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JAMA Network Open Oct 2023Little is known about the specific timing and sequence of incident psychiatric comorbidities at different stages of dementia diagnosis.
IMPORTANCE
Little is known about the specific timing and sequence of incident psychiatric comorbidities at different stages of dementia diagnosis.
OBJECTIVES
To examine the temporal risk patterns of psychiatric disorders, including depression, anxiety, stress-related disorders, substance use disorders, sleep disorders, somatoform/conversion disorders, and psychotic disorders, among patients with dementia before, at the time of, and after receipt of a diagnosis.
DESIGN, SETTING, AND PARTICIPANTS
This population-based, nationwide cohort study analyzed data from 796 505 participants obtained from 6 registers between January 1, 2000, and December 31, 2017, including the Swedish registry for cognitive/dementia disorders. Patients with dementia were matched on year of birth (±3 years), sex, and region of residence with up to 4 controls. Data were analyzed between March 1, 2023, and August 31, 2023.
EXPOSURES
Any cause of dementia and dementia subtypes.
MAIN OUTCOMES AND MEASURES
Flexible parametric survival models to determine the time-dependent risk of initial diagnosis of psychiatric disorders, from 7 years prior to dementia diagnosis to 10 years after diagnosis. Subgroup analysis was conducted for psychiatric drug use among persons receiving a diagnosis of dementia from January 1, 2011, to December 31, 2012.
RESULTS
Of 796 505 patients included in the study (mean [SD] age at diagnosis, 80.2 [8.3] years; 448 869 (56.4%) female), 209 245 had dementia, whereas 587 260 did not, across 7 824 616 person-years. The relative risk of psychiatric disorders was consistently higher among patients with dementia compared with control participants and began to increase from 3 years before diagnosis (hazard ratio, [HR], 1.72; 95% CI, 1.67-1.76), peaked during the week after diagnosis (HR, 4.74; 95% CI, 4.21-5.34), and decreased rapidly thereafter. Decreased risk relative to controls was observed from 5 years after diagnosis (HR, 0.93; 95% CI, 0.87-0.98). The results were similar for Alzheimer disease, mixed dementia, vascular dementia and unspecified dementia. Among patients with dementia, markedly elevated use of psychiatric medications was observed in the year leading up to the dementia diagnosis and peaked 6 months after diagnosis. For example, antidepressant use was persistently higher among patients with dementia compared with controls, and the difference increased from 2 years before dementia diagnosis (15.9% vs 7.9%, P < .001), peaked approximately 6 months after dementia diagnosis (29.1% vs 9.7%, P < .001), and then decreased slowly from 3 years after diagnosis but remained higher than controls 5 years after diagnosis (16.4% vs 6.9%, P < .001).
CONCLUSIONS AND RELEVANCE
The findings of this cohort study that patients with dementia had markedly increased risks of psychiatric disorders both before and after dementia diagnosis highlight the significance of incorporating psychiatric preventative and management interventions for individuals with dementia across various diagnostic stages.
Topics: Humans; Female; Child; Male; Cohort Studies; Risk; Anxiety Disorders; Cognition Disorders; Alzheimer Disease; Substance-Related Disorders
PubMed: 37847498
DOI: 10.1001/jamanetworkopen.2023.38080 -
Nature Communications Nov 2023Emerging evidence shows that the meninges conduct essential immune surveillance and immune defense at the brain border, and the dysfunction of meningeal immunity...
Emerging evidence shows that the meninges conduct essential immune surveillance and immune defense at the brain border, and the dysfunction of meningeal immunity contributes to aging and neurodegeneration. However, no study exists on the molecular properties of cell types within human leptomeninges. Here, we provide single nuclei profiling of dissected postmortem leptomeninges from aged individuals. We detect diverse cell types, including unique meningeal endothelial, mural, and fibroblast subtypes. For immune cells, we show that most T cells express CD8 and bear characteristics of tissue-resident memory T cells. We also identify distinct subtypes of border-associated macrophages (BAMs) that display differential gene expressions from microglia and express risk genes for Alzheimer's Disease (AD), as nominated by genome-wide association studies (GWAS). We discover cell-type-specific differentially expressed genes in individuals with Alzheimer's dementia, particularly in fibroblasts and BAMs. Indeed, when cultured, leptomeningeal cells display the signature of ex vivo AD fibroblasts upon amyloid-β treatment. We further explore ligand-receptor interactions within the leptomeningeal niche and computationally infer intercellular communications in AD. Thus, our study establishes a molecular map of human leptomeningeal cell types, providing significant insight into the border immune and fibrotic responses in AD.
Topics: Humans; Aged; Genome-Wide Association Study; Meninges; Alzheimer Disease; Macrophages; Aging; Microglia
PubMed: 37923721
DOI: 10.1038/s41467-023-42825-y -
Neuropharmacology Jul 2024Every year, 10 million people develop dementia, the most common of which is Alzheimer's disease (AD). To date, there is no way to prevent cognitive decline and therapies... (Review)
Review
Every year, 10 million people develop dementia, the most common of which is Alzheimer's disease (AD). To date, there is no way to prevent cognitive decline and therapies are limited. This review provides a neuroimmunological perspective on the progression of AD, and discusses the immune-targeted therapies that are in preclinical and clinical trials that may impact the development of this disease. Specifically, we look to the role of the NLRP3 inflammasome, its triggers in the brain and how its activation can contribute to the progression of dementia. We summarise the range of inhibitors targeting the NLRP3 inflammasome and its downstream pathways that are under investigation, and discuss future therapeutic perspectives for this devastating condition.
Topics: Animals; Humans; Alzheimer Disease; Brain; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction
PubMed: 38565393
DOI: 10.1016/j.neuropharm.2024.109941 -
Biomolecules Mar 2024Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging,... (Review)
Review
Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD).
Topics: Humans; Biomarkers; Neurodegenerative Diseases; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Parkinson Disease; Animals
PubMed: 38672416
DOI: 10.3390/biom14040398 -
Immunity Jan 2024Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with...
Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with neurodegenerative diseases, including Alzheimer's disease. Trem2 is essential for microglia-mediated synaptic refinement, but whether Trem2 contributes to shaping neuronal development remains unclear. Here, we demonstrate that Trem2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in the hippocampal cornus ammonis (CA)1 but not in CA3 subfield displayed compromised energetic metabolism, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This was paralleled by the transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation, and mitochondrial gene signatures, accompanied by a delay in the maturation of CA1 neurons. Our results unveil a role of Trem2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner.
Topics: Alzheimer Disease; Brain; Energy Metabolism; Microglia; Neurons; Animals; Mice
PubMed: 38159572
DOI: 10.1016/j.immuni.2023.12.002 -
Aging Sep 2023Observational studies suggest that cardiovascular disease (CVD) increases the risk of developing Alzheimer's disease (AD). However, the causal relationship between the...
Observational studies suggest that cardiovascular disease (CVD) increases the risk of developing Alzheimer's disease (AD). However, the causal relationship between the two is not clear. This study applied a two-sample bidirectional Mendelian randomization method to explore the causal relationship between CVD and AD. Genome-wide association study (GWAS) data from 46 datasets of European populations (21,982 cases of AD and 41,944 controls) were utilized to obtain genetic instrumental variables for AD. In addition, genetic instrumental variables for atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI), coronary heart disease (CHD), angina pectoris (AP), and ischemic stroke (IS) (including large-artery atherosclerotic stroke [LAS] and cardioembolic stroke [CES]) were selected from GWAS data of European populations ( < 5E-8). The inverse variance weighting method was employed as the major Mendelian randomization analysis method. Genetically predicted AD odds ratios (OR) (1.06) (95% CI: 1.02-1.10, = 0.003) were linked to higher AP analysis. A higher genetically predicted OR for CES (0.9) (95% CI 0.82-0.99, = 0.02) was linked to a decreased AD risk. This Mendelian randomized study identified AD as a risk factor for AP. In addition, CES was related to a reduced incidence of AD. Therefore, these modifiable risk factors are crucial targets for preventing and treating AD.
Topics: Humans; Cardiovascular Diseases; Mendelian Randomization Analysis; Alzheimer Disease; Genome-Wide Association Study; Causality; Angina Pectoris
PubMed: 37665672
DOI: 10.18632/aging.205013 -
International Journal of Molecular... May 2024The connection between body weight alterations and Alzheimer's disease highlights the intricate relationship between the brain and adipose tissue in the context of... (Review)
Review
The connection between body weight alterations and Alzheimer's disease highlights the intricate relationship between the brain and adipose tissue in the context of neurological disorders. During midlife, weight gain increases the risk of cognitive decline and dementia, whereas in late life, weight gain becomes a protective factor. Despite their substantial impact on metabolism, the role of adipokines in the transition from healthy aging to neurological disorders remains largely unexplored. We aim to investigate how the adipose tissue milieu and the secreted adipokines are involved in the transition between biological and pathological aging, highlighting the bidirectional relationship between the brain and systemic metabolism. Understanding the function of these adipokines will allow us to identify biomarkers for early detection of Alzheimer's disease and uncover novel therapeutic options.
Topics: Alzheimer Disease; Humans; Adipokines; Adipose Tissue; Brain; Animals; Biomarkers; Aging
PubMed: 38892118
DOI: 10.3390/ijms25115932 -
International Journal of Molecular... Oct 2023Alzheimer's disease (AD) represents a major diagnostic challenge, as early detection is crucial for effective intervention. This review examines the diagnostic... (Review)
Review
Alzheimer's disease (AD) represents a major diagnostic challenge, as early detection is crucial for effective intervention. This review examines the diagnostic challenges facing current AD evaluations and explores the emerging field of retinal alterations as early indicators. Recognizing the potential of the retina as a noninvasive window to the brain, we emphasize the importance of identifying retinal biomarkers in the early stages of AD. However, the examination of AD is not without its challenges, as the similarities shared with other retinal diseases introduce complexity in the search for AD-specific markers. In this review, we address the relevance of using the retina for the early diagnosis of AD and the complex challenges associated with the search for AD-specific retinal biomarkers. We provide a comprehensive overview of the current landscape and highlight avenues for progress in AD diagnosis by retinal examination.
Topics: Humans; Alzheimer Disease; Retina; Retinal Diseases; Biomarkers; Brain
PubMed: 37958816
DOI: 10.3390/ijms242115834 -
European Journal of Medicinal Chemistry Jul 2023Alzheimer's Disease (AD) remains one of the most challenging health-related issues for our society. It is becoming increasingly prevalent, especially in developed... (Review)
Review
Alzheimer's Disease (AD) remains one of the most challenging health-related issues for our society. It is becoming increasingly prevalent, especially in developed countries, due to the rising life expectancy and, moreover, represents a considerable economic burden worldwide. All efforts at the discovery of new diagnostic and therapeutic tools in the last decades have invariably met with failure, making AD an incurable illness and underscoring the need for new approaches. In recent years, theranostic agents have emerged as an interesting strategy. They are molecules able to simultaneously provide diagnostic information and deliver therapeutic activity, allowing for the assessment of the molecule activity, the organism response and the pharmacokinetics. This makes these compounds promising for streamlining research on AD drugs and for their application in personalized medicine. We review here the field of small-molecule theranostic agents as promising tools for the development of novel diagnostic and therapeutic resources against AD, highlighting the positive and significant impact that theranostics can be expected to have in the near future in clinical practice.
Topics: Humans; Alzheimer Disease; Precision Medicine; Amyloid beta-Peptides
PubMed: 37141706
DOI: 10.1016/j.ejmech.2023.115382 -
Biochemical Pharmacology Jul 2023Alzheimer's disease (AD) is the most common form of progressive dementia and there is no truly efficacious treatment. Accumulating evidence indicates that impaired... (Review)
Review
Alzheimer's disease (AD) is the most common form of progressive dementia and there is no truly efficacious treatment. Accumulating evidence indicates that impaired autophagic function for removal of damaged mitochondria and protein aggregates such as amyloid and tau protein aggregates may contribute to the pathogenesis of AD. Epidemiologic studies have implicated alcohol abuse in promoting AD, yet the underlying mechanisms are poorly understood. In this review, we discuss mechanisms of selective autophagy for mitochondria and protein aggregates and how these mechanisms are impaired by aging and alcohol consumption. We also discuss potential genetic and pharmacological approaches for targeting autophagy/mitophagy, as well as lysosomal and mitochondrial biogenesis, for the potential prevention and treatment of AD.
Topics: Humans; Alzheimer Disease; Protein Aggregates; Autophagy; Mitophagy; Ethanol; Transcription Factors; Amyloid beta-Peptides
PubMed: 37127251
DOI: 10.1016/j.bcp.2023.115576