Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 7 appraisals
Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology
Limb apraxia in Parkinson's disease and atypical parkinsonian syndromes: a systematic review
BACKGROUND: Evidence regarding the clinical manifestations, disease-specific profiles and diagnostic significance of limb apraxia in Parkinson's disease and Atypical Parkinsonian Syndromes (APS) is limited. OBJECTIVES: The present systematic review aims to consolidate current knowledge on limb apraxia across neurodegenerative disorders, including Parkinson's disease (PD), corticobasal syndrome (CBS), Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA). METHODS: A systematic literature review was conducted in accordance with PRISMA guidelines. Studies were included if they enrolled ≥ 10 patients in at least one of the patient groups and ≥ 10 control subjects with quantitative data on apraxic deficits. Risk of bias assessment was assessed. RESULTS: Twenty-two studies met inclusion criteria (PD n = 11; CBS n = 10; PSP n = 7; MSA n = 3). Across PD and APS, praxis assessment primarily involved gesture imitation, pantomime, action sequencing, actual tool use and measures of fine motor coordination. CBS demonstrated the most severe/widespread apraxic impairment, affecting both meaningless and meaningful (transitive and intransitive) gestures, as well as action sequencing and fine motor control. In PD, apraxic deficits were generally milder but shared overlapping features with CBS. Direct comparative studies between PD and CBS remain scarce. PSP was characterized by less frequent and predominantly sequence-related impairments, whereas findings in MSA were heterogeneous and less pronounced. CONCLUSIONS: Limb apraxia phenotypes differ across PD, CBS, PSP and MSA and may contribute to their differential diagnosis. Future research should adopt standardized, multimodal praxis assessment protocols in larger cohorts including all major neurodegenerative parkinsonian disorders, to facilitate the direct comparison of limb apraxia across these diseases.
4 July 2026
Read appraisal →Neurology. Clinical practice
Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial
BACKGROUND AND OBJECTIVES: Understanding the meaningfulness of clinical trial outcomes is essential for people living with Alzheimer disease (AD) and their clinicians to make evidence-based shared treatment decisions in real-world clinical care. Donanemab, a monoclonal antibody targeting the insoluble form of β-amyloid found in plaques, significantly slows cognitive and functional decline of AD in participants with mild cognitive impairment (MCI) or mild AD-related dementia. This analysis reviews the efficacy of donanemab across various clinical outcome assessments, using both published data and new complementary analyses to provide context on its potential benefits for patients and caregivers. METHODS: We present findings from prespecified and post hoc analyses from the TRAILBLAZER-ALZ 2 trial. Clinical outcomes assessed were Integrated AD Rating Scale (iADRS), comprising the 13-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog13) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL); Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) for clinical severity and individual cognitive and functional domains; CDR-Global for clinical severity stage progression; meaningful within-patient change (MWPC); and ADCS-Activities of Daily Living dependence score. RESULTS: Donanemab reduced the risk of progression from MCI to mild AD by 33% (hazard ratio [HR] = 0.67; 95% CI 0.52-0.87; p = 0.003) and from mild to moderate AD by 50% (HR = 0.50; 95% CI 0.33-0.78; p = 0.002). In addition, donanemab reduced MWPC risk over 76 weeks by 38% for CDR-SB (HR = 0.62; 95% CI 0.52-0.75; p < 0.001) and 30% for iADRS (HR = 0.70; 95% CI 0.58-0.84; p < 0.001). Donanemab-treated participants exhibited significant slowing of clinical progression across multiple ADAS-Cog13 and ADCS-iADL items and all CDR-SB cognitive and functional domains. Donanemab also slowed progression of dependence least-squares mean change difference, -0.14 [95% CI -0.24 to -0.04; p = 0.007]), representing 23% slowing of progression (95% CI 6.17%-40.32%), and reduced risk of progression to requiring in-home support by 27% (HR = 0.74; 95% CI 0.59-0.91; p = 0.005). DISCUSSION: These results add to the evidence and further support clinically meaningful donanemab-mediated effects on cognition and function for patients and their caregivers and may aid communication of realistic treatment expectations and informed decision-making. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04437511. Submitted: June 17, 2020; First patient enrolled: June 19, 2020. clinicaltrials.gov/study/NCT04437511 EudraCT Number 2020-000077-25. Start date of recruitment: June 19, 2020. clinicaltrialsregister.eu/ctr-search/trial/2020-000077-25/results.
15 May 2026
Read appraisal →AJNR. American journal of neuroradiology
Hippocampal Subfield Susceptibility Alterations in Mild Cognitive Impairment Revealed by 7T MRI
BACKGROUND AND PURPOSE: Hippocampal magnetic susceptibility alterations may serve as early neurodegenerative biomarkers of Alzheimer disease (AD), but subfield-level evidence in mild cognitive impairment (MCI) remains limited. This study uses submillimeter high-resolution quantitative susceptibility mapping (QSM) to investigate hippocampal subfield susceptibility changes in MCI. MATERIALS AND METHODS: Thirteen individuals with MCI and 13 cognitively normal controls (NC) underwent 7T MRI scans including MP2RAGE and multiecho gradient echo imaging (for QSM). The visibility of hippocampal strata radiatum, lacunosum, and moleculare (SRLM) was assessed using a visual rating scale. Hippocampal subfields (Cornu Ammonis 1 [CA1], CA2, CA3, dentate gyrus [DG], and subiculums) were segmented, and magnetic susceptibility values (χ) were extracted for each subfield. The susceptibility difference between the DG and other subfields was also calculated. Associations between subfield susceptibility measures and cognitive performance were then assessed. RESULTS: Qualitative analysis revealed a distinct hyperintense curved pattern in the hippocampus on the 7T QSM image, corresponding to the SRLM. In NC, this pattern was clearly visible exhibiting consistently delineated boundaries, while it appeared blurred or absent in most subjects with MCI. The visual rating results showed that NC had significantly higher scores than subjects with MCI (Hedgesg = 1.43, 95% confidence interval) [95% CI, 0.60-2.35; P = .003], with most NC rating 3-4 and most subjects with MCI rating 1-2. Quantitative analysis of hippocampal subfield susceptibility revealed significantly elevated susceptibility [χ] in the left DG in those with MCI compared with NC (Hedgeg = 0.88, 95% CI, 0.10-1.72; P = .03), leading to reduced susceptibility contrast between the SRLM and adjacent CA1-CA3 or DG. Furthermore, regional differences of susceptibility between key subfields (left CA1 versus DG and subiculum versus DG) were significantly reduced in MCI, reflecting a loss of subfield contrast. These quantitative changes were significantly associated with lower cognitive performance, even when controlling for age. CONCLUSIONS: 7T QSM reveals susceptibility changes in hippocampal substructures in individuals with MCI, providing a potential early biomarker for AD.
11 May 2026
Read appraisal →AJNR. American journal of neuroradiology
Comparative Analysis of Artificial Intelligence-Based Quantification versus Visual Rating of Enlarged Perivascular Spaces in the Multi-Ethnic Study of Atherosclerosis Cohort
BACKGROUND AND PURPOSE: Enlarged perivascular spaces (PVS) are fluid-filled spaces surrounding small cerebral vessels. Current PVS research has been limited by the absence of efficient and scalable quantification tools. We compared visual ratings versus artificial intelligence (AI)-based quantification in identifying associations of PVS with vascular risk factors and cognitive performance. MATERIALS AND METHODS: This cross-sectional study included 235 participants from the Multi-Ethnic Study of Atherosclerosis who had undergone brain MRI and had available both visual ratings and AI-derived PVS quantification. Visual ratings were performed by an expert neuroradiologist (K.D.H.) using a semiquantitative scale. AI-derived counts were based on a fully automated deep learning algorithm. Visual and AI-derived counts were grouped into 4 a priori-defined anatomic locations: basal ganglia, frontoparietal cerebrum, midbrain, and cerebellum. The relationships of PVS counts with demographic characteristics, vascular risk factors, and global and domain-specific cognitive scores were examined using ordinal logistic regression (for ordinal categoric outcomes) and linear regression (for continuous outcomes) models. RESULTS: Mean age (SD) was 72.1 (6.8) years; 95 (40%) participants were men; and 126 (54%) self-reported as black. Means (SD) of AI-derived regional PVS counts were 63.7 (24.6) for basal ganglia, 414.9 (167.5) for frontoparietal cerebrum, and 9.8 (4.4) for midbrain. On visual ratings, the most prevalent count category for each region was 11-20 for basal ganglia (40%), 21-40 (31%) for frontoparietal cerebrum, and 1-5 (83%) for midbrain. For basal ganglia PVS, while both methods were associated with older age and white race/ethnicity, AI-derived counts exhibited additional associations with higher systolic blood pressure (β, 0.20; 95% CI, 0.05-0.36) and diabetes (unstandardized β coefficient [β], 11.51; 95% CI, 3.48-19.55), as well as poorer global cognition (β, -0.012; 95% CI, -0.023 to -0.0004), delayed memory (β, -0.005; 95% CI, -0.010 to -0.0005), and attention/processing speed (β, -0.005; 95% CI, -0.009 to -0.001) cognitive performance. CONCLUSIONS: In this cross-sectional study, AI-derived PVS quantification was more sensitive in detecting associations with vascular risk factors and cognitive outcomes than traditional visual ratings. AI-based quantification may aid in the analysis of large-scale epidemiologic data, advancing PVS research.
11 May 2026
Read appraisal →PloS one
Reducing annotation burden in medical imaging with ADGNET: A semi-supervised deep learning strategy
We propose ADGNET, a semi-supervised framework for Alzheimer's disease (AD) diagnosis that jointly optimizes image reconstruction and classification through shared feature representations. The architecture integrates a residual backbone with attention modulation for dynamic feature selection, an encoder-decoder reconstruction branch for unsupervised representation learning, and a classification branch with focal loss to address class imbalance. This dual-task design enables effective feature learning from limited annotations. On two public MRI datasets-KACD (2D, 6,400 images) and ROAD (3D, 532 scans)-ADGNET achieves average performance improvements of 4.1% and 7.2% over state-of-the-art methods (ResNeXt WSL, SimCLR) across six metrics. Interpretability analysis using Grad-CAM and attention visualization confirms that the model focuses on clinically relevant neuroanatomical structures, particularly the hippocampus and temporal lobes, with strong correlation to established AD pathology (r = 0.67, p < 0.001). These results validate the model's exceptional generalization capability and feature representation effectiveness across multi-modal medical imaging data, offering an efficient solution for few-shot medical image analysis.
10 May 2026
Read appraisal →Journal of neurology
Iron accumulation in multiple sclerosis and implications for cognitive and clinical progression: a systematic review of advanced neuroimaging studies
BACKGROUND AND AIMS: Iron-related alterations are frequently implicated in multiple sclerosis (MS) neurodegeneration, but its relationship with clinical symptoms and cognitive impairment remains unclear. We systematically reviewed evidence linking iron-sensitive susceptibility-based magnetic resonance imaging (MRI) metrics to cognitive outcomes, in order to evaluate their potential role as diagnostic and prognostic biomarkers of cognitive decline in MS. MATERIALS AND METHODS: A systematic review was conducted using the PRISMA guidelines. 600 studies were identified by searching PubMed, Scopus, Web of Science, and Embase in October 2025. After screening, 12 studies fulfilled the eligibility criteria and were included. RESULTS: Two main patterns emerged: (i) higher basal ganglia susceptibility/iron-related metrics are consistently linked to worse cognitive performance, particularly information processing speed and executive control; and (ii) thalamic findings are more variable in direction and clinical meaning, with susceptibility often capturing a mixed signal that overlaps with thalamic atrophy. CONCLUSIONS: Iron-sensitive quantitative MRI captures clinically relevant deep gray matter (DGM) pathology associated with cognitive impairment in MS, with basal ganglia measures showing the strongest linkage with cognitive and clinical outcomes. Future studies should include harmonized methodology and a longitudinal component.
19 Apr 2026
Read appraisal →The Cochrane database of systematic reviews
Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease
RATIONALE: Alzheimer's disease is a neurodegenerative disorder and the most common cause of dementia. Aggregated amyloid-beta protein deposits are implicated in its pathogenesis. Amyloid-beta-targeting monoclonal antibodies (sometimes represented as Aβ-mAbs) are potentially disease-modifying for Alzheimer's disease: through the clearance of amyloid in the brain, they may slow cognitive and functional decline. OBJECTIVES: To assess the clinical benefits and harms of amyloid-beta-targeting monoclonal antibodies aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, ponezumab, remternetug, and solanezumab in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. SEARCH METHODS: We searched CENTRAL, MEDLINE (PubMed), Embase, and two clinical trials registries (Clinicaltrials.gov and WHO International Clinical Trials Registry Platform), and we undertook reference checking and citation research. The most recent search date was 7 August 2025. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared amyloid-beta-targeting monoclonal antibodies with placebo or no treatment in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. We included both parallel-group and cluster designs. OUTCOMES: Our outcomes of critical importance were: cognitive function; dementia severity; functional ability; any amyloid-related imaging abnormality (ARIA), which includes oedema (E) and haemorrhage (H); any symptomatic ARIA E and H; symptomatic brain haemorrhage; serious adverse events; and any-cause mortality. We analysed data at 12, 18, 24, and over 24 months of treatment. RISK OF BIAS: We used the Cochrane risk of bias tool RoB 2 to assess the risk of bias in outcomes of critical importance. SYNTHESIS METHODS: We meta-analysed results for each outcome within each comparison using the inverse variance method and the random-effects model. We used GRADE to assess the certainty of evidence for each outcome as very low, low, moderate, or high. INCLUDED STUDIES: Overall, we included 17 studies with 20,342 participants. The mean age of participants in the studies ranged from 70 to 74 years. Seven studies enroled only participants with mild dementia, and one study enroled only participants with mild cognitive impairment. The remaining studies included a mixed population. The mean duration of participants' cognitive impairment ranged from 17 to 52 months. The 17 studies assessed seven different amyloid-beta-targeting monoclonal antibodies: aducanumab (n = 3), bapineuzumab (n = 4), crenezumab (n = 2), donanemab (n = 1), gantenerumab (n = 4), lecanemab (n = 1), and solanezumab (n = 2). All used placebo as a comparison. Eleven studies lasted 18 months, four lasted 24 months, and two lasted more than 24 months. All studies were funded by the pharmaceutical industry. SYNTHESIS OF RESULTS: Below, we report the results of the studies at 18 months. Cognitive function Compared to placebo, amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in cognitive function as measured by the ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive) scale (standardised mean difference (SMD) -0.11, 95% confidence interval (CI) -0.16 to -0.06; 13 studies, 9895 participants; moderate certainty). Dementia severity Amyloid-beta-targeting monoclonal antibodies may result in little to no difference in dementia severity as measured by the CDR-SB (Clincal Dementia Rating Sum of Boxes) scale (SMD -0.12, 95% CI -0.24 to -0.00; 9 studies, 8053 participants; low certainty). Functional ability Amyloid-beta-targeting monoclonal antibodies probably result in little to no difference in functional ability as measured on the ADCS-ADL (Alzheimer's Disease Cooperative Study - Activities of Daily Living) scale (SMD 0.09, 95% CI 0.03 to 0.16; 3 studies, 3478 participants; moderate certainty) and may result in a small increase in functional ability if measured with the ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) scale (SMD 0.21, 95% CI 0.10 to 0.32; 1 study, 1252 participants; low certainty) or ADCS-ADL-MCI (Alzheimer's Disease Cooperative Study - Activities of Daily Living for Mild Cognitive Impairment) scale (SMD 0.23, 95% CI 0.12 to 0.33; 4 studies, 2802 participants; low certainty). Adverse events Amyloid-beta-targeting monoclonal antibodies probably result in a small increase in the occurrence of any ARIA E (ARD (absolute risk difference) 107 more per 1000, 95% CI 77 more to 148 more; 11 studies, 13,595 participants; moderate certainty) and probably little to no difference in symptomatic ARIA E (ARD 29 more per 1000, 95% CI 22 more to 38 more; 2 studies, 3522 participants; moderate certainty) or symptomatic ARIA H (ARD 4 more per 1000, 95% CI 1 fewer to 31 more; 1 study, 1795 participants; moderate certainty). Three studies assessing any ARIA H showed heterogeneous results (I2 = 81%), which prevented pooled analysis. At 18 months, amyloid-beta-targeting monoclonal antibodies do not increase serious adverse events (ARD 6 more events per 1000, 95% CI 10 fewer to 26 more; 9 studies, 11,904 participants; high certainty) or overall mortality (ARD 2 more events per 1000, 95% CI 3 fewer to 11 more; 7 studies, 9733 participants; high certainty). We judged the overall risk of bias as low for the outcomes of serious adverse events and mortality. We had some concerns about the overall risk of bias for efficacy outcomes, mainly due to the risk of functional unblinding (i.e. participants and investigators correctly guessing whether a participant is receiving the active drug or placebo because of noticeable side effects). AUTHORS' CONCLUSIONS: The effect of amyloid-beta-targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer's disease is trivial, while on functional ability, it is small at best. Amyloid-beta-targeting monoclonal antibodies increase the risk of amyloid-related imaging abnormalities. Both desirable outcomes and adverse events were inconsistently reported in the studies included in the review. Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Future research on disease-modifying treatments for Alzheimer's disease should focus on other mechanisms of action. FUNDING: This Cochrane review was funded in part by the Drug and Medical Devices Governance Area, Regione Emilia-Romagna, Bologna, Italy. The publication of this article was supported by "Ricerca Corrente" funding from the Italian Ministry of Health. REGISTRATION: Protocol (2025): PROSPERO registration number CRD420251114325.
17 Apr 2026
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