Brain atrophy trajectories predict differential functional performance in Alzheimer's disease: Moderations with apolipoprotein E and sex

Sapkota, Shraddha; Ramirez, Joel; Yhap, Vanessa; Masellis, Mario; Black, Sandra E.

doi:10.1002/dad2.12244

Cited by 5 publications

(4 citation statements)

References 62 publications

(103 reference statements)

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“…We revealed the effect of disease duration on the integrity of the brain. Pyun et al (2017) noted that women had an increased risk of brain atrophy (Ferretti et al, 2018;Sapkota et al, 2021), but our results showed men had a higher proportion of worse global cerebral frontal atrophy and MTA. This might be because brain atrophy accelerates over time, and many factors such as hypertension, hyperlipidemia, smoking, and drinking result in small vessel disease, which may lead to brain atrophy, while these factors occur mostly in men.…”

Section: Discussioncontrasting

confidence: 64%

Associations of multiple visual rating scales based on structural magnetic resonance imaging with disease severity and cerebrospinal fluid biomarkers in patients with Alzheimer’s disease

Wan

Liu²,

Liu³

et al. 2022

Front. Aging Neurosci.

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The relationships between multiple visual rating scales based on structural magnetic resonance imaging (sMRI) with disease severity and cerebrospinal fluid (CSF) biomarkers in patients with Alzheimer’s disease (AD) were ambiguous. In this study, a total of 438 patients with clinically diagnosed AD were recruited. All participants underwent brain sMRI scan, and medial temporal lobe atrophy (MTA), posterior atrophy (PA), global cerebral atrophy-frontal sub-scale (GCA-F), and Fazekas rating scores were visually evaluated. Meanwhile, disease severity was assessed by neuropsychological tests such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR). Among them, 95 patients were tested for CSF core biomarkers, including Aβ1–42, Aβ1–40, Aβ1–42/Aβ1–40, p-tau, and t-tau. As a result, the GCA-F and Fazekas scales showed positively significant correlations with onset age (r = 0.181, p < 0.001; r = 0.411, p < 0.001, respectively). Patients with late-onset AD (LOAD) showed higher GCA-F and Fazekas scores (p < 0.001, p < 0.001). With regard to the disease duration, the MTA and GCA-F were positively correlated (r = 0.137, p < 0.05; r = 0.106, p < 0.05, respectively). In terms of disease severity, a positively significant association emerged between disease severity and the MTA, PA GCA-F, and Fazekas scores (p < 0.001, p < 0.001, p < 0.001, p < 0.05, respectively). Moreover, after adjusting for age, gender, and APOE alleles, the MTA scale contributed to moderate to severe AD in statistical significance independently by multivariate logistic regression analysis (p < 0.05). The model combining visual rating scales, age, gender, and APOE alleles showed the best performance for the prediction of moderate to severe AD significantly (AUC = 0.712, sensitivity = 51.5%, specificity = 84.6%). In addition, we observed that the MTA and Fazekas scores were associated with a lower concentration of Aβ1–42 (p < 0.031, p < 0.022, respectively). In summary, we systematically analyzed the benefits of multiple visual rating scales in predicting the clinical status of AD. The visual rating scales combined with age, gender, and APOE alleles showed best performance in predicting the severity of AD. MRI biomarkers in combination with CSF biomarkers can be used in clinical practice.

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Section: Discussioncontrasting

confidence: 64%

Associations of multiple visual rating scales based on structural magnetic resonance imaging with disease severity and cerebrospinal fluid biomarkers in patients with Alzheimer’s disease

Wan

Liu²,

Liu³

et al. 2022

Front. Aging Neurosci.

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“…In the worst prognosis group, there were almost twice as many female than male APOE ε4 carriers, suggesting that the ε4 allele has a disproportionately detrimental effect in women. Women had a greater association between whole brain atrophy and functional decline than men, and female ε4 carriers had the greatest functional decline for a given level of whole brain atrophy 290 . The interaction between sex and APOE influences the accumulation of AD pathology.…”

Section: Adni's Contributions To Understanding Ad Disease Progressionmentioning

confidence: 95%

“…Women had a greater association between whole brain atrophy and functional decline than men, and female ε4 carriers had the greatest functional decline for a given level of whole brain atrophy. 290 The interaction between sex and APOE influences the accumulation of AD pathology. Female ε4 carriers had a faster accumulation of Aβ in the striatum, followed by accumulation of tau in limbic regions than male ε4 carriers or female ε4 non‐carriers.…”

Section: Adni's Contributions To Understanding Ad Disease Progressionmentioning

confidence: 99%

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

Veitch,

Weiner,

Miller

et al. 2023

Alzheimer's & Dementia

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The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co‐pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI‐4 aims to address by enrolling a diverse cohort.

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“…When examining combined APOE4 and WMH effects, prior studies have demonstrated worse attention/executive function in APOE4 carriers with dementia [ 22 ]. Additionally, APOE4 status was a key moderator in the relationship between brain atrophy and functional impairment in the dementia stage [ 23 ]. However, it remains to be known if APOE4 is a key effect modifier in the relationship between WMH and GMV, especially early in the disease course.…”

Section: Introductionmentioning

confidence: 99%

APOE4 carrier status determines association between white matter disease and grey matter atrophy in early-stage dementia

et al. 2023

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Background White matter hyperintensities, a neuroimaging marker of small-vessel cerebrovascular disease and apolipoprotein ε4 (APOE4) allele, are important dementia risk factors. However, APOE4 as a key effect modifier in the relationship between white matter hyperintensities and grey matter volume needs further exploration. Methods One hundred ninety-two early-stage dementia (including mild cognitive impairment and mild dementia) and 259 cognitively unimpaired participants from a neurocognitive research cohort with neuroimaging data, APOE genotyping, and neuropsychological assessments were studied. We investigated independent and interactive effects of white matter hyperintensities and APOE4 on whole-brain voxel-wise grey matter volume using voxel-based morphometry (uncorrected p < 0.001; minimum cluster size = 100 voxels). We further assessed interactive effects between APOE4 and white matter hyperintensities on global cognition, memory, and executive function in early-stage dementia and cognitively unimpaired participants. Results Independent of APOE4 status, higher white matter hyperintensity load was associated with greater grey matter atrophy across frontal, parietal, temporal, and occipital lobes in cognitively unimpaired and early-stage dementia subjects. However, interaction analyses and independent sample analyses revealed that APOE4 non-carriers demonstrated greater white matter hyperintensity-associated grey matter atrophy compared to APOE4 carriers in both cognitively unimpaired and early-stage dementia groups. Additional confirmatory analyses among APOE4 non-carriers demonstrated that white matter hyperintensities resulted in widespread grey matter loss. Analyses of cognitive function demonstrated that higher white matter hyperintensity load was associated with worse global (Mini-Mental State Examination, Montreal Cognitive Assessment) and executive function (Color Trails 2) in APOE4 non-carriers compared to APOE4 carriers in early-stage dementia but not cognitively unimpaired participants. Conclusions The association between white matter hyperintensities and grey matter loss is more pronounced in APOE4 non-carriers than APOE4 carriers in the cognitively unimpaired and early-stage dementia stages. Furthermore, white matter hyperintensity presence results in poorer executive function in APOE4 non-carriers compared to APOE4 carriers. This finding may have significant impact on the design of clinical trials with disease modifying therapies.

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Brain atrophy trajectories predict differential functional performance in Alzheimer's disease: Moderations with apolipoprotein E and sex

Cited by 5 publications

References 62 publications

Associations of multiple visual rating scales based on structural magnetic resonance imaging with disease severity and cerebrospinal fluid biomarkers in patients with Alzheimer’s disease

Associations of multiple visual rating scales based on structural magnetic resonance imaging with disease severity and cerebrospinal fluid biomarkers in patients with Alzheimer’s disease

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

APOE4 carrier status determines association between white matter disease and grey matter atrophy in early-stage dementia

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