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Molecular Neurodegeneration Jul 2023Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related... (Review)
Review
Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. Severe VCID includes post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. While VCID is acknowledged as the second most common form of dementia after Alzheimer's disease (AD) accounting for 20% of dementia cases, VCID and AD frequently coexist. In VCID, cerebral small vessel disease (cSVD) often affects arterioles, capillaries, and venules, where arteriolosclerosis and cerebral amyloid angiopathy (CAA) are major pathologies. White matter hyperintensities, recent small subcortical infarcts, lacunes of presumed vascular origin, enlarged perivascular space, microbleeds, and brain atrophy are neuroimaging hallmarks of cSVD. The current primary approach to cSVD treatment is to control vascular risk factors such as hypertension, dyslipidemia, diabetes, and smoking. However, causal therapeutic strategies have not been established partly due to the heterogeneous pathogenesis of cSVD. In this review, we summarize the pathophysiology of cSVD and discuss the probable etiological pathways by focusing on hypoperfusion/hypoxia, blood-brain barriers (BBB) dysregulation, brain fluid drainage disturbances, and vascular inflammation to define potential diagnostic and therapeutic targets for cSVD.
Topics: Humans; Dementia, Vascular; Alzheimer Disease; Causality; Risk Factors; Cerebral Small Vessel Diseases
PubMed: 37434208
DOI: 10.1186/s13024-023-00640-5 -
Australian Journal of General Practice Aug 2023Dementia is a debilitating neurological condition that affects millions of patients and families worldwide and remains a significant public health concern. Understanding...
BACKGROUND
Dementia is a debilitating neurological condition that affects millions of patients and families worldwide and remains a significant public health concern. Understanding the underlying neurobiology and pathophysiology of dementia is an important step towards finding effective treatment options.
OBJECTIVE
This article provides an overview of the pathophysiological processes of the most common types of dementia in older adults and highlights some of the developments in the research of biomarkers.
DISCUSSION
The most common forms of late-onset dementia are Alzheimer's disease, dementia with Lewy bodies, vascular dementia and frontotemporal dementia. The pathophysiology of dementia is broadly characterised by the aggregation of misfolded proteins (such as amyloid-β plaques and neurofibrillary tangles in Alzheimer's disease) and cerebrovascular disease. Mixed neuropathologies are frequently detected in the brains of older people with dementia and have important clinical implications.
Topics: Humans; Aged; Alzheimer Disease; Neurofibrillary Tangles; Brain
PubMed: 37532448
DOI: 10.31128/AJGP-02-23-6736 -
Journal of Neuroinflammation Jan 2024Some studies have shown that gut microbiota may be associated with dementia. However, the causal effects between gut microbiota and different types of dementia and...
BACKGROUND
Some studies have shown that gut microbiota may be associated with dementia. However, the causal effects between gut microbiota and different types of dementia and whether cytokines act as a mediator remain unclear.
METHODS
Gut microbiota, cytokines, and five dementia types, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy body (DLB), vascular dementia (VD), and Parkinson's disease dementia (PDD) were identified from large-scale genome-wide association studies (GWAS) summary data. We used Mendelian randomization (MR) to investigate the causal relationships between gut microbiota, cytokines, and five types of dementia. Inverse variance weighting (IVW) was used as the main statistical method. In addition, we explored whether cytokines act as a mediating factor in the pathway from gut microbiota to dementia.
RESULTS
There were 20 positive and 16 negative causal effects between genetic liability in the gut microbiota and dementia. Also, there were five positive and four negative causal effects between cytokines and dementias. Cytokines did not act as mediating factors.
CONCLUSIONS
Gut microbiota and cytokines were causally associated with five types of dementia, and cytokines seemed not to be the mediating factors in the pathway from gut microbiota to dementia.
Topics: Humans; Gastrointestinal Microbiome; Cytokines; Genome-Wide Association Study; Mendelian Randomization Analysis; Parkinson Disease; Alzheimer Disease; Frontotemporal Dementia
PubMed: 38178103
DOI: 10.1186/s12974-023-02999-0 -
European Heart Journal Dec 2023Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated... (Observational Study)
Observational Study
BACKGROUND AND AIMS
Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated with atherosclerosis in experimental studies. This study aimed to investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches.
METHODS
Observational studies were conducted in the Copenhagen General Population Study (n = 101 730). Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank (n = 365 913); secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium (n = 563 085). Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation.
RESULTS
Observational analyses showed associations between high neutrophil counts with high risks of all outcomes. In the UK Biobank, odds ratios (95% confidence intervals) per 1-SD higher genetically predicted neutrophil counts were 1.15 (1.08, 1.21) for ischaemic heart disease, 1.22 (1.12, 1.34) for myocardial infarction, and 1.19 (1.04, 1.36) for peripheral arterial disease; similar results were observed in men and women separately. In two-sample MR, corresponding estimates were 1.14 (1.05, 1.23) for ischaemic heart disease and 1.11 (1.02, 1.20) for myocardial infarction; multiple sensitivity analyses showed consistent results. No robust associations in two-sample MR analyses were found for other types of leucocytes.
CONCLUSIONS
Observational and genetically determined high neutrophil counts were associated with atherosclerotic cardiovascular disease, supporting that high blood neutrophil counts is a causal risk factor for atherosclerotic cardiovascular disease.
Topics: Male; Humans; Female; Cardiovascular Diseases; Neutrophils; Brain Ischemia; Stroke; Myocardial Infarction; Myocardial Ischemia; Atherosclerosis; Peripheral Arterial Disease; Coronary Artery Disease; Mendelian Randomization Analysis; Genome-Wide Association Study; Polymorphism, Single Nucleotide
PubMed: 37950632
DOI: 10.1093/eurheartj/ehad649 -
Acta Neuropathologica Communications Jun 2023Vascular cognitive impairment (VCI) describes a wide spectrum of cognitive deficits related to cerebrovascular diseases. Although the loss of blood flow to cortical... (Review)
Review
Vascular cognitive impairment (VCI) describes a wide spectrum of cognitive deficits related to cerebrovascular diseases. Although the loss of blood flow to cortical regions critically involved in cognitive processes must feature as the main driver of VCI, the underlying mechanisms and interactions with related disease processes remain to be fully elucidated. Recent clinical studies of cerebral blood flow measurements have supported the role of chronic cerebral hypoperfusion (CCH) as a major driver of the vascular pathology and clinical manifestations of VCI. Here we review the pathophysiological mechanisms as well as neuropathological changes of CCH. Potential interventional strategies for VCI are also reviewed. A deeper understanding of how CCH can lead to accumulation of VCI-associated pathology could potentially pave the way for early detection and development of disease-modifying therapies, thus allowing preventive interventions instead of symptomatic treatments.
Topics: Humans; Cognitive Dysfunction; Brain Ischemia; Cognition Disorders; Cerebrovascular Circulation; Neuropathology
PubMed: 37309012
DOI: 10.1186/s40478-023-01590-1 -
Hypertension (Dallas, Tex. : 1979) Jan 2024Hypertension-associated cerebral small vessel disease is a common finding in older people. Strongly associated with age and hypertension, small vessel disease is found... (Review)
Review
Hypertension-associated cerebral small vessel disease is a common finding in older people. Strongly associated with age and hypertension, small vessel disease is found at autopsy in over 50% of people aged ≥65 years, with a spectrum of clinical manifestations. It is the main cause of lacunar stroke and a major source of vascular contributions to cognitive impairment and dementia. The brain areas affected are subcortical and periventricular white matter and deep gray nuclei. Neuropathological sequelae are diffuse white matter lesions (seen as white matter hyperintensities on T2-weighted magnetic resonance imaging), small ischemic foci (lacunes or microinfarcts), and less commonly, subcortical microhemorrhages. The most common form of cerebral small vessel disease is concentric, fibrotic thickening of small penetrating arteries (up to 300 microns outer diameter) termed arteriolosclerosis. Less common forms are small artery atheroma and lipohyalinosis (the lesions described by C. Miller Fisher adjacent to lacunes). Other microvascular lesions that are not reviewed here include cerebral amyloid angiopathy and venous collagenosis. Here, we review the epidemiology, neuropathology, clinical management, genetics, preclinical models, and pathogenesis of hypertensive small vessel disease. Knowledge gaps include initiating factors, molecular pathogenesis, relationships between arterial pathology and tissue damage, possible reversibility, pharmacological targets, and molecular biomarkers. Progress is anticipated from multicell transcriptomic and proteomic profiling, novel experimental models and further target-finding and interventional clinical studies.
Topics: Humans; Aged; Proteomics; Cerebral Small Vessel Diseases; Hypertension; Dementia; Cognitive Dysfunction; Magnetic Resonance Imaging; Dementia, Vascular
PubMed: 38044814
DOI: 10.1161/HYPERTENSIONAHA.123.19943 -
Neuron Oct 2023In Alzheimer's disease (AD), Aβ deposits form slowly, several decades before further pathological events trigger neurodegeneration and dementia. However, a substantial... (Review)
Review
In Alzheimer's disease (AD), Aβ deposits form slowly, several decades before further pathological events trigger neurodegeneration and dementia. However, a substantial proportion of affected individuals remains non-demented despite AD pathology, raising questions about the underlying factors that determine the transition to clinical disease. Here, we emphasize the critical function of resilience and resistance factors, which we extend beyond the concept of cognitive reserve to include the glial, immune, and vascular system. We review the evidence and use the metaphor of "tipping points" to illustrate how gradually forming AD neuropathology in the preclinical stage can transition to dementia once adaptive functions of the glial, immune, and vascular system are lost and self-reinforcing pathological cascades are unleashed. Thus, we propose an expanded framework for pathomechanistic research that focuses on tipping points and non-neuronal resilience mechanisms, which may represent previously untapped therapeutic targets in preclinical AD.
Topics: Humans; Alzheimer Disease; Neuroglia; Amyloid beta-Peptides
PubMed: 37385247
DOI: 10.1016/j.neuron.2023.05.031