitudinal community-based study was based on UK Biobank participants aged 40-69 years who were free from dementia and other neurologic diseases at baseline. LE8 score at baseline was assessed with 8 measures and tertiled as low, moderate, and high CVH. Structural and functional brain MRI scans were performed approximately 9 years after baseline, and 1,079 measures from 6 neuroimaging modalities were used to model brain age. A Least Absolute Shrinkage and Selection Operator regression model was trained in 4,355 healthy participants and then used to calculate brain age and brain-PAD in the whole population. Data were analyzed using linear regression models.

The study included 32,646 participants (mean age at baseline 54.74 years; 53.44% female; mean LE8 score: 71.90). In multivariable-adjusted linear regression, higher LE8 score was associated with younger brain age (β [95% CI] -0.037 [-0.043 to -0.031]) and more negative brain-PAD (β [95% CI] -0.043 [-0.048 to -0.038]) (brain looks younger for chronological age). Compared with high CVH, low/moderate CVH was associated with older brain age (β [95% CI] 1.030 [0.852-1.208]/0.475 [0.303-0.647]) and increased brain-PAD (β [95% CI] 1.193 [1.029-1.357]/0.528 [0.370-0.686]). The associations between low CVH and older brain age/brain-PAD remained similar and significant in both middle-aged (β [95% CI] 1.199 [0.992-1.405]/1.351 [1.159-1.542]) and older adults (β [95% CI] 0.764 [0.417-1.110]/0.948 [0.632-1.263]).

Low CVH is associated with older brain age and greater brain-PAD, even among middle-aged adults. Our findings suggest that optimizing CVH could support brain health. The main limitation of our study is that the study sample was healthier than the general population, thus caution is required when generalizing our findings to other populations.

The relationship between amyloidosis and vasculature in cognitive impairment and Alzheimer's disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative and topographic assessment of retinal perivascular amyloid plaque (AP) distribution in individuals with both normal and impaired cognition. Using a retrospective dataset of scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects with varying cognitive states, we developed a novel image processing method to examine retinal peri-arteriolar and peri-venular curcumin-positive AP burden. We further correlated retinal perivascular amyloidosis with neuroimaging measures and neurocognitive scores. Our study unveiled that peri-arteriolar AP counts surpassed peri-venular counts throughout the entire cohort (P < 0.0001), irrespective of the primary, secondary, or tertiary vascular branch location, with a notable increase among cognitively impaired individuals. Moreover, secondary branch peri-venular AP count was elevated in the cognitively impaired (P < 0.01). Significantly, peri-venular AP count, particularly in secondary and tertiary venules, exhibited a strong correlation with clinical dementia rating, Montreal cognitive assessment score, hippocampal volume, and white matter hyperintensity count. In conclusion, our exploratory analysis detected greater peri-arteriolar versus peri-venular amyloidosis and a marked elevation of amyloid deposition in secondary branch peri-venular regions among cognitively impaired subjects. These findings underscore the potential feasibility of retinal perivascular amyloid imaging in predicting cognitive decline and AD progression. Larger longitudinal studies encompassing diverse populations and AD-biomarker confirmation are warranted to delineate the temporal-spatial dynamics of retinal perivascular amyloid deposition in cognitive impairment and the AD continuum.

The vascular contribution to Alzheimer's disease (AD) is tightly connected to cognitive performance across the AD continuum. We topographically describe retinal perivascular amyloid plaque (AP) burden in subjects with normal or impaired cognition.

Using scanning laser ophthalmoscopy, we quantified retinal peri-arteriolar and peri-venular curcumin-positive APs in the first, secondary and tertiary branches in twenty-eight subjects. Perivascular AP burden among cognitive states was correlated with neuroimaging and cognitive measures.

Peri-arteriolar exceeded peri-venular AP count (p<0.0001). Secondary branch AP count was significantly higher in cognitively impaired (p<0.01). Secondary small and tertiary peri-venular AP count strongly correlated with clinical dementia rating, hippocampal volumes, and white matter hyperintensity count.

Our topographic analysis indicates greater retinal amyloid accumulation in the retinal peri-arteriolar regions overall, and distal peri-venular regions in cognitively impaired individuals. Larger longitudinal studies are warranted to understand the temporal-spatial relationship between vascular dysfunction and perivascular amyloid deposition in AD.

Retinal peri-arteriolar region exhibits more amyloid compared with peri-venular regions.Secondary retinal vascular branches have significantly higher perivascular amyloid burden in subjects with impaired cognition, consistent across sexes.Cognitively impaired individuals have significantly greater retinal peri-venular amyloid deposits in the distal small branches, that correlate with CDR and hippocampal volumes.

Alzheimer's disease (AD) is the most common form of dementia and is a progressive neurodegenerative disorder of the brain. Most AD experimental animal models are pharmacological or transgenic in origin. The existing pharmacological approaches for developing AD are poorly developed and most of them fail to replicate the complete characteristics of disease pathology. Developing a cost-effective and reliable experimental animal model will meet this research gap. Zebrafish (ZF) are progressively emerging as a powerful drug discovery disease model to evaluate central nervous system (CNS) disorders due to their homologous similarities to humans as well as cost-effectiveness. The present research is conceptualized to develop and evaluate a reliable ZF AD model using aluminum chloride (AlCl3). Chronic exposure of 0.04 mM of AlCl3 for 28 days increased the expression of amyloid-β, phosphorylated tau protein and senile plaque development in the ZF brain. The observed changes were associated with learning and memory impairment. Furthermore, decreased brain-derived neurotrophic factor (BDNF) level and elevated oxidative stress indices, pro-inflammatory cytokines levels and acetylcholine esterase (AChE) activity was observed upon exposure to AlCl3 in the ZF brain. Chronic exposure to 0.04 mM of AlCl3 would be a cost-effective ZF AD model for pharmacological screening and may also be used to unravel the molecular mechanism underlying the neuropathology of the disease.

Blood-brain barrier (BBB) dysfunction could favor the pathogenesis and progression of Alzheimer's disease (AD). Vascular risk factors (VRF) could worsen BBB integrity, thus promoting neurode generation.

To investigate BBB permeability and its relation with VRF along the AD continuum (ADc). Cerebrospinal fluid (CSF) Amyloid (A) and p-tau (T) levels were used to stratify patients.

We compared CSF/plasma albumin ratio (QAlb) of 131 AD patients and 24 healthy controls (HC). APOE genotype and VRF were evaluated for each patient. Spearman's Rho correlation was used to investigate the associations between Qalb and CSF AD biomarkers. Multivariate regression analyses were conducted to explore the relationship between Qalb and AD biomarkers, sex, age, cognitive status, and VRF.

QAlb levels did not show significant difference between ADc patients and HC (p = 0.984). However, QAlb was significantly higher in A + T-compared to A + T+ (p = 0.021). In ADc, CSF p-tau demonstrated an inverse correlation with QAlb, a finding confirmed in APOE4 carriers (p = 0.002), but not in APOE3. Furthermore, in APOE4 carriers, sex, hypertension, and hypercholesterolemia were associated with QAlb (p = 0.004, p = 0.038, p = 0.038, respectively), whereas only sex showed an association in APOE3 carriers (p = 0.026).

BBB integrity is preserved in ADc. Among AT categories, A + T-have a more permeable BBB than A + T+. In APOE4 carriers, CSF p-tau levels display an inverse association with BBB permeability, which in turn, seems to be affected by VRF. These data suggest a possible relationship between BBB efficiency, VRF and CSF p-tau levels depending on APOE genotype.

Alzheimer's disease (AD) is the most common form of dementia worldwide [...].

Background and Objectives: Elderly patients affected by acute heart failure (AHF) often show different patterns of comorbidities. In this paper, we aimed to evaluate how chronic comorbidities cluster and which pattern of comorbidities is more strongly related to in-hospital death in AHF. Materials and Methods: All patients admitted for AHF to an Internal Medicine Department (01/2015−01/2019) were retrospectively evaluated; the main outcome of this study was in-hospital death during an admission for AHF; age, sex, the Charlson comorbidity index (CCI), and 17 different chronic pathologies were investigated; the association between the comorbidities was studied with Pearson’s bivariate test, considering a level of p ≤ 0.10 significant, and considering p < 0.05 strongly significant. Thus, we identified the clusters of comorbidities associated with the main outcome and tested the CCI and each cluster against in-hospital death with logistic regression analysis, assessing the accuracy of the prediction with ROC curve analysis. Results: A total of 459 consecutive patients (age: 83.9 ± 8.02 years; males: 56.6%). A total of 55 (12%) subjects reached the main outcome; the CCI and 16 clusters of comorbidities emerged as being associated with in-hospital death from AHF. Of these, CCI and six clusters showed an accurate prediction of in-hospital death. Conclusions: Both the CCI and specific clusters of comorbidities are associated with in-hospital death from AHF among elderly patients. Specific phenotypes show a greater association with a worse short-term prognosis than a more generic scale, such as the CCI.

Early-onset Alzheimer’s disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer’s disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G>A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future.