Accurate and reproducible automated segmentation of human hippocampal subfields is of interest to study their roles in cognitive functions and disease processes. Multispectral structural MRI methods ...have been proposed to improve automated hippocampal subfield segmentation accuracy, but the reproducibility in a multicentric setting is, to date, not well characterized. Here, we assessed test–retest reproducibility of FreeSurfer 6.0 hippocampal subfield segmentations using multispectral MRI analysis pipelines (22 healthy subjects scanned twice, a week apart, at four 3T MRI sites). The harmonized MRI protocol included two 3D-T1, a 3D-FLAIR, and a high-resolution 2D-T2. After within-session T1 averaging, subfield volumes were segmented using three pipelines with different multispectral data: two longitudinal (“long_T1s” and “long_T1s_FLAIR”) and one cross-sectional (“long_T1s_FLAIR_crossT2”). Volume reproducibility was quantified in magnitude (reproducibility error—RE) and space (DICE coefficient). RE was lower in all hippocampal subfields, except for hippocampal fissure, using the longitudinal pipelines compared to long_T1s_FLAIR_crossT2 (average RE reduction of 0.4–3.6%). Similarly, the longitudinal pipelines showed a higher spatial reproducibility (1.1–7.8% of DICE improvement) in all hippocampal structures compared to long_T1s_FLAIR_crossT2. Moreover, long_T1s_FLAIR provided a small but significant RE improvement in comparison to long_T1s (
p
= 0.015), whereas no significant DICE differences were found. In addition, structures with volumes larger than 200 mm
3
had better RE (1–2%) and DICE (0.7–0.95) than smaller structures. In summary, our study suggests that the most reproducible hippocampal subfield FreeSurfer segmentations are derived from a longitudinal pipeline using 3D-T1s and 3D-FLAIR. Adapting a longitudinal pipeline to include high-resolution 2D-T2 may lead to further improvements.
The medial temporal lobe atrophy (MTA) and the posterior atrophy (PA) scales allow to assess the degree hippocampal and parietal atrophy from magnetic resonance imaging (MRI) scans. Despite reliable, ...easy and widespread employment, appropriate normative values are still missing. We aim to provide norms for the Italian population.
Two independent raters assigned the highest MTA and PA score between hemispheres, based on 3D T1-weighted MRI of 936 Italian Brain Normative Archive subjects (age: mean ± SD: 50.2 ± 14.7, range: 20–84; MMSE>26 or CDR = 0). The inter-rater agreement was assessed with the absolute intraclass correlation coefficient (aICC). We assessed the association between MTA and PA scores and sociodemographic features and APOE status, and normative data were established by age decade based on percentile distributions.
Raters agreed in 90% of cases for MTA (aICC = 0.86; 95% CI = 0.69–0.98) and in 86% for PA (aICC = 0.82; 95% CI = 0.58–0.98). For both rating scales, score distribution was skewed, with MTA = 0 in 38% of the population and PA = 0 in 52%, while a score ≥ 2 was only observed in 12% for MTA and in 10% for PA. Median denoted overall hippocampal (MTA: median = 1, IQR = 0–1) and parietal (PA: median = 0, IQR = 0–1) integrity. The 90th percentile of the age-specific distributions increased from 1 (at age 20–59) for both scales, to 2 for PA over age 60, and up to 4 for MTA over age 80. Gender, education and APOE status did not significantly affect the percentile distributions in the whole sample, nor in the subset over age 60.
Our normative data for the MTA and PA scales are consistent with previous studies and overcome their main limitations (in particular uneven representation of ages and missing percentile distributions), defining the age-specific norms to be considered for proper brain atrophy assessment.
•MTA and PA have a skewed scores' distribution, prevailing scores 0 and 1.•The 90th percentile increases from 1 up to 4 for MTA, and from 1 to 2 for PA.•Gender, education and APOE-ε4 status does not affect the percentiles' distribution.
Metagenomic data support an association between certain bacterial strains and Alzheimer's disease (AD), but their functional dynamics remain elusive.
To investigate the association between amyloid ...pathology, bacterial products such as lipopolysaccharide (LPS) and short chain fatty acids (SCFAs: acetate, valerate, butyrate), inflammatory mediators, and markers of endothelial dysfunction in AD.
Eighty-nine older persons with cognitive performance from normal to dementia underwent florbetapir amyloid PET and blood collection. Brain amyloidosis was measured with standardized uptake value ratio versus cerebellum. Blood levels of LPS were measured by ELISA, SCFAs by mass spectrometry, cytokines by using real-time PCR, and biomarkers of endothelial dysfunction by flow cytometry. We investigated the association between the variables listed above with Spearman's rank test.
Amyloid SUVR uptake was positively associated with blood LPS (rho≥0.32, p≤0.006), acetate and valerate (rho≥0.45, p < 0.001), pro-inflammatory cytokines (rho≥0.25, p≤0.012), and biomarkers of endothelial dysfunction (rho≥0.25, p≤0.042). In contrast, it was negatively correlated with butyrate (rho≤-0.42, p≤0.020) and the anti-inflammatory cytokine IL10 (rho≤-0.26, p≤0.009). Endothelial dysfunction was positively associated with pro-inflammatory cytokines, acetate and valerate (rho≥0.25, p≤0.045) and negatively with butyrate and IL10 levels (rho≤-0.25, p≤0.038).
We report a novel association between gut microbiota-related products and systemic inflammation with brain amyloidosis via endothelial dysfunction, suggesting that SCFAs and LPS represent candidate pathophysiologic links between the gut microbiota and AD pathology.
Epidemiological and logistical reasons are slowing the clinical validation of the molecular imaging biomarkers in the initial stages of neurocognitive disorders. We provide an updated systematic ...review of the recent advances (2017-2022), highlighting methodological shortcomings.
Studies reporting the diagnostic accuracy values of the molecular imaging techniques (i.e., amyloid-, tau-, 18FFDG-PETs, DaT-SPECT, and cardiac 123I-MIBG scintigraphy) in predicting progression from mild cognitive impairment (MCI) to dementia were selected according to the Preferred Reporting Items for a Systematic Review and Meta-Analysis (PRISMA) method and evaluated with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Main eligibility criteria were as follows: (1) ≥ 50 subjects with MCI, (2) follow-up ≥ 3 years, (3) gold standard: progression to dementia or diagnosis on pathology, and (4) measures of prospective accuracy.
Sensitivity (SE) and specificity (SP) in predicting progression to dementia, mainly to Alzheimer's dementia were 43-100% and 63-94% for
FFDG-PET and 64-94% and 48-93% for amyloid-PET. Longitudinal studies were lacking for less common disorders (Dementia with Lewy bodies-DLB and Frontotemporal lobe degeneration-FTLD) and for tau-PET, DaT-SPECT, and 123I-MIBG scintigraphy. Therefore, the accuracy values from cross-sectional studies in a smaller sample of subjects (n > 20, also including mild dementia stage) were chosen as surrogate outcomes. DaT-SPECT showed 47-100% SE and 71-100% SP in differentiating Lewy body disease (LBD) from non-LBD conditions; tau-PET: 88% SE and 100% SP in differentiating DLB from Posterior Cortical Atrophy.
I-MIBG scintigraphy differentiated LBD from non-LBD conditions with 47-100% SE and 71-100% SP.
Molecular imaging has a moderate-to-good accuracy in predicting the progression of MCI to Alzheimer's dementia. Longitudinal studies are sparse in non-AD conditions, requiring additional efforts in these settings.
Introduction
Etiological diagnosis of neurocognitive disorders of middle‐old age relies on biomarkers, although evidence for their rational use is incomplete. A European task force is defining a ...diagnostic workflow where expert experience fills evidence gaps for biomarker validity and prioritization. We report methodology and preliminary results.
Methods
Using a Delphi consensus method supported by a systematic literature review, 22 delegates from 11 relevant scientific societies defined workflow assumptions.
Results
We extracted diagnostic accuracy figures from literature on the use of biomarkers in the diagnosis of main forms of neurocognitive disorders. Supported by this evidence, panelists defined clinical setting (specialist outpatient service), application stage (MCI‐mild dementia), and detailed pre‐assessment screening (clinical‐neuropsychological evaluations, brain imaging, and blood tests).
Discussion
The Delphi consensus on these assumptions set the stage for the development of the first pan‐European workflow for biomarkers’ use in the etiological diagnosis of middle‐old age neurocognitive disorders at MCI‐mild dementia stages.
Highlights
Rational use of biomarkers in neurocognitive disorders lacks consensus in Europe.
A consensus of experts will define a workflow for the rational use of biomarkers.
The diagnostic workflow will be patient‐centered and based on clinical presentation.
The workflow will be updated as new evidence accrues.
Abstract
Background
Apolipoprotein E (APOE) ε4 allele is the main genetic risk factor for AD and has different roles in modulating the disease process along with the continuum from intact cognition ...to dementia due to AD, with its strongest influence at the earliest stages. The aim of this study is to test our hypothesis that places APOEε4 as a trigger in the perturbation of gut microbiota homeostasis.
Method
Fecal samples were collected from 28 cognitively intact elderly with known APOE genotype. Bacterial 16S rRNA gene was sequenced according to the 16S‐protocol on MiSeq (Illumina). Taxonomic abundance was computed with the free software package QIIME 2 (Quantitative Insights into Microbial Ecology; Bokulich, Microbiome, 2018; https://qiime2.org/). Plasma levels of cytokines were measured using a commercially available multiplex beads immunoassay, based on the Luminex platform.
Result
APOEε4 carriers showed altered abundance in 5 genera (LEfSe, p<0.048), 3 more (Bifidobacterium, Actinomyces, Lactococcus) and 2 less (Ruminococcaceae UCG‐003, Candidatus Melainabacteria) abundant, as well as decreased blood levels of IL‐8 (p=0.047) compared with non‐carriers. Elevated abundance of Bifidobacterium, Actinomyces, Lactococcus were associated with decreased levels of IL‐8 and IL‐6 (rho<‐0.41, p<0.040).
Conclusion
Structural microbiota alterations are associated with the restraint of some peripheral pro‐inflammatory signaling pathways in healthy subjects at genetic risk for AD. As a “good” form of inflammation (i.e. I‐6, IL1‐beta, TNF‐alpha) has been proposed to be beneficial in the early phases of the disease in several AD mouse models (Chakrabarty, J Neurosci 2010; Shaftel, J Neurosci 2007), these preliminary data suggest that the deleterious impact of the APOE4 allele on AD development might start in the gut.
Background
Apolipoprotein E (APOE) ε4 allele is the main genetic risk factor for AD and has different roles in modulating the disease process along with the continuum from intact cognition to ...dementia due to AD, with its strongest influence at the earliest stages. The aim of this study is to test our hypothesis that places APOEε4 as a trigger in the perturbation of gut microbiota homeostasis.
Method
Fecal samples were collected from 28 cognitively intact elderly with known APOE genotype. Bacterial 16S rRNA gene was sequenced according to the 16S‐protocol on MiSeq (Illumina). Taxonomic abundance was computed with the free software package QIIME 2 (Quantitative Insights into Microbial Ecology; Bokulich, Microbiome, 2018; https://qiime2.org/). Plasma levels of cytokines were measured using a commercially available multiplex beads immunoassay, based on the Luminex platform.
Result
APOEε4 carriers showed altered abundance in 5 genera (LEfSe, p<0.048), 3 more (Bifidobacterium, Actinomyces, Lactococcus) and 2 less (Ruminococcaceae UCG‐003, Candidatus Melainabacteria) abundant, as well as decreased blood levels of IL‐8 (p=0.047) compared with non‐carriers. Elevated abundance of Bifidobacterium, Actinomyces, Lactococcus were associated with decreased levels of IL‐8 and IL‐6 (rho<‐0.41, p<0.040).
Conclusion
Structural microbiota alterations are associated with the restraint of some peripheral pro‐inflammatory signaling pathways in healthy subjects at genetic risk for AD. As a “good” form of inflammation (i.e. I‐6, IL1‐beta, TNF‐alpha) has been proposed to be beneficial in the early phases of the disease in several AD mouse models (Chakrabarty, J Neurosci 2010; Shaftel, J Neurosci 2007), these preliminary data suggest that the deleterious impact of the APOE4 allele on AD development might start in the gut.
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