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Alzheimer's & Dementia : the Journal of... May 2024We conducted a rapid systematic review of minimal clinically important differences (MCIDs) for Alzheimer's disease (AD) trial endpoints.
INTRODUCTION
We conducted a rapid systematic review of minimal clinically important differences (MCIDs) for Alzheimer's disease (AD) trial endpoints.
METHODS
Two reviewers searched EMBASE, MEDLINE, and PubMed from inception to June 4, 2023.
RESULTS
Ten articles were retrieved. For mild cognitive impairment (MCI), a change of +2 to +3 points on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), +1 points on the Clinical Dementia Rating scale sum of boxes (CDR-SB), -5 points on the integrated Alzheimer's Disease Rating Scale (iADRS), or -1 to -2 points on the Mini-Mental State Examination (MMSE) was considered meaningful. For patients with mild AD, a change of +3 on the ADAS-Cog, +2 points on CDR-SB, -9 points on the iADRS, or -2 points on the MMSE was considered meaningful. For patients with moderate to severe AD, a change of +2 points on the CDR-SB or a change of -1.4 to -3 points on the MMSE was considered meaningful.
CONCLUSION
This review identified previously published MCIDs for AD trial endpoints. Input from patients and caregivers will be needed to derive more meaningful endpoints and thresholds.
HIGHLIGHTS
This systematic rapid review identified thresholds for minimal clinically important differences (MCIDs) for recently used Alzheimer's disease (AD) trial endpoints: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating scale sum of boxes (CDR-SB), integrated Alzheimer's Disease Rating Scale (iADRS), Mini-Mental State Examination (MMSE). MCIDs were higher for more severe stages of AD. Average treatment effects in recent trials of anti-amyloid disease modifying monoclonal antibodies are lower than previously published MCIDs. In future trials of disease modifying treatments for AD, the proportion of participants in each treatment group that experienced a clinically meaningful decline could be reported. More work is needed to incorporate the values and preferences of patients and care partners in deriving MCIDs.
Topics: Alzheimer Disease; Humans; Minimal Clinically Important Difference; Cognitive Dysfunction; Mental Status and Dementia Tests; Neuropsychological Tests; Clinical Trials as Topic
PubMed: 38561021
DOI: 10.1002/alz.13770 -
Applied Health Economics and Health... Jul 2024There has been an increase in model-based economic evaluations of interventions for dementia. The most recent systematic review of economic evaluations for dementia...
BACKGROUND
There has been an increase in model-based economic evaluations of interventions for dementia. The most recent systematic review of economic evaluations for dementia highlighted weaknesses in studies, including lack of justification for model assumptions and data inputs.
OBJECTIVE
This study aimed to update the last published systematic review of model-based economic evaluations of interventions for dementia, including Alzheimer's disease, with a focus on any methodological improvements and quality assessment of the studies.
METHODS
Systematic searches in eight databases, including PubMed, Cochrane, Embase, CINAHL, PsycINFO, EconLit, international HTA database, and the Tufts Cost-Effectiveness Analysis Registry were undertaken from February 2018 until August 2022. The quality of the included studies was assessed using the Philips checklist and the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 checklist. The findings were summarized through narrative analysis.
RESULTS
This review included 23 studies, comprising cost-utility analyses (87%), cost-benefit analyses (9%) and cost-effectiveness analyses (4%). The studies covered various interventions, including pharmacological (n = 10, 43%), non-pharmacological (n = 4, 17%), prevention (n = 4, 17%), diagnostic (n = 4, 17%) and integrated (n = 1, 4%) [diagnostics-pharmacologic] strategies. Markov transition models were commonly employed (65%), followed by decision trees (13%) and discrete-event simulation (9%). Several interventions from all categories were reported as being cost effective. The quality of reporting was suboptimal for the Methods and Results sections in almost all studies, although the majority of studies adequately addressed the decision problem, scope, and model-type selection in their economic evaluations. Regarding the quality of methodology, only a minority of studies addressed competing theories or clearly explained the rationale for model structure. Furthermore, few studies systematically identified key parameters or assessed data quality, and uncertainty was mostly addressed partially.
CONCLUSIONS
This review informs future research and resource allocation by providing insights into model-based economic evaluations for dementia interventions and highlighting areas for improvement.
Topics: Humans; Dementia; Cost-Benefit Analysis; Models, Economic
PubMed: 38554246
DOI: 10.1007/s40258-024-00878-0 -
Pharmaceutics Feb 2024The blood-brain barrier (BBB) regulates brain substance entry, posing challenges for treating brain diseases. Traditional methods face limitations, leading to the... (Review)
Review
BACKGROUND
The blood-brain barrier (BBB) regulates brain substance entry, posing challenges for treating brain diseases. Traditional methods face limitations, leading to the exploration of non-invasive intranasal drug delivery. This approach exploits the direct nose-to-brain connection, overcoming BBB restrictions. Intranasal delivery enhances drug bioavailability, reduces dosage, and minimizes systemic side effects. Notably, lipid nanoparticles, such as solid lipid nanoparticles and nanostructured lipid carriers, offer advantages like improved stability and controlled release. Their nanoscale size facilitates efficient drug loading, enhancing solubility and bioavailability. Tailored lipid compositions enable optimal drug release, which is crucial for chronic brain diseases. This review assesses lipid nanoparticles in treating neuro-oncological and neurodegenerative conditions, providing insights for effective nose-to-brain drug delivery.
METHODS
A systematic search was conducted across major medical databases (PubMed, Ovid MEDLINE, and Scopus) up to 6 January 2024. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "lipid nanoparticles", "intranasal administration", "neuro-oncological diseases", and "neurodegenerative disorders". This review consists of studies in vitro, in vivo, or ex vivo on the intranasal administration of lipid-based nanocarriers for the treatment of brain diseases.
RESULTS
Out of the initial 891 papers identified, 26 articles met the eligibility criteria after a rigorous analysis. The exclusion of 360 articles was due to reasons such as irrelevance, non-reporting selected outcomes, the article being a systematic literature review or meta-analysis, and lack of method/results details. This systematic literature review, focusing on nose-to-brain drug delivery via lipid-based nanocarriers for neuro-oncological, neurodegenerative, and other brain diseases, encompassed 60 studies. A temporal distribution analysis indicated a peak in research interest between 2018 and 2020 (28.3%), with a steady increase over time. Regarding drug categories, Alzheimer's disease was prominent (26.7%), followed by antiblastic drugs (25.0%). Among the 65 drugs investigated, Rivastigmine, Doxorubicin, and Carmustine were the most studied (5.0%), showcasing a diverse approach to neurological disorders. Notably, solid lipid nanoparticles (SLNs) were predominant (65.0%), followed by nanostructured lipid carriers (NLCs) (28.3%), highlighting their efficacy in intranasal drug delivery. Various lipids were employed, with glyceryl monostearate being prominent (20.0%), indicating preferences in formulation. Performance assessment assays were balanced, with in vivo studies taking precedence (43.3%), emphasizing the translation of findings to complex biological systems for potential clinical applications.
CONCLUSIONS
This systematic review reveals the transformative potential of intranasal lipid nanoparticles in treating brain diseases, overcoming the BBB. Positive outcomes highlight the effectiveness of SLNs and NLCs, which are promising new approaches for ailments from AD to stroke and gliomas. While celebrating progress, addressing challenges like nanoparticle toxicity is also crucial.
PubMed: 38543223
DOI: 10.3390/pharmaceutics16030329 -
Nutrients Mar 2024The gut microbiota in healthy older individuals typically show a decrease in beneficial bacteria like Bifidobacterium and Lactobacillus, alongside an increase in...
BACKGROUND
The gut microbiota in healthy older individuals typically show a decrease in beneficial bacteria like Bifidobacterium and Lactobacillus, alongside an increase in pro-inflammatory microbes such as Enterobacteriaceae and Clostridia. These changes contrast with younger and middle-aged individuals and appear to correlate with cognitive status. Although there is extensive research on gut microbiota and cognitive functions in cognitively impaired elderly individuals, its impact on cognitively healthy elderly populations has not been extensively studied.
METHOD
A comprehensive literature search was conducted across PubMed, EBSCO, Web of Science, and Scopus databases to identify studies exploring the relationship between gut microbiota composition and cognitive functioning in healthy older adults. During the literature screening process, each record was initially assessed by its title, abstract, and keywords to exclude articles that did not align with the scope of this review. Three authors independently screened and retrieved the records. The inclusion criteria included: (1) publication in peer-reviewed journals; (2) studies involving neurologically, cognitively, and medically healthy populations; (3) participants identified as older adults, defined for this review as individuals aged 45 years and older due to the limited number of records; (4) analysis of gut microbiota; and (5) assessment of cognitive function. Subsequently, full texts were analyzed to determine eligibility. The exclusion criteria encompassed: (1) incorrect publication type; (2) inappropriate sample population; (3) unsuitable study design; (4) absence of one or more inclusion criteria; and (5) studies based on animal research. A risk of bias assessment was performed for each included study using the Joanna Briggs Institute (JBI) checklist, ensuring all selected studies met established quality standards.
RESULTS
A total of 6 eligible research articles from a possible 1752 published until March 2024 were identified and included. We categorized the included studies into two groups based on their focus: the taxonomic composition of gut microbiota and the alpha diversity, which is the variety of organisms within a sample. Additionally, two methods were identified for assessing cognition: neuropsychological tests and physiological measurements, notably electroencephalography (EEG). The studies show varying results regarding the abundance of specific bacterial taxa and their cognitive associations. Notably, the relationship between certain bacteria and cognition may vary when analyzed at different taxonomic levels, such as phylum versus family.
CONCLUSIONS
Changes in gut microbiota composition in the elderly, even without a cognitive impairment diagnosis, could potentially serve as early biological markers for Alzheimer's disease or other dementias before mild cognitive impairment appears.
Topics: Aged; Humans; Alzheimer Disease; Bacteria; Cognition; Cognitive Dysfunction; Gastrointestinal Microbiome; Healthy Aging
PubMed: 38542764
DOI: 10.3390/nu16060852 -
Life (Basel, Switzerland) Feb 2024Olfactory disorders (ODs) are reported to be an early non-motor sign before the onset of deterioration in neurodegenerative diseases (NDs) such as Alzheimer's and... (Review)
Review
BACKGROUND
Olfactory disorders (ODs) are reported to be an early non-motor sign before the onset of deterioration in neurodegenerative diseases (NDs) such as Alzheimer's and Parkinson's. This systematic revision aims to review the current literature and the value of subjective olfactometry (SO) in the early diagnosis of cognitive decline and NDs.
METHODS
A systematic literature review was conducted following the PRISMA framework. Four different authors reviewed six different databases. The main variables analyzed were olfactory function and cognitive status. The quality of results was evaluated using the Oxford Centre of Evidence-based Medicine Levels.
RESULTS
Twenty-one cross-sectional and cohort studies and six meta-analyses were included. Most of them found an association between ODs and NDs. A prevalence of ODs greater than 80% was shown in Parkinson's disease, proportional to the severity of symptoms. In Alzheimer's, ODs were associated with early diagnosis and prognosis. All SO tests employed in the literature showed enough predictive value to correlate with early stages of cognitive decline.
CONCLUSIONS
SO should be considered a pivotal tool when diagnosing NDs due to their association with early symptoms and prognosis. However, in the current literature, no firm consensus exists on the optimal SO tests and protocols that should be applied to the study of NDs, which prevents the interpretability and comparability of results among studies.
PubMed: 38541625
DOI: 10.3390/life14030298 -
International Journal of Environmental... Mar 2024The prevalence of dementia increases with nearly 10 million new cases each year, with Alzheimer's disease contributing to 60-70% of cases. Environmental factors such as...
The prevalence of dementia increases with nearly 10 million new cases each year, with Alzheimer's disease contributing to 60-70% of cases. Environmental factors such as drinking water have been evaluated to determine if a relationship exists between trace elements in drinking water and the risk of developing cognitive disorders in the elderly. The purpose of the current systematic review was to evaluate an association between the composition of drinking water and cognitive function in the elderly. In accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines, a literature search was conducted using PubMed and CINAHL databases. A total of 10 studies were included in the current systematic review. Aluminum is the most commonly evaluated trace element in studies ( = 8), followed by silica ( = 5), calcium ( = 4), and fluoride ( = 4). Aluminum exposure showed an increased risk of cognitive decline in four studies, with no association reported in the other studies. Higher silica and pH levels were shown to be protective against a decline in cognitive function. A similar protective effect of calcium was found in two studies. Future research should measure multiple trace mineral levels in all water sources to evaluate the impact on cognitive function.
Topics: Aged; Humans; Aluminum; Calcium; Cognition; Cognitive Dysfunction; Drinking Water; Silicon Dioxide; Trace Elements
PubMed: 38541362
DOI: 10.3390/ijerph21030362 -
Biomedicines Feb 2024The murine models of Alzheimer's disease (AD) have advanced our understanding of the pathophysiology. In vivo studies of the retina using optical coherence tomography... (Review)
Review
The murine models of Alzheimer's disease (AD) have advanced our understanding of the pathophysiology. In vivo studies of the retina using optical coherence tomography (OCT) have complemented histological methods; however, the lack of standardisation in OCT methodologies for murine models of AD has led to significant variations in the results of different studies. A literature search in PubMed and Scopus has been performed to review the different methods used in these models using OCT and to analyse the methodological characteristics of each study. In addition, some recommendations are offered to overcome the challenges of using OCT in murine models. The results reveal a lack of consensus on OCT device use, retinal area analysed, segmentation techniques, and analysis software. Although some studies use the same OCT device, variations in other parameters make the direct comparison of results difficult. Standardisation of retinal analysis criteria in murine models of AD using OCT is crucial to ensure consistent and comparable results. This implies the application of uniform measurement and segmentation protocols. Despite the absence of standardisation, OCT has proven valuable in advancing our understanding of the pathophysiology of AD.
PubMed: 38540142
DOI: 10.3390/biomedicines12030528 -
Alzheimer's Research & Therapy Mar 2024Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid...
BACKGROUND
Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations.
METHODS
Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data.
RESULTS
We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers.
CONCLUSIONS
These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.
Topics: Male; Humans; Female; Progranulins; Frontotemporal Dementia; Intercellular Signaling Peptides and Proteins; Virulence; Mutation; Membrane Proteins; Nerve Tissue Proteins
PubMed: 38539243
DOI: 10.1186/s13195-024-01420-z -
Neuroradiology Jul 2024We reviewed 33 original research studies assessing brain perfusion, using consensus guidelines from a "white paper" issued by the International Society for Magnetic... (Review)
Review
We reviewed 33 original research studies assessing brain perfusion, using consensus guidelines from a "white paper" issued by the International Society for Magnetic Resonance in Medicine Perfusion Study Group and the European Cooperation in Science and Technology Action BM1103 ("Arterial Spin Labelling Initiative in Dementia"; https://www.cost.eu/actions/BM1103/ ). The studies were published between 2011 and 2023 and included participants with subjective cognitive decline plus; neurocognitive disorders, including mild cognitive impairment (MCI), Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB) and vascular cognitive impairment (VCI); as well as schizophrenia spectrum disorders, bipolar and major depressive disorders, autism spectrum disorder, attention-deficit/hyperactivity disorder, panic disorder and alcohol use disorder. Hypoperfusion associated with cognitive impairment was the major finding across the spectrum of cognitive decline. Regional hyperperfusion also was reported in MCI, AD, frontotemporal dementia phenocopy syndrome and VCI. Hypoperfused structures found to aid in diagnosing AD included the precunei and adjacent posterior cingulate cortices. Hypoperfused structures found to better diagnose patients with FTLD were the anterior cingulate cortices and frontal regions. Hypoperfusion in patients with DLB was found to relatively spare the temporal lobes, even after correction for partial volume effects. Hyperperfusion in the temporal cortices and hypoperfusion in the prefrontal and anterior cingulate cortices were found in patients with schizophrenia, most of whom were on medication and at the chronic stage of illness. Infratentorial structures were found to be abnormally perfused in patients with bipolar or major depressive disorders. Brain perfusion abnormalities were helpful in diagnosing most neurocognitive disorders. Abnormalities reported in VCI and the remaining mental disorders were heterogeneous and not generalisable.
Topics: Humans; Spin Labels; Mental Disorders; Magnetic Resonance Imaging; Cerebrovascular Circulation; Cognitive Dysfunction
PubMed: 38536448
DOI: 10.1007/s00234-024-03323-0 -
Current Issues in Molecular Biology Mar 2024Subjective cognitive decline (SCD) has been described as a probable early stage of dementia, as it has consistently appeared to precede the onset of objective cognitive... (Review)
Review
Subjective cognitive decline (SCD) has been described as a probable early stage of dementia, as it has consistently appeared to precede the onset of objective cognitive impairment. SCD is related to many risk factors, including genetic predisposition for dementia. The Apolipoprotein (APOE) ε4 allele, which has been thoroughly studied, seems to explain genetic risk for SCD only partially. Therefore, we aimed to summarize existing data regarding genetic factors related to SCD, beyond APOE ε4, in order to improve our current understanding of SCD. We conducted a PRISMA systematic search in PubMed/MEDLINE and Embase databases using the keywords "subjective cognitive decline" and "genetic predisposition" with specific inclusion and exclusion criteria. From the 270 articles identified, 16 were finally included for the qualitative analysis. Family history of Alzheimer's disease (AD) in regard to SCD was explored in eight studies, with conflicting results. Other genes implicated in SCD, beyond APOE ε4, were investigated in six studies, which were not strong enough to provide clear conclusions. Very few data have been published regarding the association of polygenic risk for AD and SCD. Thus, many more genes related to AD must be studied, with polygenic risk scores appearing to be really promising for future investigation.
PubMed: 38534745
DOI: 10.3390/cimb46030129