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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 -
Signal Transduction and Targeted Therapy Sep 2023Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with... (Review)
Review
Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington's disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.
Topics: Animals; Neurodegenerative Diseases; Microglia; Neuroinflammatory Diseases; Protein Aggregates; Alzheimer Disease
PubMed: 37735487
DOI: 10.1038/s41392-023-01588-0 -
International Journal of Molecular... Jul 2023Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social,... (Review)
Review
Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social, economic, and emotional burden for the patients and caregivers. It is characterised by a (at least initially) selective degeneration of the frontal and/or temporal lobe, generally leading to behavioural alterations, speech disorders, and psychiatric symptoms. Despite the recent advances, given its extreme heterogeneity, an overview that can bring together all the data currently available is still lacking. Here, we aim to provide a state of the art on the pathogenesis of this disease, starting with established findings and integrating them with more recent ones. In particular, advances in the genetics field will be examined, assessing them in relation to both the clinical manifestations and histopathological findings, as well as considering the link with other diseases, such as amyotrophic lateral sclerosis (ALS). Furthermore, the current diagnostic criteria will be explored, including neuroimaging methods, nuclear medicine investigations, and biomarkers on biological fluids. Of note, the promising information provided by neurophysiological investigations, i.e., electroencephalography and non-invasive brain stimulation techniques, concerning the alterations in brain networks and neurotransmitter systems will be reviewed. Finally, current and experimental therapies will be considered.
Topics: Middle Aged; Humans; Frontotemporal Dementia; Neurodegenerative Diseases; Pick Disease of the Brain; Amyotrophic Lateral Sclerosis; Temporal Lobe
PubMed: 37511491
DOI: 10.3390/ijms241411732 -
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 -
Journal of Neurology, Neurosurgery, and... Aug 2023Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in the gene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants in lead to the inclusion of a cryptic exon in messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of leads to impaired neurotransmission. Recent discoveries have identified as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of as a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.
Topics: Humans; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Neurodegenerative Diseases; Nerve Tissue Proteins; Polymorphism, Genetic
PubMed: 36737245
DOI: 10.1136/jnnp-2022-330504 -
Neurotherapeutics : the Journal of the... Jul 2023Frontotemporal dementia (FTD) comprises a diverse group of clinical neurodegenerative syndromes characterized by progressive changes in behavior, personality, executive...
Frontotemporal dementia (FTD) comprises a diverse group of clinical neurodegenerative syndromes characterized by progressive changes in behavior, personality, executive function, language, and motor function. Approximately 20% of FTD cases have a known genetic cause. The three most common genetic mutations causing FTD are discussed. Frontotemporal lobar degeneration refers to the heterogeneous group of neuropathology underlying FTD clinical syndromes. While there are no current disease-modifying treatments for FTD, management includes off-label pharmacotherapy and non-pharmacological approaches to target symptoms. The utility of several different drug classes is discussed. Medications used in the treatment of Alzheimer's disease have no benefit in FTD and can worsen neuropsychiatric symptoms. Non-pharmacological approaches to management include lifestyle modifications, speech-, occupational-, and physical therapy, peer and caregiver support, and safety considerations. Recent developments in the understanding of the genetics, pathophysiology, neuropathology, and neuroimmunology underlying FTD clinical syndromes have expanded possibilities for disease-modifying and symptom-targeted treatments. Different pathogenetic mechanisms are targeted in several active clinical trials, opening up exciting possibilities for breakthrough advances in treatment and management of FTD spectrum disorders.
Topics: Humans; Frontotemporal Dementia; Syndrome; Frontotemporal Lobar Degeneration; Alzheimer Disease
PubMed: 37157041
DOI: 10.1007/s13311-023-01380-6 -
BMC Medicine Jul 2023Increasing evidence suggests an association between pro-inflammatory diets and cognitive function. However, only a few studies based on small sample sizes have explored...
BACKGROUND
Increasing evidence suggests an association between pro-inflammatory diets and cognitive function. However, only a few studies based on small sample sizes have explored the association between pro-inflammatory diets and dementia using the dietary inflammatory index (DII). Additionally, the relationship between DII and different subtypes of dementia, such as Alzheimer's dementia and vascular dementia, remains largely unexplored. Given the changes in brain structure already observed in patients with dementia, we also investigated the association between DII and magnetic resonance imaging (MRI) measures of brain structure to provide some hints to elucidate the potential mechanisms between pro-inflammatory diet and cognitive decline.
METHODS
A total of 166,377 UK Biobank participants without dementia at baseline were analyzed. DII calculations were based on the information collected by the 24-h recall questionnaire. Brain structural anatomy and tissue-specific volumes were measured using brain MRI. Cox proportional hazards models, competing risk models, and restricted cubic spline were applied to assess the longitudinal associations. The generalized linear model was used to assess the association between DII and MRI measurements.
RESULTS
During a median follow-up time of 9.46 years, a total of 1372 participants developed dementia. The incidence of all-cause dementia increased by 4.6% for each additional unit of DII [hazard ratio (HR): 1.046]. Besides, DII displayed a "J-shaped" non-linear association with Alzheimer's dementia (P = 0.003). When DII was above 1.30, an increase in DII was significantly associated with an increased risk of Alzheimer's dementia (HR: 1.391, 95%CI: 1.085-1.784, P = 0.009). For brain MRI, the total volume of white matter hyperintensities increased with an increase in DII, whereas the volume of gray matter in the hippocampus decreased.
CONCLUSIONS
In this cohort study, higher DII was associated with a higher risk of all-cause dementia and Alzheimer's dementia. However, our findings suggested that the association with DII and vascular and frontotemporal dementia was not significant.
Topics: Humans; Prospective Studies; Alzheimer Disease; Cohort Studies; Biological Specimen Banks; Diet; United Kingdom
PubMed: 37480061
DOI: 10.1186/s12916-023-02940-5