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Frontiers in Aging Neuroscience 2024The number of people with dementia is soaring. Cognitive reserve has been thought to be associated with dementia risk. It is not clear at which period in the life course... (Review)
Review
BACKGROUND
The number of people with dementia is soaring. Cognitive reserve has been thought to be associated with dementia risk. It is not clear at which period in the life course and which cognitive reserve proxies contribute to the reduced risk of dementia.
METHODS
By scanning four databases (PubMed, Embase, Web of Science, and MEDLINE) up to Jun 3, 2023, longitudinal studies of life-course cognitive reserve and risk of dementia were found. The HRs and 95% CIs for each study were summarized using random effects models. Subgroup analyses and sensitivity analyses were conducted. Utilizing funnel plots, Begg and Egger tests, publication bias was investigated.
RESULTS
A total of 27 studies were included, containing 10 in early-life, 10 in middle-life, and 13 in late-life. All studies used validated questionnaires to measure cognitive reserve, and dementia diagnosis followed recognized worldwide guidelines. All included studies were of medium or low risk. Cognitive reserve in early-life (Hazard ratio (HR): 0.82; 95% confidence interval (CI): 0.79-0.86), middle-life (HR: 0.91; 95% CI: 0.84-0.98) and late-life (HR: 0.81; 95% CI: 0.75-0.88) all have protective effects on dementia risk. Multiple sensitivity analyses showed consistent results.
CONCLUSION
Dementia risk is reduced by the buildup of cognitive reserves during life-course. Accumulation of proxies for cognitive reserve in early and late life had the greatest effect on dementia risk reduction. Social connection may be an effective approach to lower dementia risk.
PubMed: 38681665
DOI: 10.3389/fnagi.2024.1358992 -
Alzheimer's Research & Therapy Apr 2024Clinical trials in Alzheimer's disease (AD) had high failure rates for several reasons, including the lack of biological endpoints. Fluid-based biomarkers may present a...
BACKGROUND
Clinical trials in Alzheimer's disease (AD) had high failure rates for several reasons, including the lack of biological endpoints. Fluid-based biomarkers may present a solution to measure biologically relevant endpoints. It is currently unclear to what extent fluid-based biomarkers are applied to support drug development.
METHODS
We systematically reviewed 272 trials (clinicaltrials.gov) with disease-modifying therapies starting between 01-01-2017 and 01-01-2024 and identified which CSF and/or blood-based biomarker endpoints were used per purpose and trial type.
RESULTS
We found that 44% (N = 121) of the trials employed fluid-based biomarker endpoints among which the CSF ATN biomarkers (Aβ (42/40), p/tTau) were used most frequently. In blood, inflammatory cytokines, NFL, and pTau were most frequently employed. Blood- and CSF-based biomarkers were used approximately equally. Target engagement biomarkers were used in 26% (N = 72) of the trials, mainly in drugs targeting inflammation and amyloid. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis and, gut-brain axis targeting drugs. Positive biomarker results did not always translate to cognitive effects, most commonly the small significant reductions in CSF tau isoforms that were seen following anti-Tau treatments. On the other hand, the positive anti-amyloid trials results on cognitive function were supported by clear effect in most fluid markers.
CONCLUSIONS
As the field moves towards primary prevention, we expect an increase in the use of fluid-based biomarkers to determine disease modification. Use of blood-based biomarkers will rapidly increase, but CSF markers remain important to determine brain-specific treatment effects. With improving techniques, new biomarkers can be found to diversify the possibilities in measuring treatment effects and target engagement. It remains important to interpret biomarker results in the context of the trial and be aware of the performance of the biomarker. Diversifying biomarkers could aid in the development of surrogacy biomarkers for different drug targets.
Topics: Alzheimer Disease; Humans; Biomarkers; Clinical Trials as Topic; tau Proteins; Amyloid beta-Peptides
PubMed: 38678292
DOI: 10.1186/s13195-024-01456-1 -
Genes Apr 2024Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in ALS.
METHODS
Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to 17 August 2023, and investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS. The study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in cerebrospinal fluid (CSF) and blood, and clinical outcome were recorded. The protocol was registered with PROSPERO, CRD42022376939.
RESULTS
Sixty studies with 8801 participants were included. Both NfL and pNfH measured in CSF showed high sensitivity and specificity in distinguishing ALS from disease mimics. Both NfL and pNfH measured in CSF correlated with their corresponding levels in blood (plasma or serum); however, there were stronger correlations between CSF NfL and blood NfL. NfL measured in blood exhibited high sensitivity and specificity in distinguishing ALS from controls. Both higher levels of NfL and pNfH either measured in blood or CSF were correlated with more severe symptoms as assessed by the ALS Functional Rating Scale Revised score and with a faster disease progression rate; however, only blood NfL levels were associated with shorter survival.
DISCUSSION
Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores and disease progression, while CSF NfL correlates strongly with blood (either plasma or serum) and is also associated with survival, supporting its use in clinical diagnostics and prognosis. Future work must be conducted in a prospective manner with standardized bio-specimen collection methods and analytical platforms, further improvement in immunoassays for quantification of pNfH in blood, and the identification of cut-offs across the ALS spectrum and controls.
Topics: Amyotrophic Lateral Sclerosis; Humans; Neurofilament Proteins; Biomarkers; Intermediate Filaments; Prognosis
PubMed: 38674431
DOI: 10.3390/genes15040496 -
Medicina (Kaunas, Lithuania) Apr 2024: The study aims to provide a comprehensive neuropsychological analysis of psychotic spectrum disorders, including schizophrenia, bipolar disorder, and depression. It... (Review)
Review
: The study aims to provide a comprehensive neuropsychological analysis of psychotic spectrum disorders, including schizophrenia, bipolar disorder, and depression. It focuses on the critical aspects of cognitive impairments, diagnostic tools, intervention efficacy, and the roles of genetic and environmental factors in these disorders. The paper emphasizes the diagnostic significance of neuropsychological tests in identifying cognitive deficiencies and their predictive value in the early management of psychosis. : The study involved a systematic literature review following the PRISMA guidelines. The search was conducted in significant databases like Scopus, PsycINFO, PubMed, and Web of Science using keywords relevant to clinical neuropsychology and psychotic spectrum disorders. The inclusion criteria required articles to be in English, published between 2018 and 2023, and pertinent to clinical neuropsychology's application in these disorders. A total of 153 articles were identified, with 44 ultimately included for detailed analysis based on relevance and publication status after screening. The review highlights several key findings, including the diagnostic and prognostic significance of mismatch negativity, neuroprogressive trajectories, cortical thinning in familial high-risk individuals, and distinct illness trajectories within psychosis subgroups. The studies evaluated underline the role of neuropsychological tests in diagnosing psychiatric disorders and emphasize early detection and the effectiveness of intervention strategies based on cognitive and neurobiological markers. : The systematic review underscores the importance of investigating the neuropsychological components of psychotic spectrum disorders. It identifies significant cognitive impairments in attention, memory, and executive function, correlating with structural and functional brain abnormalities. The paper stresses the need for precise diagnoses and personalized treatment modalities, highlighting the complex interplay between genetic, environmental, and psychosocial factors. It calls for a deeper understanding of these neuropsychological processes to enhance diagnostic accuracy and therapeutic outcomes.
Topics: Humans; Psychotic Disorders; Neuropsychological Tests; Neuropsychology; Cognitive Dysfunction; Bipolar Disorder; Schizophrenia; Cognition
PubMed: 38674291
DOI: 10.3390/medicina60040645 -
Journal of Clinical Medicine Apr 2024The impact of oral anticoagulants (OACs) on cognitive impairment and dementia in patients with atrial fibrillation (AF) is not well characterized. This systematic... (Review)
Review
The impact of oral anticoagulants (OACs) on cognitive impairment and dementia in patients with atrial fibrillation (AF) is not well characterized. This systematic review aims to address this knowledge gap. SCOPUS and PubMed searches were conducted to identify articles in the English language investigating the association between the use of OACs and cognitive impairment and dementia. We excluded non-original research studies and studies that did not report data on cognitive impairment or included patients who underwent open heart surgery or had psychiatric illnesses or cancer. : Out of 22 studies ( = 606,404 patients), 13 studies ( = 597,744 patients) reported a reduction in cognitive impairment/dementia in those undergoing thromboprophylaxis. Using direct oral anticoagulants (DOACs) was associated with a lower incidence of cognitive impairment in 10 studies ( = 284,636 patients). One study found that patients undergoing dual therapy ( = 6794 patients) had a greater incidence of cognitive impairment compared to those undergoing monotherapy ( = 9994 patients). Three studies ( = 61,991 patients) showed that AF patients on DOACs had a lower likelihood of dementia diagnosis than those on vitamin K antagonists (VKAs). Dementia incidence was lower when VKAs were under good control. : The use of oral anticoagulants has the potential to prevent cognitive impairment and dementia in patients with AF. Since most of the published research on this subject is observational in nature, more randomized controlled trials are needed to fully understand the effect of anticoagulants on cognitive function.
PubMed: 38673694
DOI: 10.3390/jcm13082418 -
Journal of Clinical Epidemiology Apr 2024To review the findings of studies that have evaluated the design and/or usability of key risk of bias (RoB) tools for the assessment of RoB in primary studies, as...
OBJECTIVES
To review the findings of studies that have evaluated the design and/or usability of key risk of bias (RoB) tools for the assessment of RoB in primary studies, as categorized by the Library of Assessment Tools and InsTruments Used to assess Data validity in Evidence Synthesis Network (a searchable library of RoB tools for evidence synthesis): Prediction model Risk Of Bias ASessment Tool (PROBAST) , Risk of Bias-2 (RoB2), Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I), Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2), Quality Assessment of Diagnostic Accuracy Studies-Comparative (QUADAS-C), Quality Assessment of Prognostic Accuracy Studies (QUAPAS), Risk Of Bias in Non-randomised Studies of Exposures (ROBINS-E), and the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) RoB checklist.
STUDY DESIGN AND SETTING
Systematic review of methodological studies. We conducted a forward citation search from the primary report of each tool, to identify primary studies that aimed to evaluate the design and/or usability of the tool. Two reviewers assessed studies for inclusion. We extracted tool features into Microsoft Word and used NVivo for document analysis, comprising a mix of deductive and inductive approaches. We summarized findings within each tool and explored common findings across tools.
RESULTS
We identified 13 tool evaluations meeting our inclusion criteria: PROBAST (3), RoB2 (3), ROBINS-I (4), and QUADAS-2 (3). We identified no evaluations for the other tools. Evaluations varied in clinical topic area, methodology, approach to bias assessment, and tool user background. Some had limitations affecting generalizability. We identified common findings across tools for 6/14 themes: (1) challenging items (eg, RoB2/ROBINS-I "deviations from intended interventions" domain), (2) overall RoB judgment (concerns with overall risk calculation in PROBAST/ROBINS-I), (3) tool usability (concerns about complexity), (4) time to complete tool (varying demands on time, eg, depending on number of outcomes assessed), (5) user agreement (varied across tools), and (6) recommendations for future use (eg, piloting) and development (add intermediate domain answer to QUADAS-2/PROBAST; provide clearer guidance for all tools). Of the other eight themes, seven only had findings for the QUADAS-2 tool, limiting comparison across tools, and one ("reorganization of questions") had no findings.
CONCLUSION
Evaluations of key RoB tools have posited common challenges and recommendations for tool use and development. These findings may be helpful to people who use or develop RoB tools. Guidance is necessary to support the design and implementation of future RoB tool evaluations.
PubMed: 38670243
DOI: 10.1016/j.jclinepi.2024.111370 -
BMC Public Health Apr 2024Dementia is one of the major causes of disability and dependency among older people worldwide. The formation of an aging population in Iran can be associated with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dementia is one of the major causes of disability and dependency among older people worldwide. The formation of an aging population in Iran can be associated with societal problems, including age-related disorders such as dementia. This study aimed to estimate the prevalence of dementia& Alzheimer disease in adults aged 60 years or older and it's its geographical distribution in Iran.
METHODS
A systematic review and meta-analysis study included articles published in both English and Persian languages and utilized various databases including: Google Scholar, PubMed, Web of Science, Magiran, and thesis database of medicine universities up to December 2022. The pooled prevalence was calculated using random effects models. The prevalence was reported separately for different geographical locations and types of area sampling, and age adjustment was performed for the selected studies. All statistical analyses were conducted using metaprop package in STATA version 17. The I2 statistic was applied to assess heterogeneity.
RESULTS
The meta-analysis considered nine relevant studies that were carried out up to 2023 in Iran. The study found that the prevalence of dementia in central and east counties was estimated to be 0.14 (95% CI; 0.04-0.31), while in western counties, the prevalence was estimated to be 0.1 (95%CI; 0.01-0.27). The estimated overall crude prevalence of dementia was estimated at 0.14 (95% CI; 0.03-0.31). Estimated prevalence-based health centers sampling and hospital-based studies were 0.02 (95% CI; 0.02-0.03), 0.05 (95% CI 0.06-0.11), respectively. One study used nursing home sampling as the sampling method, and the estimated prevalence was 0.43 (95%CI 0.38-0.49).
CONCLUSION
This is the first systematic review and meta-analysis of the prevalence of dementia's disease up to 2023 in Iran. The estimated overall prevalence of dementia is lower than the reported prevalence in European countries and similar to other Asian countries.
Topics: Humans; Iran; Dementia; Prevalence; Aged; Middle Aged; Aged, 80 and over; Male; Female
PubMed: 38664651
DOI: 10.1186/s12889-024-18415-y -
BMC Geriatrics Apr 2024The National Institute for Health and Care Excellence guidelines state that psychosocial interventions should be the first line of treatment for people with dementia who...
BACKGROUND
The National Institute for Health and Care Excellence guidelines state that psychosocial interventions should be the first line of treatment for people with dementia who are experiencing distress behaviours, such as agitation and depression. However, little is known about the characteristics and outcomes of psychosocial interventions or the facilitators and barriers to implementation on inpatient mental health dementia wards which provide care for people with dementia who are often experiencing high levels of distress.
METHODS
A systematic search was conducted on MEDLINE, CINAHL, PsycINFO, Psychology and Behavioural Sciences Collection, and Scopus in May 2023, following PRISMA guidelines. Reference and citation searches were conducted on included articles. Peer-reviewed literature of any study design, relating to psychosocial interventions in inpatient mental health dementia wards, was included. One author reviewed all articles, with a third of results reviewed independently by a second author. Data were extracted to a bespoke form and synthesised using a narrative review. The quality of included studies was appraised using the Mixed Methods Appraisal Tool.
RESULTS
Sixteen studies were included in the synthesis, which together included a total of 538 people with dementia. Study methods and quality varied. Psychosocial interventions delivered on wards included music therapy (five studies), multisensory interventions (four studies), multicomponent interventions (two studies), technology-based interventions (two studies), massage interventions (two studies) and physical exercise (one study). Reduction in distress and improvement in wellbeing was demonstrated inconsistently across studies. Delivering interventions in a caring and individualised way responding to patient need facilitated implementation. Lack of staff time and understanding of interventions, as well as high levels of staff turnover, were barriers to implementation.
CONCLUSION
This review highlights a striking lack of research and therefore evidence base for the use of psychosocial interventions to reduce distress in this vulnerable population, despite current healthcare guidelines. More research is needed to understand which psychosocial interventions can reduce distress and improve wellbeing on inpatient mental health dementia wards, and how interventions should be delivered, to establish clinical and cost effectiveness and minimise staff burden.
Topics: Humans; Dementia; Psychosocial Intervention; Inpatients; Psychiatric Department, Hospital
PubMed: 38654223
DOI: 10.1186/s12877-024-04965-8 -
Age and Ageing Apr 2024Physical activity (PA) has multiple benefits for older adults (≥70 years old). Despite this many older adults do not undertake the World Health Organisation guideline...
BACKGROUND
Physical activity (PA) has multiple benefits for older adults (≥70 years old). Despite this many older adults do not undertake the World Health Organisation guideline recommended amount of PA. This systematic review examines barriers and motivators to PA in adults aged ≥70 years.
METHODS
We analysed the quantitative literature, including observational studies and baseline data from randomised controlled trials. Studies examining specific diseases (e.g. cognitive impairment), or care home residents were excluded. Database searches of ASSIA, CINAHL, Embase, Medline, PsycINFO and Web of Science were undertaken on 7 March 2023. Quality assessment was performed using the ROBANS tool. We synthesised the results using the socioecological model. The protocol was registered on PROSPERO (CRD42021160503).
RESULTS
We identified 37 papers, n = 26,961, age 70-101 years (median 78), 62% female. We undertook a narrative review; meta-analysis was not possible. Overall risk of bias was low. A total of 23 studies addressed barriers, seven motivators, seven both. The most cited barriers were: concern about physical health/fitness (14 studies), lack of motivation/interest (13 studies), fear of falls/history of falling (11 studies) and environmental barriers (10 studies). Key motivators were: support from family/friends (five studies), social interaction (five studies), personal benefits (five studies) and outside facilities (five studies). Results varied across gender, age, functional ability and geographical location.
DISCUSSION
To maximise PA in older adults, important modifiable factors identified in this review should be targeted: support from healthcare professionals; reducing fear of falls; and prioritising ease of access and safety of outdoor facilities. When considering future policy, a person-centred, age group appropriate approach will have the most impact.
Topics: Humans; Motivation; Exercise; Aged; Aged, 80 and over; Female; Male; Age Factors
PubMed: 38651329
DOI: 10.1093/ageing/afae080 -
CNS Neuroscience & Therapeutics Apr 2024Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as... (Review)
Review
BACKGROUND
Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.
AIMS
Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD.
METHODS
A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.
RESULTS
Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).
DISCUSSION
The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).
CONCLUSION
The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.
Topics: Humans; Alzheimer Disease; CCAAT-Enhancer-Binding Protein-beta; Disease Progression; Animals; Amyloid beta-Peptides
PubMed: 38644578
DOI: 10.1111/cns.14721