Search Results (49)

Background: Chronological age is an imprecise proxy for cognitive aging. The Cognitive Age Delta (CAD)—the difference between predicted cognitive age and chronological age—offers a scalable, individualized marker of functional brain aging. We examined determinants of CAD in cognitively unimpaired (CU) adults stratified by Alzheimer’s disease (AD) and vascular biomarkers. Methods: We analyzed 177 CU participants from the Gipuzkoa Alzheimer Project (Basque Country, Northern Spain) classified as amyloid-negative/vascular-negative (CUA−V−, n = 140), amyloid-positive (CUA+, n = 23), or vascular-positive (CUV+, n = 14) using CSF and MRI criteria; vascular burden was defined as Fazekas ≥ 2 on T2-FLAIR or ≥4 microbleeds on SWI, excluding non-traumatic superficial siderosis and established ischemic lesions. MRI was used solely for vascular classification. Associations with demographic, genetic, lifestyle, and reserve measures were tested with General Linear Models. Results: CAD did not differ across biomarker groups (Kruskal–Wallis H(2) = 0.17, p = 0.91). Median (IQR) CAD values were 0.28 (−4.13, 4.69) for CUA−V−, −0.14 (−3.15, 2.87) for CUA+, and 0.77 (−2.22, 3.76) for CUV+, indicating comparable distributions. Higher vocabulary scores (proxy of cognitive reserve) related to a younger cognitive age in CUA−V− (β = −1.39, p < 0.001) and CUA+ (β = −2.08, p = 0.054). In CUA+, greater sedentary time—particularly computer-based sitting—was also associated with lower CAD (daily sitting β = −2.13, p = 0.009; workday computer sitting β = −2.32, p = 0.015). CAD showed no associations with CSF Aβ42, p-tau or t-tau, APOE ε4 load, or vascular risk factors (all p > 0.05). Conclusions: CAD captures interindividual resilience-related variability beyond classical AD biomarkers. Vocabulary, a marker of lifelong enrichment, emerged as a robust determinant of a younger cognitive age, while amyloid and vascular pathology exerted limited influence at preclinical stages. These findings support CAD as a sensitive, scalable endpoint for identifying protective factors and guiding personalized prevention in early Aging. Full article

Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke, disproportionately affecting older adults and is associated with high rates of mortality, functional dependence, and long-term cognitive decline. Aging profoundly alters the structure and function of the cerebral vasculature, predisposing the brain to both covert hemorrhage and the development of cerebral microbleeds (CMBs), small, often subclinical lesions that share common pathophysiological mechanisms with ICH. These mechanisms include endothelial dysfunction, impaired cerebral autoregulation, blood–brain barrier breakdown, vascular senescence, and chronic inflammation. Systemic factors such as age-related insulin-like growth factor 1 (IGF-1) deficiency further exacerbate microvascular vulnerability. CMBs and ICH represent distinct yet interconnected manifestations along a continuum of hemorrhagic small vessel disease, with growing recognition of their contribution to vascular cognitive impairment and dementia (VCID). Despite their increasing burden, older adults remain underrepresented in clinical trials, and few therapeutic approaches specifically target aging-related mechanisms. This review synthesizes current knowledge on the cellular, molecular, and systemic drivers of ICH and CMBs in aging, highlights diagnostic and therapeutic challenges, and outlines opportunities for age-sensitive prevention and individualized care strategies. Full article

Background/Objectives: Frank’s sign, a diagonal earlobe crease, may reflect systemic microvascular dysfunction. We investigated whether Frank’s sign serves as a clinical marker of white matter hyperintensity (WMH) burden in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a monogenic model of pure cerebral small vessel disease. Methods: We analyzed 81 genetically confirmed CADASIL patients (61.8 ± 12.6 years, 40.7% female) and 54 age/sex-matched controls (70.3 ± 6.6 years, 48.1% female). Frank’s sign was detected using deep learning from brain MRI-reconstructed 3D facial surfaces. WMH volumes were automatically quantified and adjusted for confounders using Random Forest regression residuals. We compared Frank’s sign prevalence between groups, assessed within-CADASIL associations, and evaluated dose–response relationships across WMH tertiles. Results: Frank’s sign prevalence was significantly higher in CADASIL versus controls (66.7% vs. 42.6%, p = 0.020), with strengthened association after multivariate adjustment (OR = 4.214, 95% CI: 1.128–15.733, p = 0.032). Within CADASIL, Frank’s sign-positive patients showed 72% greater WMH burden (51.5 ± 27.1 vs. 30.0 ± 26.1 mL, p < 0.001) and lower Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) total scores (57.7 ± 19.6 vs. 71.2 ± 22.8, p = 0.006), but similar lacunes, microbleeds, and hippocampal volumes. A robust dose–response relationship emerged across WMH tertiles, with Frank’s sign prevalence increasing from 37.0% (lowest) to 74.1% (highest tertile; adjusted OR = 3.571, 95% CI: 1.134–11.253, p = 0.030). Conclusions: Frank’s sign represents an accessible biomarker of WMH burden in CADASIL, demonstrating disease-specificity and dose–response characteristics independent of vascular risk factors. The automated MRI-based detection method of Frank’s sign enables retrospective analysis of existing neuroimaging databases, transforming a bedside observation into a quantifiable neuroimaging biomarker for genetic small vessel disease stratification. Full article

A 56-year-old man, accompanied by city hall staff, visited our neurorehabilitation clinic. Despite hyperuricemia being diagnosed several years ago, he refused treatment. He had no history of hypertension and antihypertensive drug use. He developed painful joint tophi around the age of 51, which were managed with over-the-counter painkillers. At age 54, a knee tophus was removed, histologically confirming gouty tophi. Subsequently, he lost his chef’s job, and his lifestyle deteriorated. Gouty tophi were observed in the right ear, knuckles, elbows, and ankles, with some ulceration. Blood tests showed anemia and hyperuricemia (10.1 mg/dL: reference 3.6–7.0 mg/dL). Chest–abdominal CT demonstrated calcification of the aorta. Brain MRI revealed an old putaminal hemorrhage and numerous microbleeds. Dementia (Clinical Dementia Rating: 1) was diagnosed based on neuropsychological testing. Public services and social assistance were arranged for him. This case is hypothesis-generating. In settings with adequate healthcare access, the presentation of severe, uncontrolled gouty tophi with poor engagement should prompt a selective, stepwise evaluation—beginning with cognitive screening and proceeding to neurologic assessment if indicated; routine preventive brain imaging is not recommended. The presence of lobar and deep microbleeds should be interpreted within the context of standardized diagnostic criteria and lesion distribution patterns to inform differential diagnosis. Full article

Free fatty acids (FFAs) are a risk factor for recurrent ischemic stroke, primarily via the overproduction of reactive oxygen species. However, the association between FFA concentrations and cerebral small vessel disease (SVD), including lacunes, cerebral microbleeds, and white matter lesions on brain magnetic resonance imaging, remains unclear. This study included 95 patients with acute ischemic stroke (median age: 59 [interquartile range: 49–73] years). The patients were divided into two groups: those aged ≤59 years (midlife patients) and those aged ≥60 years (late-life patients). In the midlife patients, the low serum total FFA concentration was an independent risk factor of lacunes (adjusted odds ratio [aOR]: 0.82, 95% confidence interval [CI]: 0.69–0.96; p = 0.013). Among FFA fractions, low serum free C14:0 (aOR: 0.80, 95% CI: 0.66–0.98; p = 0.028), and free C18:3n-3 (aOR: 0.93, 95% CI: 0.87–0.99; p = 0.015) concentrations were independent risk factors of lacunes in the midlife patients. However, the serum total FFA concentrations did not differ according to the SVD findings in the late-life patients. Therefore, low blood FFA concentrations in midlife can be a novel “nonvascular,” nonatheromatous risk factor of SVD, including the presence of lacunes identified on brain magnetic resonance imaging. Full article

Background/Objectives: Cardiovascular disease (CVD) contributes to stroke and dementia. Individuals with CVD have high risk for adverse cognitive outcomes and stroke, possibly due to shared risk factors between CVD, stroke, and dementia, which may be attributed to cerebral small vessel disease (CSVD). We aim to determine the association between prevalent CVD and atrial fibrillation (AF) with CSVD. Methods: Composite of CVD [coronary heart disease, heart failure (HF)], its individual components, and AF were assessed. Multi-marker CSVD score was used to reflect increasing CSVD burden (cerebral microbleeds (CMBs), high-burden perivascular spaces, extensive white matter hyperintensity, cortical superficial siderosis, or covert brain infarcts were assigned 1 point each, with a range of 0–5). We related prevalent CVD, its individual components, and AF to multi-marker CSVD score and individual CSVD markers using logistic regression analyses adjusted for age, sex, FHS cohort, time between MRI and clinic exam (model-1), and vascular risk factors (model-2). Results: In 3413 participants (mean age: 59 ± 14 years, 53.4% women), 11% had prevalent CVD or AF, 8% had prevalent CVD, and 4% had prevalent AF. One CSVD marker was seen in 23% participants, and 9% had ≥ 2 markers. In multivariable-adjusted analyses, composite prevalent CVD and AF was associated with the presence of one CSVD marker (OR: 1.38, 95% confidence interval [CI]: 1.05–1.84). The association with ≥2 CSVD markers was not significant. Only CMBs were associated with components of CVD and AF, with the highest odds of association with HF. Conclusions: Prevalent CVD (including AF) is associated with the presence of CSVD, with all components associated with CMBs. Full article

Background: Cerebral amyloid angiopathy (CAA) represents a progressive cerebrovascular disorder, characterized by aberrant accumulation of beta-amyloid isoforms in cortical and leptomeningeal vessel walls of cerebrum and cerebellum. Methods: We sought to investigate the clinical manifestations, current different diagnostic tools, various therapeutic strategies and most uncommon subtypes of the disease. Results: The vast majority of CAA remains sporadic, with increasing prevalence with age and very frequent coexistence with Alzheimer’s disease. Clinically, CAA can present with spontaneous lobar intracerebral hemorrhage, transient focal neurologic episodes attributed to convexity subarachnoid hemorrhage or cortical superficial siderosis, and progressive cognitive decline leading to dementia. Inflammatory CAA subtype should be recognized early and treated promptly so that better functional outcomes may be achieved. Moreover, genetic and iatrogenic CAA forms are rare, yet increasingly recognized during the last years. Therapeutic management remains challenging for clinicians, especially when markers indicative of higher bleeding risk are present. A targeted therapy does not currently exist. However, various clinical trials are in progress, focusing on offering new promising insights into the disease treatment. Conclusions: This review aims to deepen our understanding of CAA diagnosis and therapeutic approach but also summarizes current evidence on the most uncommon subtypes of this cerebral small-vessel disease. Full article

Cerebral microbleeds (CMBs) are increasingly detected in patients with aortic and cardiac diseases following transcatheter aortic valve implantation (TAVI), thoracic endovascular aortic repair (TEVAR), or cardiac surgery. CMBs can be observed in magnetic resonance imaging (MRI) when susceptibility-weighted imaging (SWI) or T2*-Gradient-Echo (GRE) sequences are used. Differential diagnosis of CMBs from other causes, such as cerebral amyloid angiopathy (CAA), is crucial because of its clinical implications, particularly for anticoagulation management. A literature search was conducted using publicly available online databases to identify relevant studies for this review. The selection criteria focused on publications utilizing MRI with T2*-GRE or SWI sequences to detect CMBs in patients following cardiac or endovascular procedures. The extracted data included study characteristics, lesion distribution, and associated clinical factors. Ten studies were included in this review, with 50% analyzing a prospective cohort. Cerebral T2*-GRE or SWI hypointensities after cardiac and vascular procedures often showed a lobar distribution, thus complicating the differential diagnosis with “probable” CAA. However, CMBs seem predominantly located in subcortical white matter (SWM), unlike CAA, and commonly not associated with other alterations. Furthermore, CMBs seem to correlate with prolonged procedural duration, especially in the case of cardiopulmonary bypass, and anticoagulation therapy. Regarding etiology, various hypotheses have been proposed, with the most widely accepted being microhemorrhagic. CMBs are a common finding following cardiac procedures, either surgical or endovascular. Their distribution patterns may aid in differentiating from CAA-related lesions, with important implications for anticoagulation strategies. Identifying and characterizing these lesions is essential for optimizing postoperative management. Full article

Cerebral small vessel disease (cSVD) is a common cause of stroke and dementia. Ageing, hypertension, hyperglycaemia, and smoking make up the biggest risk factors for cSVD. They individually or collectively increase the levels of reactive oxygen species, pro-inflammatory cytokines and matrix metalloproteinases, decrease the bioavailability of nitric oxide, and, in the process, compromise the structural integrity and function of the vascular endothelium, blood–brain barrier, and brain parenchyma. These then appear as white matter hyperintensities, enlarged perivascular spaces, cerebral microbleeds, and atrophy in cerebral imaging. As there is currently no curative therapy for cSVD, prevention or delay of cSVD remains of particular importance to preserve quality of life for as long as possible. Bearing that in mind, this review explores whether drugs used for other neurovascular conditions may prevent neuroinflammation and oxidative damage and effectively maintain endothelial function and blood–brain barrier integrity. It also examines whether potential benefits may be extended to cSVD. The list of drugs includes anti-anginal drugs, acetylcholine esterase inhibitors, β-hydroxy β-methylglutaryl-CoA reductase inhibitors, lithium drugs, phosphodiesterase inhibitors, oral antihyperglycaemic drugs, and tetracycline antibiotics. This review discusses the mechanisms of action of these agents and critically evaluates preclinical, translational, and clinical research pertaining to cSVD. Full article

Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most prevalent forms of dementia, sharing overlapping clinical features yet distinct pathophysiological mechanisms. While AD is primarily driven by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles, VaD results from cerebrovascular pathology, including ischemic lesions and chronic hypoperfusion. However, accumulating evidence suggests that vascular dysfunction is a crucial contributor to both conditions, bridging neurodegenerative and cerebrovascular pathologies. In this review, we explore the interplay between AD and VaD, focusing on shared pathways such as blood–brain barrier (BBB) breakdown, neuroinflammation, and microvascular damage. Notably, cerebral microbleeds have emerged as a common feature in both AD and VaD, further linking vascular pathology to neurodegeneration. Microbleeding contributes to BBB disruption, iron deposition, and exacerbated oxidative stress, creating a vicious cycle that accelerates cognitive decline. We highlight the role of iron dysregulation as a key driver in AD, exacerbating Aβ accumulation, tau hyperphosphorylation, and ferroptosis. Conversely, bilirubin emerges as a molecule with theranostic potential, acting as both a biomarker and a neuroprotective agent due to its antioxidant and anti-inflammatory properties. Despite its protective role, bilirubin’s dysregulation under pathological conditions may contribute to oxidative damage and neurovascular dysfunction. In this context, the accumulation of iron from recurrent microbleeds may further disrupt bilirubin homeostasis, amplifying oxidative injury and inflammation. We propose a vascular hypothesis that integrates iron metabolism and bilirubin homeostasis, suggesting that their imbalance plays a central role in AD pathogenesis and worsening. Understanding the intricate molecular interplay between neurodegeneration and vascular dysfunction could provide novel insights into targeted interventions aimed at mitigating cognitive decline. Finally, we discuss the potential of bilirubin-based therapeutic strategies, including its role in counteracting oxidative stress and modulating neuroinflammatory pathways, offering promising avenues for future research and precision medicine in dementia. Full article

Anti-amyloid therapies (AATs) are increasingly being recognized as promising treatment options for Alzheimer’s disease (AD). Amyloid-related imaging abnormalities (ARIAs), small areas of edema and microbleeds in the brain presenting as abnormal signals in MRIs of the brain for patients with AD, are the most common side effects of AATs. While most ARIAs are asymptomatic, they can be associated with symptoms like nausea, headache, confusion, and gait instability and, less commonly, with more serious complications such as seizures and death. Cerebral amyloid angiopathy (CAA) has been found to be a major risk for ARIA development. The identification of sensitive and reliable non-invasive biomarkers for CAA has been an area of AD research over the years, but with the approval of AATs, this area has taken on a new urgency. This comprehensive review highlights several potential biomarkers, such as Aβ40, Aβ40/42, phosphorylated-tau217, neurofilament light chain, glial fibrillary acidic protein, secreted phosphoprotein 1, placental growth factor, triggering receptor expressed on myeloid cells 2, cluster of differentiation 163, proteomics, and microRNA. Identifying and staging CAA even before its consequences can be detected via neuroimaging are critical to allow clinicians to judiciously select appropriate candidates for AATs, stratify monitoring, properly manage therapeutic regimens for those experiencing symptomatic ARIAs, and optimize the treatment to achieve the best outcomes. Future studies can test potential plasma biomarkers in human beings and evaluate predictive values of individual markers for CAA severity. Full article

Background/Objectives: Virtual autopsy (virtopsy) is a new domain of research for interdisciplinary teams of radiologists and forensic specialists. This scoping review aims to underline the current state-of-the-art research using combined imaging modalities. Methods: We searched the PubMed database using the term virtopsy for articles that are available in free full text, indexed in the Medline Database, and published in English. The query returned 49 articles on this subject that have been published since 2002. Results: The main imaging modalities used for postmortem imaging were computed tomography (PMCT), angiography (PMCTA), magnetic resonance imaging (PMMRI), and ultrasonography (PMUS). PMCT is highly effective for detecting complex osseous injuries, tracing bullet trajectories, or identifying characteristic findings in drowning cases. PMCTA is valuable for evaluating vascular lesions, particularly in natural death cases. PMMRI is superior in analyzing soft tissues, including brain and spinal structures, cerebrospinal fluid, microbleeds, and laryngohyoid lesions, and identifying cardiomyopathies in young individuals. PMUS serves as an alternative, and its portability also allows for use in forensic settings. One specific situation observed was the increased number of studies published about virtopsy during the COVID-19 pandemic. Another aspect is the increased focus on this alternative to conventional autopsy in the regions where maneuvering of the deceased is limited according to cultural and social customs. Conclusions: We underline the advantages and limitations of each imaging modality used for virtopsy. Further studies need to be developed in order to gather supplementary data regarding the use of these imaging modalities in the new era of artificial intelligence in medicine. Full article

Background/Objectives: Cognitive impairment represents a core and prodromal clinical feature of cerebral amyloid angiopathy (CAA). We sought to assess specific cognitive domains which are mainly affected among patients with CAA and to investigate probable associations with neuroimaging markers and Cerebrospinal Fluid (CSF) biomarkers. Methods: Thirty-five patients fulfilling the Boston Criteria v1.5 or v2.0 for the diagnosis of probable/possible CAA were enrolled in this prospective cohort study. Brain Magnetic Resonance Imaging and CSF biomarker data were collected. Every eligible participant underwent a comprehensive neurocognitive assessment. Spearman’s rank correlation tests were used to identify possible relationships between the Addenbrooke’s Cognitive Examination—Revised (ACE-R) sub-scores and other neurocognitive test scores and the CSF biomarker and neuroimaging parameters among CAA patients. Moreover, linear regression analyses were used to investigate the effects of CSF biomarkers on the ACE-R total score and Mini-Mental State Examination (MMSE) score, based on the outcomes of univariate analyses. Results: Cognitive impairment was detected in 80% of patients, and 60% had a coexistent Alzheimer’s disease (AD) pathology based on CSF biomarker profiles. Notable correlations were identified between increased levels of total tau (t-tau) and phosphorylated tau (p-tau) and diminished performance in terms of overall cognitive function, especially memory. In contrast, neuroimaging indicators, including lobar cerebral microbleeds and superficial siderosis, had no significant associations with cognitive scores. Among the CAA patients, those without AD had superior neurocognitive test performance, with significant differences observed in their ACE-R total scores and memory sub-scores. Conclusions: The significance of tauopathy in cognitive impairment associated with CAA may be greater than previously imagined, underscoring the necessity for additional exploration of the non-hemorrhagic facets of the disease and new neuroimaging markers. Full article

Atrial fibrillation (AF) and dementia are major global public health issues and share common risk factors, especially after the age of 65 and regardless of the presence of stroke. Despite accounting for potential confounders, AF appears to be an independent risk factor for cognitive decline and dementia. The mechanisms are likely to be multifactorial and may include AF-related ischemic stroke, cerebral hypoperfusion, microbleeds, systemic inflammation, genetic factors, and small vessel disease, leading to brain atrophy and white matter damage. The early aggressive management of AF and comorbidities may reduce the risk of dementia. Indeed, the early detection of AF-related cognitive impairment should allow for the early implementation of measures to prevent the development of dementia, mainly through integrative approaches involving the correction of risk factors and maintenance of rhythm control. Well-designed prospective studies are needed to determine whether early detection and AF treatment can prevent dementia and identify whether optimal integrative measures are effective in preventing cognitive impairment and dementia. Full article

Cerebral small vessel disease (CSVD) is a group of pathologies that affect the cerebral blood vessels. CSVD accounts for 25% of strokes and contributes to 45% of dementia. However, the pathogenesis of CSVD remains unclear, involving a variety of complex mechanisms. CSVD may result from dysfunction in the glymphatic system (GS). The GS contains aquaporin-4 (AQP-4), which is in the perivascular space, at the endfeet of the astrocyte. The GS contributes to the removal of waste products from the central nervous system, occupying perivascular spaces and regulating the exchange and movement of cerebrospinal fluid and interstitial fluid. The GS involves astrocytes and aquaporin channels, which are components of the blood–brain barrier, and problems with them may constitute the pathogenesis of CSVD. Vascular risk factors, including diabetes, dilate the perivascular space, disrupting the glymphatic system and the active regulation of AQP-4. CSVD exacerbation due to disorders of the GS is associated with multiple vasculopathies. Dysfunction of the glymphatic system and AQP-4 interferes with the functioning of the blood–brain barrier, which exacerbates CSVD. In a long-term follow-up of CSVD patients with microbleeds, lacunar infarcts, and white matter hyperintensity, several vascular risk factors, including hypertension, increased the risk of ischemic stroke. Dysfunction of the GS may be the cause of CSVD; however, the underlying treatment needs to be studied further. Full article