The development and evolution of inhibitory neurons in primate cerebrum.

Neuroanatomists have long speculated that expanded primate brains contain an increased morphological diversity of inhibitory neurons (INs)1, and recent studies have identified primate-specific neuronal populations at the molecular level2. However, we know little about the developmental mechanisms that specify evolutionarily novel cell types in the brain. Here, we reconstruct gene expression trajectories specifying INs generated throughout the neurogenic period in macaques and mice by analysing the transcriptomes of 250,181 cells. We find that the initial classes of INs generated prenatally are largely conserved among mammals. Nonetheless, we identify two contrasting developmental mechanisms for specifying evolutionarily novel cell types during prenatal development. First, we show that recently identified primate-specific TAC3 striatal INs are specified by a unique transcriptional programme in progenitors followed by induction of a distinct suite of neuropeptides and neurotransmitter receptors in new-born neurons. Second, we find that multiple classes of transcriptionally conserved olfactory bulb (OB)-bound precursors are redirected to expanded primate white matter and striatum. These classes include a novel peristriatal class of striatum laureatum neurons that resemble dopaminergic periglomerular cells of the OB. We propose an evolutionary model in which conserved initial classes of neurons supplying the smaller primate OB are reused in the enlarged striatum and cortex. Together, our results provide a unified developmental taxonomy of initial classes of mammalian INs and reveal multiple developmental mechanisms for neural cell type evolution.

Enhancing cognitive performance prediction by white matter hyperintensity connectivity assessment.

White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (1) LNM-informed markers surpass WMH volumes in predicting cognitive performance, and (2) WMH contributing to cognitive impairment map to specific brain networks. We analyzed cross-sectional data of 3,485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in 4 cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based gray and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in gray and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

Neighborhood Socioeconomic Disadvantage and Acute Care Utilization in Washington State Medicaid: A Retrospective Cohort Study.

BACKGROUND: Neighborhood disadvantage has been associated with potentially preventable acute care utilization among Medicare beneficiaries, but this association has not been studied in a Medicaid population, which is important for informing more equitable care and policies for this population. OBJECTIVE: To describe the association between Area Deprivation Index (ADI) and acute care utilization (including potentially preventable utilization) among Medicaid beneficiaries in Washington State. DESIGN: Retrospective cohort study of 100% Medicaid claims. Mixed effects logistic regression was applied to estimate the association between state-level ADI decile and acute care utilization, adjusting for age, sex, self-identified race and ethnicity, Charlson Comorbidity Index, primary spoken language, individual Federal Poverty Level, homelessness, and rurality. Standard errors were clustered at the Census block group level. PARTICIPANTS: 1.5 million unique adult Medicaid beneficiaries enrolled for at least 11 months of a calendar year during the period 2017-2021. MAIN MEASURES: Binary measures denoting receipt of ED visits, low-acuity ED visits, hospitalizations in a calendar year. KEY RESULTS: Increasing levels of neighborhood socioeconomic disadvantage (by ADI decile) were associated with greater odds of any ED visits (adjusted odds ratio (aOR) 1.07, 95% confidence interval (CI) 1.06-1.07), low-acuity ED visits (aOR 1.08, CI 1.08-1.08), and any hospitalizations (aOR 1.02, CI 1.02-1.02). CONCLUSIONS: Among Medicaid beneficiaries, greater neighborhood socioeconomic disadvantage was associated with increased acute care utilization, including potentially preventable utilization. These findings signal potential barriers to outpatient care access that could be amenable to future intervention by health systems and payers.

Endothelial Damage Arising From High Salt Hypertension Is Elucidated by Vascular Bed Systematic Profiling.

BACKGROUND: Considerable evidence links dietary salt intake with the development of hypertension, left ventricular hypertrophy, and increased risk of stroke and coronary heart disease. Despite extensive epidemiological and basic science interrogation of the relationship between high salt (HS) intake and blood pressure, it remains unclear how HS impacts endothelial cell (EC) and vascular structure in vivo. This study aims to elucidate HS-induced vascular pathology using a differential systemic decellularization in vivo approach. METHODS: We performed systematic molecular characterization of the endothelial glycocalyx and EC proteomes in mice with HS (8%) diet-induced hypertension versus healthy control animals. Isolation of eGC and EC compartments was achieved using differential systemic decellularization in vivo methodology. Altered protein expression in hypertensive compared to normal mice was characterized by liquid chromatography tandem mass spectrometry. Proteomic results were validated using functional assays, microscopic imaging, and histopathologic evaluation. RESULTS: Proteomic analysis revealed a significant downregulation of eGC and associated proteins in HS diet-induced hypertensive mice (among 1696 proteins identified in this group, 723 were markedly decreased in abundance, while only 168 were increased in abundance. Bioinformatic analysis indicated substantial derangement of the eGC layer, which was subsequently confirmed by fluorescent and electron microscopy assessment of vessel damage ex vivo. In the EC fraction, HS-induced hypertension significantly altered protein mediators of contractility, metabolism, mechanotransduction, renal function, and the coagulation cascade. In particular, we observed dysregulation of integrin subunits α2, α2b, and α5, which was associated with arterial wall inflammation and substantial infiltration of CD68+ monocyte-macrophages. Consequently, HS-induced hypertensive mice also displayed reduced vascular integrity of multiple organs including lungs, kidneys, and heart. CONCLUSIONS: These findings provide novel molecular insight into HS-induced structural changes in eGC and EC composition that may increase cardiovascular risk and potentially guide the development of new diagnostics and therapeutic interventions.

Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients.

INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-ß1-42 (Aß42)-positive status. METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume. RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001). DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter. HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aß42 status in 11 memory clinic cohorts. Aß42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

Sex Differences in Poststroke Cognitive Impairment: A Multicenter Study in 2343 Patients With Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women. METHODS: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278). RESULTS: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively). CONCLUSIONS: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

BACKGROUND: White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts. METHODS: We pooled and harmonized individual patient data (n=1568) from 9 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Included cohorts comprised patients with available magnetic resonance imaging and multidomain cognitive assessment <15 months poststroke. In this individual patient data meta-analysis, linear mixed models were used to determine the association between WMH volume and domain-specific cognitive functioning (Z scores; attention and executive functioning, processing speed, language and verbal memory) for the total sample and stratified by infarct type. Preexisting brain injury was accounted for in the multivariable models and all analyses were corrected for the study site as a random effect. RESULTS: In the total sample (67 years [SD, 11.5], 40% female), we found a dose-dependent inverse relationship between WMH volume and poststroke cognitive functioning across all 4 cognitive domains (coefficients ranging from -0.09 [SE, 0.04, P=0.01] for verbal memory to -0.19 [SE, 0.03, P<0.001] for attention and executive functioning). This relation was independent of acute infarct volume and the presence of lacunes and old infarcts. In stratified analyses, the relation between WMH volume and domain-specific functioning was also largely independent of infarct type. CONCLUSIONS: In patients with ischemic stroke, increasing WMH volume is independently associated with worse cognitive functioning across all major domains, regardless of old ischemic lesions and infarct type.

Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer's disease but not Lewy body dementias.

BACKGROUND: Chronically dysregulated neuroinflammation has been implicated in neurodegenerative dementias, with separate studies reporting increased brain levels of inflammatory mediators and gliosis in Alzheimer's disease (AD) as well as in Lewy body dementias (LBD). However, it is unclear whether the nature and extent of neuroinflammatory responses in LBD are comparable to those in AD. In this study, we performed head-to-head measurements of a panel of cytokines in the post-mortem neocortex of AD versus the two major clinical subtypes of LBD, namely, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). METHODS: Post-mortem tissues from the mid-temporal cortex (Brodmann area 21) of a cohort of neuropathologically well-defined AD, PDD and DLB patients were processed and measured for a comprehensive range of cytokines (IL-1α, IL-1Ra, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, GM-CSF and FGF-2) using a multiplex immunoassay platform. Associations between inflammation markers and neuropathological measures of neuritic plaques, neurofibrillary tangles as well as Lewy bodies were also performed. RESULTS: We found IL-1α, IFN-γ, GM-CSF and IL-13 to be elevated in the mid-temporal cortex of AD patients. In contrast, none of the measured cytokines were significantly altered in either DLB or PDD. Similar cytokine changes were observed in two other neocortical areas of AD patients. Furthermore, increases of IL-1α, IFN-γ, GM-CSF, IL-10 and IL-13 associated with moderate-to-severe neurofibrillary tangle burden, but not with neuritic plaques or Lewy bodies. Our findings of elevated neocortical pro- and anti-inflammatory cytokines in AD, but not in DLB or PDD, suggest that neuroinflammatory responses are strongly linked to neurofibrillary tangle burden, which is higher in AD compared to LBD. In conclusion, neuroinflammation may not play a prominent role in the pathophysiology of late-stage LBD.

Strategic white matter hyperintensity locations for cognitive impairment: A multicenter lesion-symptom mapping study in 3525 memory clinic patients.

INTRODUCTION: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study. METHODS: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses. RESULTS: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains. DISCUSSION: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment. HIGHLIGHTS: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains.

Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer's disease: a focused review on recent advances.

Discovery and development of clinically useful biomarkers for Alzheimer's disease (AD) and related dementias have been the focus of recent research efforts. While cerebrospinal fluid and positron emission tomography or MRI-based neuroimaging markers have made the in vivo detection of AD pathology and its consequences possible, the high cost and invasiveness have limited their widespread use in the clinical setting. On the other hand, advances in potentially more accessible blood-based biomarkers had been impeded by lack of sensitivity in detecting changes in markers of the hallmarks of AD, including amyloid-ß (Aß) peptides and phosphorylated tau (P-tau). More recently, however, emerging technologies with superior sensitivity and specificity for measuring Aß and P-tau have reported high concordances with AD severity. In this focused review, we describe several emerging technologies, including immunoprecipitation-mass spectrometry (IP-MS), single molecule array and Meso Scale Discovery immunoassay platforms, and appraise the current literature arising from their use to identify plaques, tangles and other AD-associated pathology. While there is potential clinical utility in adopting these technologies, we also highlight the further studies needed to establish Aß and P-tau as blood-based biomarkers for AD, including validation with existing large sample sets, new independent cohorts from diverse backgrounds as well as population-based longitudinal studies. In conclusion, the availability of sensitive and reliable measurements of Aß peptides and P-tau species in blood holds promise for the diagnosis, prognosis and outcome assessments in clinical trials for AD.

Improved amyloid burden quantification with nonspecific estimates using deep learning.

PURPOSE: Standardized uptake value ratio (SUVr) used to quantify amyloid-ß burden from amyloid-PET scans can be biased by variations in the tracer's nonspecific (NS) binding caused by the presence of cerebrovascular disease (CeVD). In this work, we propose a novel amyloid-PET quantification approach that harnesses the intermodal image translation capability of convolutional networks to remove this undesirable source of variability. METHODS: Paired MR and PET images exhibiting very low specific uptake were selected from a Singaporean amyloid-PET study involving 172 participants with different severities of CeVD. Two convolutional neural networks (CNN), ScaleNet and HighRes3DNet, and one conditional generative adversarial network (cGAN) were trained to map structural MR to NS PET images. NS estimates generated for all subjects using the most promising network were then subtracted from SUVr images to determine specific amyloid load only (SAßL). Associations of SAßL with various cognitive and functional test scores were then computed and compared to results using conventional SUVr. RESULTS: Multimodal ScaleNet outperformed other networks in predicting the NS content in cortical gray matter with a mean relative error below 2%. Compared to SUVr, SAßL showed increased association with cognitive and functional test scores by up to 67%. CONCLUSION: Removing the undesirable NS uptake from the amyloid load measurement is possible using deep learning and substantially improves its accuracy. This novel analysis approach opens a new window of opportunity for improved data modeling in Alzheimer's disease and for other neurodegenerative diseases that utilize PET imaging.

Plasma P-tau181 to Aß42 ratio is associated with brain amyloid burden and hippocampal atrophy in an Asian cohort of Alzheimer's disease patients with concomitant cerebrovascular disease.

INTRODUCTION: There is increasing evidence that phosphorylated tau (P-tau181) is a specific biomarker for Alzheimer's disease (AD) pathology, but its potential utility in non-White patient cohorts and patients with concomitant cerebrovascular disease (CeVD) is unknown. METHODS: Single molecule array (Simoa) measurements of plasma P-tau181, total tau, amyloid beta (Aß)40 and Aß42, as well as derived ratios were correlated with neuroimaging modalities indicating brain amyloid (Aß+), hippocampal atrophy, and CeVD in a Singapore-based cohort of non-cognitively impaired (NCI; n = 43), cognitively impaired no dementia (CIND; n = 91), AD (n = 44), and vascular dementia (VaD; n = 22) subjects. RESULTS: P-tau181/Aß42 ratio showed the highest area under the curve (AUC) for Aß+ (AUC = 0.889) and for discriminating between AD Aß+ and VaD Aß- subjects (AUC = 0.903). In addition, P-tau181/Aß42 ratio was associated with hippocampal atrophy. None of the biomarkers was associated with CeVD. DISCUSSION: Plasma P-tau181/Aß42 ratio may be a noninvasive means of identifying AD with elevated brain amyloid in populations with concomitant CeVD.

Improved quantification of amyloid burden and associated biomarker cut-off points: results from the first amyloid Singaporean cohort with overlapping cerebrovascular disease.

PURPOSE: The analysis of the [11C]PiB-PET amyloid images of a unique Asian cohort of 186 participants featuring overlapping vascular diseases raised the question about the validity of current standards for amyloid quantification under abnormal conditions. In this work, we implemented a novel pipeline for improved amyloid PET quantification of this atypical cohort. METHODS: The investigated data correction and amyloid quantification methods included motion correction, standardized uptake value ratio (SUVr) quantification using the parcellated MRI (standard method) and SUVr quantification without MRI. We introduced a novel amyloid analysis method yielding 2 biomarkers: AßL which quantifies the global Aß burden and ns that characterizes the non-specific uptake. Cut-off points were first determined using visual assessment as ground truth and then using unsupervised classification techniques. RESULTS: Subject's motion impacts the accuracy of the measurement outcome but has however a limited effect on the visual rating and cut-off point determination. SUVr computation can be reliably performed for all the subjects without MRI parcellation while, when required, the parcellation failed or was of mediocre quality in 10% of the cases. The novel biomarker AßL showed an association increase of 29.5% with the cognitive tests and increased effect size between positive and negative scans compared with SUVr. ns was found sensitive to cerebral microbleeds, white matter hyperintensity, volume, and age. The cut-off points for SUVr using parcellated MRI, SUVr without parcellation, and AßL were 1.56, 1.39, and 25.5. Finally, k-means produced valid cut-off points without the requirement of visual assessment. CONCLUSION: The optimal processing for the amyloid quantification of this atypical cohort allows the quantification of all the subjects, producing SUVr values and two novel biomarkers: AßL, showing important increased in their association with various cognitive tests, and ns, a parameter sensitive to non-specific retention variations caused by age and cerebrovascular diseases.

iTRAQ quantitative clinical proteomics revealed role of Na(+)K(+)-ATPase and its correlation with deamidation in vascular dementia.

Dementia is a major public health burden characterized by impaired cognition and loss of function. There are limited treatment options due to inadequate understanding of its pathophysiology and underlying causative mechanisms. Discovery-driven iTRAQ-based quantitative proteomics techniques were applied on frozen brain samples to profile the proteome from vascular dementia (VaD) and age-matched nondementia controls to elucidate the perturbed pathways contributing to pathophysiology of VaD. The iTRAQ quantitative data revealed significant up-regulation of protein-l-isoaspartate O-methyltransferase and sodium-potassium transporting ATPase, while post-translational modification analysis suggested deamidation of catalytic and regulatory subunits of sodium-potassium transporting ATPase. Spontaneous protein deamidation of labile asparagines, generating abnormal l-isoaspartyl residues, is associated with cell aging and dementia due to Alzheimer's disease and may be a cause of neurodegeneration. As ion channel proteins play important roles in cellular signaling processes, alterations in their function by deamidation may lead to perturbations in membrane excitability and neuronal function. Structural modeling of sodium-potassium transporting ATPase revealed the close proximity of these deamidated residues to the catalytic site during E2P confirmation. The deamidated residues may disrupt electrostatic interaction during E1 phosphorylation, which may affect ion transport and signal transduction. Our findings suggest impaired regulation and compromised activity of ion channel proteins contribute to the pathophysiology of VaD.

Decreased immunoreactivities of neocortical AMPA receptor subunits correlate with motor disability in Lewy body dementias.

Dementia with Lewy bodies and Parkinson's disease dementia are different clinical phenotypes of Lewy body dementias differentiated by the temporal relationship between parkinsonism and dementia onset. At present, it is unclear whether the glutamatergic system is affected in these disorders. In this study, we measured α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA subunits in the postmortem neocortex of a cohort of prospectively studied Lewy body dementia cases, as well as age-matched controls by immunoblotting. We found losses of GluA2/3/4 immunoreactivities in Lewy body dementias which correlated with higher pre-death Hoehn and Yahr scores and with longer Parkinson's disease duration before dementia onset, but not with dementia severity, cortical Lewy body burden, or amyloid plaque and neurofibrillary tangle burden. Our study suggests that GluA2/3/4 losses may be a neurochemical marker of motor disability in Lewy body dementias.

Microvascular network alterations in the retina of patients with Alzheimer's disease.

BACKGROUND: Although cerebral small-vessel disease has been implicated in the development of Alzheimer's disease (AD), the cerebral microcirculation is difficult to visualize directly in vivo. Because the retina provides a noninvasive window to assess the microcirculation, we determined whether quantitatively measured retinal microvascular parameters are associated with AD. METHODS: We conducted a case-control study (case:control matching ≈ 1:2). Retinal photographs were analyzed using a computer program, and a spectrum of quantitative retinal microvascular parameters (caliber, fractal dimension, tortuosity, and bifurcation) were measured. Logistic regression models were used to compute the odds ratio (OR) and 95% confidence interval for AD adjusting for age, gender, ethnicity, smoking, hypertension, diabetes, hypercholesterolemia, and history of myocardial infarction. RESULTS: We included 136 demented patients with AD and 290 age-gender-race-matched controls. Persons with narrower venular caliber (OR per standard deviation [SD] decrease, 2.01 [1.27-3.19]), decreased arteriolar and venular fractal dimension (OR per SD decrease 1.35 [1.08-1.68], 1.47 [1.17-1.84], respectively) and increased arteriolar and venular tortuosity (OR per SD increase, 1.84 [1.40-2.31], 1.94 [1.48-2.53], respectively) were more likely to have AD. These associations still persisted when only AD cases without a history of cerebrovascular disease were included. CONCLUSIONS: Patients with AD have altered microvascular network in the retina (narrower retinal venules and a sparser and more tortuous retinal vessels) compared with matched nondemented controls. These changes in retinal microvasculature may reflect similar pathophysiological processes in cerebral microvasculature in the brains of patients with AD.

Retinal vascular fractal dimension is associated with cognitive dysfunction.

Fractal analysis is a method used to quantify the geometric branching complexity and density of retinal vessels. This study examined the relationship of retinal vascular fractal dimension and other retinal vascular parameters with cognitive dysfunction in an older Asian population. Subjects aged 60 years and older from the Singapore Malay Eye Study were selected for analysis. Retinal vascular fractal dimension (Df) and other quantitative retinal vascular parameters (branching angle, tortuosity, and caliber) were measured based on a standardized grading protocol from photographs of the retinal fundus using a computer-assisted program. Qualitative retinal signs were also assessed from photographs. Cognitive dysfunction was defined as a locally validated Abbreviated Mental Test (AMT) score ≤6/10 in participants with 0-6 years of formal education and an AMT score ≤8/10 in those with more than 6 years of formal education. Cognitive dysfunction was identified in 262 of the 1202 participants (21.8%). Decreased retinal vascular Df was significantly associated with lower AMT score (P = .019). In multivariate logistic regression analysis, participants with lower retinal vascular Df values were more likely to have cognitive dysfunction (odds ratio, 1.71; 95% confidence interval, 1.03-2.82, comparing the lowest and highest Df quintiles). In subgroup analysis stratified for cardiovascular risk factors, this association was present in participants with hypertension and current smokers. Other retinal vascular signs were not associated with cognitive dysfunction. Decreased retinal vascular Df is associated with cognitive dysfunction in older persons. Rarefaction of the retinal vasculature may reflect similar changes in the cerebral microvasculature that may contribute to cognitive deterioration.

Blood-based biomarkers of cerebral small vessel disease.

Age-associated cerebral small vessel disease (CSVD) represents a clinically heterogenous condition, arising from diverse microvascular mechanisms. These lead to chronic cerebrovascular dysfunction and carry a substantial risk of subsequent stroke and vascular cognitive impairment in aging populations. Owing to advances in neuroimaging, in vivo visualization of cerebral vasculature abnormities and detection of CSVD, including lacunes, microinfarcts, microbleeds and white matter lesions, is now possible, but remains a resource-, skills- and time-intensive approach. As a result, there has been a recent proliferation of blood-based biomarker studies for CSVD aimed at developing accessible screening tools for early detection and risk stratification. However, a good understanding of the pathophysiological processes underpinning CSVD is needed to identify and assess clinically useful biomarkers. Here, we provide an overview of processes associated with CSVD pathogenesis, including endothelial injury and dysfunction, neuroinflammation, oxidative stress, perivascular neuronal damage as well as cardiovascular dysfunction. Then, we review clinical studies of the key biomolecules involved in the aforementioned processes. Lastly, we outline future trends and directions for CSVD biomarker discovery and clinical validation.

Intermittent Metabolic Switching and Vascular Cognitive Impairment.

Intermittent fasting (IF), a dietary pattern alternating between eating and fasting periods within a 24-hour cycle, has garnered recognition for its potential to enhance both healthspan and lifespan in animal models and humans. It also shows promise in alleviating age-related diseases, including neurodegeneration. Vascular cognitive impairment (VCI) spans a severity range from mild cognitive deficits to severe cognitive deficits and loss of function in vascular dementia. Chronic cerebral hypoperfusion has emerged as a significant contributor to VCI, instigating vascular pathologies such as microbleeds, blood-brain barrier dysfunction, neuronal loss, and white matter lesions. Preclinical studies in rodents strongly suggest that IF has the potential to attenuate pathological mechanisms, including excitotoxicity, oxidative stress, inflammation, and cell death pathways in VCI models. Hence, this supports evaluating IF in clinical trials for both existing and at-risk VCI patients. This review compiles existing data supporting IF's potential in treating VCI-related vascular and neuronal pathologies, emphasizing the mechanisms by which IF may mitigate these issues. Hence providing a comprehensive overview of the available data supporting IF's potential in treating VCI by emphasizing the underlying mechanisms that make IF a promising intervention for VCI.

Serum Brevican as a Biomarker of Cerebrovascular Disease in an Elderly Cognitively Impaired Cohort.

In the brain, the extracellular matrix (ECM) composition shapes the neuronal microenvironment and can undergo substantial changes with cerebral pathology. Brevican is integral to the formation of the ECM's neuroprotective perineuronal nets (PNNs). Decreased brevican levels were reported in vascular dementia (VaD) but not in Alzheimer's disease (AD). However, the status of brevican in clinical cohorts with high concomitance of AD pathological burden and cerebrovascular disease (CeVD) is unclear. In this study, 32 non-cognitively impaired (NCI), 97 cognitively impaired no dementia (CIND), 46 AD, and 23 VaD participants recruited from memory clinics based in Singapore underwent neuropsychological and neuroimaging assessments, together with measurements of serum brevican. Association analyses were performed between serum brevican and neuroimaging measures of CeVDs, including white matter hyperintensities (WMHs), lacunes, cortical infarcts, and cerebral microbleeds. Using an aggregated score for CeVD burden, only CIND participants showed lower brevican levels with higher CeVD compared to those with lower CeVD burden (p = 0.006). Among the CeVD subtypes assessed, only elevated WMH burden was associated with lower brevican levels (OR = 2.7; 95% CI = 1.3-5.5). Our findings suggest that brevican deficits may play a role in early cerebrovascular damage in participants at risk of developing dementia.