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European Journal of Medical Research Nov 2023Alzheimer's disease (AD) is a worldwide public health problem and is difficult to cure. Drugs aimed at slowing the progression of the disease have been developed, with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Alzheimer's disease (AD) is a worldwide public health problem and is difficult to cure. Drugs aimed at slowing the progression of the disease have been developed, with the Food and Drug Administration (FDA) granting accelerated approval for aducanumab on June 21, 2021 and a new accelerated approval for lecanemab on January 22, 2023. We performed this systematic review and meta-analysis to assess the efficacy and safety of FDA-approved anti-amyloid-β (anti-Aβ) monoclonal antibodies (mabs) for the treatment of AD.
METHOD
PubMed, Embase, and Cochrane Library were systematically searched to identify relevant studies published before May 2023. Efficacy outcomes included Aβ, neuroimaging, and biomarker outcomes. Safety outcomes included amyloid-related imaging abnormalities with edema or effusions (ARIA-E) and ARIA with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (ARIA-H). Review Manager 5.4 software was used to assess the data. The standard mean differences (SMDs) or odds ratio (OR) with 95% confidence interval (95% CI) were analyzed and calculated with a random effect model or a fixed effect model.
RESULT
Overall, 4471 patients from 6 randomized controlled trials (RCTs), with 2190 patients in the treatment group and 2281 patients in the placebo group meeting the inclusion criteria. FDA-approved anti-Aβ mabs showed statistically significant improvements in clinical outcomes, including CDR-SB (P = 0.01), ADCS-ADL-MCI (P = 0.00003), ADCOMS (P < 0.00001), ADAS-Cog (P < 0.00001). Moreover, FDA-approved anti-Aβ mabs increased cerebrospinal fluid (CSF) Aβ1-42 (P = 0.002) and plasma Aβ42/40 ratios (P = 0.0008). They also decreased CSF P-Tau (P < 0.00001), CSF T-Tau (P < 0.00001), and plasma p-tau181 (P < 0.00001). FDA-approved anti-Aβ mabs perform neuroimaging changes in amyloid Positron Emission Tomography Standardized Uptake Value ratio (PET SUVr) (P < 0.00001). However, compared with placebo, FDA-approved anti-Aβ mabs had higher risk of ARIA-E (P < 0.00001) and ARIA-H (P < 0001).
CONCLUSION
FDA-approved anti-Aβ mabs have a role in slowing disease progression in patients with AD, at the cost of an increased probability of side effects.
Topics: United States; Humans; Alzheimer Disease; United States Food and Drug Administration; Randomized Controlled Trials as Topic; Amyloid beta-Peptides; Biomarkers
PubMed: 38017568
DOI: 10.1186/s40001-023-01512-w -
Neurologia Mar 2020Alzheimer disease (AD) is a neurodegenerative disease characterised by progressive dementia associated with global cognitive dysfunction. (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Alzheimer disease (AD) is a neurodegenerative disease characterised by progressive dementia associated with global cognitive dysfunction.
METHODS
We conducted a systematic review and meta-analysis of clinical trials evaluating omega-3 supplementation in patients with AD.
OBJECTIVE
To determine if there is scientific evidence of the effectiveness of omega-3 supplementation in improving cognitive function in patients with AD.
SEARCH STRATEGY
We included only randomised controlled trials (RCTs) from the following databases: Medline, Cochrane Central, Cinahl, and LILACS. An electronic search was also conducted using Google Scholar.
STUDY SELECTION
Six articles met the eligibility criteria. The risk of bias was assessed following the Cochrane method.
CONCLUSION
There is no consistent evidence to support the effectiveness of omega-3 supplementation in improving cognitive function in AD patients in the short and medium term.
Topics: Alzheimer Disease; Cognitive Dysfunction; Dietary Supplements; Fatty Acids, Omega-3; Humans; Randomized Controlled Trials as Topic
PubMed: 28986068
DOI: 10.1016/j.nrl.2017.07.009 -
BMJ Clinical Evidence Apr 2010Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired. (Review)
Review
INTRODUCTION
Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments on cognitive symptoms of dementia (Alzheimer's, Lewy body, or vascular)? What are the effects of treatments on behavioural and psychological symptoms of dementia (Alzheimer's, Lewy body, or vascular)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 33 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine), antidepressants (clomipramine, fluoxetine, imipramine, sertraline), antipsychotics (haloperidol, olanzapine, quetiapine, risperidone), aromatherapy, benzodiazepines (diazepam, lorazepam), cognitive behavioural therapy (CBT), cognitive stimulation, exercise, ginkgo biloba, memantine, mood stabilisers (carbamazepine, sodium valproate/valproic acid), music therapy, non-steroidal anti-inflammatory drugs (NSAIDs), omega 3 (fish oil), reminiscence therapy, and statins.
Topics: Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Cholinesterase Inhibitors; Dementia; Galantamine; Humans; Memantine
PubMed: 21726471
DOI: No ID Found -
Alzheimer's Research & Therapy Jan 2019Alzheimer's disease (AD) pathology begins several years before the clinical onset. The long preclinical phase is composed of three stages according to the 2011National... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alzheimer's disease (AD) pathology begins several years before the clinical onset. The long preclinical phase is composed of three stages according to the 2011National Institute on Aging and Alzheimer's Association (NIA-AA) criteria, followed by mild cognitive impairment (MCI), a featured clinical entity defined as "due to AD", or "prodromal AD", when pathophysiological biomarkers (i.e., cerebrospinal fluid or positron emission tomography with amyloid tracer) are positive. In the clinical setting, there is a clear need to detect the earliest symptoms not yet fulfilling MCI criteria, in order to proceed to biomarker assessment for diagnostic definition, thus offering treatment with disease-modifying drugs to patients as early as possible. According to the available evidence, we thus estimated the prevalence and risk of progression at each preclinical AD stage, with special interest in Stage 3.
METHODS
Cross-sectional and longitudinal studies published from April 2008 to May 2018 were obtained through MEDLINE-PubMed, screened, and systematically reviewed by four independent reviewers. Data from included studies were meta-analyzed using random-effects models. Heterogeneity was assessed by I statistics.
RESULTS
Estimated overall prevalence of preclinical AD was 22% (95% CI = 18-26%). Rate of biomarker positivity overlapped in cognitively normal individuals and people with subjective cognitive decline. The risk of progression increases across preclinical AD stages, with individuals classified as NIA-AA Stage 3 showing the highest risk (73%, 95% CI = 40-92%) compared to those in Stage 2 (38%, 95% CI = 21-59%) and Stage 1 (20%, 95% CI = 10-34%).
CONCLUSION
Available data consistently show that risk of progression increases across the preclinical AD stages, where Stage 3 shows a risk of progression comparable to MCI due to AD. Accordingly, an effort should be made to also operationalize the diagnostic work-up in subjects with subtle cognitive deficits not yet fulfilling MCI criteria. The possibility to define, in the clinical routine, a patient as "pre-MCI due to AD" could offer these subjects the opportunity to use disease-modifying drugs at best.
Topics: Alzheimer Disease; Cross-Sectional Studies; Disease Progression; Humans; Longitudinal Studies; Prevalence; Prodromal Symptoms; Risk Factors
PubMed: 30646955
DOI: 10.1186/s13195-018-0459-7 -
Molecular Neurobiology Sep 2019Currently there are 850,000 people with Alzheimer's disease in the UK, with an estimated rise to 1.1 million by 2025. Alzheimer's disease is characterised by the...
Currently there are 850,000 people with Alzheimer's disease in the UK, with an estimated rise to 1.1 million by 2025. Alzheimer's disease is characterised by the accumulation of amyloid-beta plaques and hyperphosphorylated tau in the brain causing a progressive decline in cognitive impairment. Small non-coding microRNA (miRNA) sequences have been found to be deregulated in the peripheral blood of Alzheimer patients. A systematic review was conducted to extract all miRNA found to be significantly deregulated in the peripheral blood. These deregulated miRNAs were cross-referenced against the miRNAs deregulated in the brain at Braak Stage III. This resulted in a panel of 10 miRNAs (hsa-mir-107, hsa-mir-26b, hsa-mir-30e, hsa-mir-34a, hsa-mir-485, hsa-mir200c, hsa-mir-210, hsa-mir-146a, hsa-mir-34c, and hsa-mir-125b) hypothesised to be deregulated early in Alzheimer's disease, nearly 20 years before the onset of clinical symptoms. After network analysis of the 10 miRNAs, they were found to be associated with the immune system, cell cycle, gene expression, cellular response to stress, neuron growth factor signalling, wnt signalling, cellular senescence, and Rho GTPases.
Topics: Alzheimer Disease; Animals; Biomarkers; Brain; Gene Regulatory Networks; Humans; MicroRNAs
PubMed: 30734227
DOI: 10.1007/s12035-019-1500-y -
Journal of Medical Internet Research Aug 2019Among areas that have challenged the progress of dementia care has been the assessment of change in symptoms over time. Digital biomarkers are defined as objective,...
Current State of Digital Biomarker Technologies for Real-Life, Home-Based Monitoring of Cognitive Function for Mild Cognitive Impairment to Mild Alzheimer Disease and Implications for Clinical Care: Systematic Review.
BACKGROUND
Among areas that have challenged the progress of dementia care has been the assessment of change in symptoms over time. Digital biomarkers are defined as objective, quantifiable, physiological, and behavioral data that are collected and measured by means of digital devices, such as embedded environmental sensors or wearables. Digital biomarkers provide an alternative assessment approach, as they allow objective, ecologically valid, and long-term follow-up with continuous assessment. Despite the promise of a multitude of sensors and devices that can be applied, there are no agreed-upon standards for digital biomarkers, nor are there comprehensive evidence-based results for which digital biomarkers may be demonstrated to be most effective.
OBJECTIVE
In this review, we seek to answer the following questions: (1) What is the evidence for real-life, home-based use of technologies for early detection and follow-up of mild cognitive impairment (MCI) or dementia? And (2) What transformation might clinicians expect in their everyday practices?
METHODS
A systematic search was conducted in PubMed, Cochrane, and Scopus databases for papers published from inception to July 2018. We searched for studies examining the implementation of digital biomarker technologies for mild cognitive impairment or mild Alzheimer disease follow-up and detection in nonclinic, home-based settings. All studies that included the following were examined: community-dwelling older adults (aged 65 years or older); cognitively healthy participants or those presenting with cognitive decline, from subjective cognitive complaints to early Alzheimer disease; a focus on home-based evaluation for noninterventional follow-up; and remote diagnosis of cognitive deterioration.
RESULTS
An initial sample of 4811 English-language papers were retrieved. After screening and review, 26 studies were eligible for inclusion in the review. These studies ranged from 12 to 279 participants and lasted between 3 days to 3.6 years. Most common reasons for exclusion were as follows: inappropriate setting (eg, hospital setting), intervention (eg, drugs and rehabilitation), or population (eg, psychiatry and Parkinson disease). We summarized these studies into four groups, accounting for overlap and based on the proposed technological solutions, to extract relevant data: (1) data from dedicated embedded or passive sensors, (2) data from dedicated wearable sensors, (3) data from dedicated or purposive technological solutions (eg, games or surveys), and (4) data derived from use of nondedicated technological solutions (eg, computer mouse movements).
CONCLUSIONS
Few publications dealt with home-based, real-life evaluations. Most technologies were far removed from everyday life experiences and were not mature enough for use under nonoptimal or uncontrolled conditions. Evidence available from embedded passive sensors represents the most relatively mature research area, suggesting that some of these solutions could be proposed to larger populations in the coming decade. The clinical and research communities would benefit from increasing attention to these technologies going forward.
Topics: Accelerometry; Aged; Alzheimer Disease; Automobile Driving; Biomarkers; Cognition; Cognitive Dysfunction; Disease Progression; Early Diagnosis; Geographic Information Systems; Humans; Independent Living; Surveys and Questionnaires; Technology; Telemedicine; Wearable Electronic Devices
PubMed: 31471958
DOI: 10.2196/12785 -
Accelerated Brain Volume Loss Caused by Anti-β-Amyloid Drugs: A Systematic Review and Meta-analysis.Neurology May 2023To evaluate brain volume changes caused by different subclasses of anti-β-amyloid (Aβ) drugs trailed in patients with Alzheimer disease. (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
To evaluate brain volume changes caused by different subclasses of anti-β-amyloid (Aβ) drugs trailed in patients with Alzheimer disease.
METHODS
PubMed, Embase, and ClinicalTrials.gov databases were searched for clinical trials of anti-Aβ drugs. This systematic review and meta-analysis included adults enrolled in randomized controlled trials of anti-Aβ drugs (n = 8,062-10,279). The inclusion criteria were as follows: (1) randomized controlled trials of patients treated with anti-Aβ drugs that have demonstrated to favorably change at least one biomarker of pathologic Aβ and (2) detailed MRI data sufficient to assess the volumetric changes in at least one brain region. MRI brain volumes were used as the primary outcome measure; brain regions commonly reported include hippocampus, lateral ventricle, and whole brain. Amyloid-related imaging abnormalities (ARIAs) were investigated when reported in clinical trials. Of the 145 trials reviewed, 31 were included in the final analyses.
RESULTS
A meta-analysis on the highest dose of each trial on hippocampus, ventricle, and whole brain revealed drug-induced acceleration of volume changes that varied by anti-Aβ drug class. Secretase inhibitors accelerated atrophy to the hippocampus (Δ placebo - Δ drug: -37.1 µL [19.6% more than placebo]; 95% CI -47.0 to -27.1) and whole brain (Δ placebo - Δ drug: -3.3 mL [21.8% more than placebo]; 95% CI -4.1 to 2.5). Conversely, ARIA-inducing monoclonal antibodies accelerated ventricular enlargement (Δ placebo - Δ drug: +2.1 mL [38.7% more than placebo]; 95% CI 1.5-2.8) where a striking correlation between ventricular volume and ARIA frequency was observed ( = 0.86, = 6.22 × 10). Mild cognitively impaired participants treated with anti-Aβ drugs were projected to have a material regression toward brain volumes typical of Alzheimer dementia ∼8 months earlier than if they were untreated.
DISCUSSION
These findings reveal the potential for anti-Aβ therapies to compromise long-term brain health by accelerating brain atrophy and provide new insight into the adverse impact of ARIA. Six recommendations emerge from these findings.
Topics: Adult; Humans; Amyloid beta-Peptides; Alzheimer Disease; Antibodies, Monoclonal; Brain; Atrophy
PubMed: 36973044
DOI: 10.1212/WNL.0000000000207156 -
Life Sciences Nov 2023A diverse and stable microbiota promotes a healthy state, nevertheless, an imbalance in gut or oral bacterial composition, called dysbiosis, can cause gastrointestinal... (Review)
Review
A diverse and stable microbiota promotes a healthy state, nevertheless, an imbalance in gut or oral bacterial composition, called dysbiosis, can cause gastrointestinal disorders, systemic inflammatory states and oxidative stress, among others. Recently, gut and oral dysbiosis has been linked to Alzheimer's disease (AD), which is considered the most common form of dementia and a public health priority due to its high prevalence and incidence. The aim of this review is to highlight the implications of gut and oral microbiota in the neuroinflammation characteristic of AD pathology and the subsequent cognitive impairment. It is a systematic review of the current literature obtained by searching the PubMed, Web of Science and Scopus databases. The characteristic intestinal dysbiosis in AD patients leads to increased permeability of the intestinal barrier and activates immune cells in the central nervous system due to translocation of microbiota-derived metabolites and/or bacteria into the circulation leading to increased neuroinflammation and neuronal loss, thus generating the cognitive impairment characteristic of AD. The presence in the central nervous system of Porphyromonas gingivalis can cause an increased neuroinflammation and beta-amyloid peptide accumulation.
Topics: Humans; Alzheimer Disease; Gastrointestinal Microbiome; Neuroinflammatory Diseases; Dysbiosis; Microbiota; Inflammation; Bacteria; Brain
PubMed: 37793482
DOI: 10.1016/j.lfs.2023.122132 -
Revista de Neurologia Dec 2017Alzheimer's disease (AD) is a neurodegenerative disease which involves, among other manifestations, a progressive deterioration of memory and language, as well as...
INTRODUCTION
Alzheimer's disease (AD) is a neurodegenerative disease which involves, among other manifestations, a progressive deterioration of memory and language, as well as behavioral disorders. In addition to non-curative pharmacological therapies, for the last years, music therapy has been developed as an effective non-pharmacological therapy in order to relieve many of these manifestations.
AIM
To analyze the recent scientific evidence about the effect of music therapy on cognitive and behavioral symptoms in patients with AD.
PATIENTS AND METHODS
A systematic review has been carried out by means of a bibliographical research using the database PubMed and Science Direct. The key words used for this search were 'Alzheimer's disease' and 'music therapy', as well as the boolean operator 'AND'. We selected those publications between January 2006 and December 2016 and after inclusion criteria, 21 publications were selected.
RESULTS
This systematic review has demonstrated the beneficial impact of music therapy on cognition (memory, attention, language), emotion and behavior (anxiety, depression and agitation) in AD patients.
CONCLUSIONS
Music therapy constitutes a non-pharmacological therapy effective for some cognitive, emotional and behavioral symptoms in patients with AD. However, further investigations and more evidence in this field are needed to claim conclusively the impact of music therapy on this disease.
Topics: Alzheimer Disease; Behavior; Cognition; Emotions; Humans; Language; Memory; Music Therapy; Quality of Life; Treatment Outcome
PubMed: 29235615
DOI: No ID Found -
Epidemiology (Cambridge, Mass.) Sep 2016Engaging in late-life cognitive activity is often proposed as a strategy to delay or prevent Alzheimer's disease (AD) and other dementias. However, it is unclear to what... (Review)
Review
BACKGROUND
Engaging in late-life cognitive activity is often proposed as a strategy to delay or prevent Alzheimer's disease (AD) and other dementias. However, it is unclear to what extent the available evidence supports a causal effect of cognitive activity in dementia prevention.
METHODS
We systematically searched PubMed and EMBASE through June 2014 to identify peer-reviewed epidemiologic studies of cognitive activity and incidence of AD or all-cause dementia. Eligible articles analyzed data from cohort or nested case-control studies, explicitly defined cognitive activity, evaluated participants for AD or all-cause dementia using clearly defined criteria, and provided effect estimates adjusted for at least age and sex. We describe methodologic issues and biases relevant to interpretation of these studies, and quantify the degree of bias due to confounding and reverse causation required to nullify typically observed associations.
RESULTS
We reviewed 12 studies involving 13,939 participants and 1,663 dementia cases, of which 565 were specifically evaluated as AD. Most studies found associations between late-life cognitive activity and lower AD and/or all-cause dementia incidence. Differences in cognitive activity operationalization across studies precluded meta-analysis of effect estimates. Our bias analysis indicated that the observed inverse associations are probably robust to unmeasured confounding, and likely only partially explained by reverse causation.
CONCLUSION
Our systematic review and bias analyses provide support for the hypothesis that late-life cognitive activity offers some reduction in AD and all-cause dementia risk. However, more data are needed to confirm this relationship and on the optimal type, duration, intensity, and timing of that activity.
Topics: Alzheimer Disease; Bias; Case-Control Studies; Causality; Cognition; Cohort Studies; Confounding Factors, Epidemiologic; Dementia; Humans; Incidence; Proportional Hazards Models; Protective Factors
PubMed: 27227783
DOI: 10.1097/EDE.0000000000000513