Brain-age can be inferred from structural neuroimaging and compared to chronological age (brain-age delta) as a marker of biological brain aging. Accelerated aging has been found in neurodegenerative ...disorders like Alzheimer's disease (AD), but its validation against markers of neurodegeneration and AD is lacking. Here, imaging-derived measures from the UK Biobank dataset (N=22,661) were used to predict brain-age in 2,314 cognitively unimpaired (CU) individuals at higher risk of AD and mild cognitive impaired (MCI) patients from four independent cohorts with available biomarker data: ALFA+, ADNI, EPAD, and OASIS. Brain-age delta was associated with abnormal amyloid-β, more advanced stages (AT) of AD pathology and
-ε4 status. Brain-age delta was positively associated with plasma neurofilament light, a marker of neurodegeneration, and sex differences in the brain effects of this marker were found. These results validate brain-age delta as a non-invasive marker of biological brain aging in non-demented individuals with abnormal levels of biomarkers of AD and axonal injury.
Positive associations between cerebral microbleeds (CMBs) and APOE-ε4 (apolipoprotein E) genotype have been reported in Alzheimer’s disease, but show conflicting results. We investigated the effect ...of APOE genotype on CMBs in a cohort of cognitively unimpaired middle- and old-aged individuals enriched for APOE-ε4 genotype. Participants from ALFA (Alzheimer and Families) cohort were included and their magnetic resonance scans assessed (n = 564, 50% APOE-ε4 carriers). Quantitative magnetic resonance analyses included visual ratings, atrophy measures, and white matter hyperintensity (WMH) segmentations. The prevalence of CMBs was 17%, increased with age (p < 0.05), and followed an increasing trend paralleling APOE-ε4 dose. The number of CMBs was significantly higher in APOE-ε4 homozygotes compared to heterozygotes and non-carriers (p < 0.05). This association was driven by lobar CMBs (p < 0.05). CMBs co-localized with WMH (p < 0.05). No associations between CMBs and APOE-ε2, gray matter volumes, and cognitive performance were found. Our results suggest that cerebral vessels of APOE-ε4 homozygous are more fragile, especially in lobar locations. Co-occurrence of CMBs and WMH suggests that such changes localize in areas with increased vascular vulnerability.
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•We investigated the effect of APOE genotype on cerebral microbleeds (CMBs).•The number of APOE-ε4 alleles parallels both the prevalence and the number of CMBs.•CMBs co-localize with white matter hyperintensities.•Lobar CMBs are associated with REGICOR cardiovascular mortality risk score.
Purpose
Glial activation is one of the earliest mechanisms to be altered in Alzheimer’s disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in ...both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose (
18
FFDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants.
Methods
We included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β (Aβ) positive. Associations between GFAP markers and
18
FFDG uptake were studied. We also investigated whether these associations were modified by Aβ and tau status (AT stages).
Results
Plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with
18
FFDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism.
Conclusions
Higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes.
•Neurofilament light in cerebrospinal fluid is increased in subjective cognitive decline.•This association is driven by individuals harboring amyloid-beta pathology.•When amyloid pathology and ...subjective cognitive decline concur there is a negative association between neurofilament levels and hippocampal volume.•These associations are independent of age, gender, mood and cardiovascular risk.
Neurofilament light chain (NfL) is an axonal protein that when measured in cerebrospinal fluid (CSF) serves as a biomarker of neurodegeneration. We aimed at investigating the association among CSF NfL, presence of Subjective Cognitive Decline (SCD) and hippocampal volume, and how CSF amyloid-β (Aβ) modifies these associations. We included 278 cognitively unimpaired participants from the Alfa+ cohort (78 SCD and 200 Controls). Linear models accounting for covariates (age, gender, and mood) were used to test the association between CSF NfL and SCD status, and between CSF NfL and bilateral hippocampal volumes. Interactions with Aβ were also explored. Individuals with SCD had higher CSF NfL and lower CSF Aβ42/40 than Controls. There was a significant interaction between SCD and CSF-Aβ42/40 levels. Stratified analyses showed a significant association between SCD and NfL only in Aβ+ individuals. Higher CSF NfL was significantly associated with lower hippocampal volume specifically in Aβ+ individuals with SCD. The presence of SCD in Aβ+ individuals may represent an early symptom in the Alzheimer's continuum related to incipient neurodegeneration.
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INTRODUCTION
Poor sleep quality is associated with cognitive outcomes in Alzheimer's disease (AD). We analyzed the associations between self‐reported sleep quality and brain structure and function in ...cognitively unimpaired (CU) individuals.
METHODS
CU adults (N = 339) underwent structural magnetic resonance imaging, lumbar puncture, and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. A subset (N = 295) performed 18F fluorodeoxyglucose positron emission tomography scans. Voxel‐wise associations with gray matter volumes (GMv) and cerebral glucose metabolism (CMRGlu) were performed including interactions with cerebrospinal fluid (CSF) AD biomarkers status.
RESULTS
Poorer sleep quality was associated with lower GMv and CMRGlu in the orbitofrontal and cingulate cortices independently of AD pathology. Self‐reported sleep quality interacted with altered core AD CSF biomarkers in brain areas known to be affected in preclinical AD stages.
DISCUSSION
Poor sleep quality may impact brain structure and function independently from AD pathology. Alternatively, AD‐related neurodegeneration in areas involved in sleep–wake regulation may induce or worsen sleep disturbances.
Highlights
Poor sleep impacts brain structure and function independent of Alzheimer's disease (AD) pathology.
Poor sleep exacerbates brain changes observed in preclinical AD.
Sleep is an appealing therapeutic strategy for preventing AD.
Magnetic resonance imaging (MRI) has unveiled specific alterations at different stages of Alzheimer's disease (AD) pathophysiologic continuum constituting what has been established as "AD signature". ...To what extent MRI can detect amyloid-related cerebral changes from structural MRI in cognitively unimpaired individuals is still an area open for exploration.
Longitudinal 3D-T1 MRI scans were acquired from a subset of the ADNI cohort comprising 403 subjects: 79 controls (Ctrls), 50 preclinical AD (PreAD), and 274 MCI and dementia due to AD (MCI/AD). Amyloid CSF was used as gold-standard measure with established cutoffs (< 192 pg/mL) to establish diagnostic categories. Cognitively unimpaired individuals were defined as Ctrls if were amyloid negative and PreAD otherwise. The MCI/AD group was amyloid positive. Only subjects with the same diagnostic category at baseline and follow-up visits were considered for the study. Longitudinal morphometric analysis was performed using SPM12 to calculate Jacobian determinant maps. Statistical analysis was carried out on these Jacobian maps to identify structural changes that were significantly different between diagnostic categories. A machine learning classifier was applied on Jacobian determinant maps to predict the presence of abnormal amyloid levels in cognitively unimpaired individuals. The performance of this classifier was evaluated using receiver operating characteristic curve analysis and as a function of the follow-up time between MRI scans. We applied a cost function to assess the benefit of using this classifier in the triaging of individuals in a clinical trial-recruitment setting.
The optimal follow-up time for classification of Ctrls vs PreAD was Δt > 2.5 years, and hence, only subjects within this temporal span are used for evaluation (15 Ctrls, 10 PreAD). The longitudinal voxel-based classifier achieved an AUC = 0.87 (95%CI 0.72-0.97). The brain regions that showed the highest discriminative power to detect amyloid abnormalities were the medial, inferior, and lateral temporal lobes; precuneus; caudate heads; basal forebrain; and lateral ventricles.
Our work supports that machine learning applied to longitudinal brain volumetric changes can be used to predict, with high precision, the presence of amyloid abnormalities in cognitively unimpaired subjects. Used as a triaging method to identify a fixed number of amyloid-positive individuals, this longitudinal voxel-wise classifier is expected to avoid 55% of unnecessary CSF and/or PET scans and reduce economic cost by 40%.
The number of APOE-ε4 alleles is a major nonmodifiable risk factor for sporadic Alzheimer disease (AD). There is increasing evidence on the benefits of dietary DHA (22:6n–3) before the onset of AD ...symptoms, particularly in APOE-ε4 carriers. Brain alterations in the preclinical stage can be detected by structural MRI.
We aimed, in middle-aged cognitively unimpaired individuals at increased risk of AD, to cross-sectionally investigate whether dietary DHA intake relates to cognitive performance and to MRI-based markers of cerebral small vessel disease and AD-related neurodegeneration, exploring the effect modification by APOE-ε4 status.
In 340 participants of the ALFA (ALzheimer and FAmilies) study, which is enriched for APOE-ε4 carriership (n = 122, noncarriers; n = 157, 1 allele; n = 61, 2 alleles), we assessed self-reported DHA intake through an FFQ. We measured cognitive performance by administering episodic memory and executive function tests. We performed high-resolution structural MRI to assess cerebral small vessel disease white matter hyperintensities (WMHs) and cerebral microbleeds (CMBs) and AD-related brain atrophy (cortical thickness in an AD signature). We constructed regression models adjusted for potential confounders, exploring the interaction DHA × APOE-ε4.
We observed no significant associations between DHA and cognitive performance or WMH burden. We observed a nonsignificant inverse association between DHA and prevalence of lobar CMBs (OR: 0.446; 95% CI: 0.195, 1.018; P = 0.055). DHA was found to be significantly related to greater cortical thickness in the AD signature in homozygotes but not in nonhomozygotes (P-interaction = 0.045). The association strengthened when analyzing homozygotes and nonhomozygotes matched for risk factors.
In cognitively unimpaired APOE-ε4 homozygotes, dietary DHA intake related to structural patterns that may result in greater resilience to AD pathology. This is consistent with the current hypothesis that those subjects at highest risk would obtain the largest benefits from DHA supplementation in the preclinical stage. This trial was registered at clinicaltrials.gov as NCT01835717.
Soundtrack of life: An fMRI study Falcon, Carles; Navarro-Plaza, Mari Carmen; Gramunt, Nina ...
Behavioural brain research,
02/2022, Letnik:
418
Journal Article
Recenzirano
Odprti dostop
Most people have a soundtrack of life, a set of special musical pieces closely linked to certain biographical experiences. Autobiographical memories (AM) and music listening (ML) involve complex ...mental processes ruled by differentiate brain networks. The aim of the paper was to determine the way both networks interact in linked occurrences. We performed an fMRI experiment on 31 healthy participants (age: 32.4 ± 7.6, 11 men, 4 left-handers). Participants had to recall AMs prompted by music they reported to be associated with personal biographical events (LMM: linked AM-ML events). In the main control task, participants were prompted to recall emotional AMs while listening known tracks from a pool of popular music (UMM: unlinked AM-ML events). We wanted to investigate to what extent LMM network exceeded the overlap of AM and ML networks by contrasting the activation obtained in LMM versus UMM. The contrast LMM>UMM showed the areas (at P < 0.05 FWE corrected at voxel level and cluster size>20): right frontal inferior operculum, frontal middle gyrus, pars triangularis of inferior frontal gyrus, occipital superior gyrus and bilateral basal ganglia (caudate, putamen and pallidum), occipital (middle and inferior), parietal (inferior and superior), precentral and cerebellum (6, 7 L, 8 and vermis 6 and 7). Complementary results were obtained from additional control tasks. Provided part of tLMM>UMM areas might not be related to ML-AM linkage, we assessed LMM brain network by an independent component analysis (ICA) on contrast images. Results from ICA suggest the existence of a cortico-ponto-cerebellar network including left precuneus, bilateral anterior cingulum, parahippocampal gyri, frontal inferior operculum, ventral anterior part of the insula, frontal medial orbital gyri, caudate nuclei, cerebellum 6 and vermis, which might rule the ML-induced retrieval of AM in closely linked AM-ML events. This topography may suggest that the pathway by which ML is linked to AM is attentional and directly related to perceptual processing, involving salience network, instead of the natural way of remembering typically associated with default mode network.
•fMRI paradigm to investigate the music-evoked (ML) recall of autobiographical memories (AM).•Maps corresponding to ML-AM linked events were contrasted with those with ML-AM unlinked ones.•Results suggest a cortico-ponto-cerebellar network involved in the music-evoked retrieval of AM.•Its topography suggest ML-AM linkage is attentional and directly related to perceptual processing.
This study investigated whether genetic factors involved in Alzheimer’s disease (AD) are associated with enlargement of Perivascular Spaces (ePVS) in the brain. A total of 680 participants with ...T2-weighted MRI scans and genetic information were acquired from the ALFA study. ePVS in the basal ganglia (BG) and the centrum semiovale (CS) were assessed based on a validated visual rating scale. We used univariate and multivariate logistic regression models to investigate associations between ePVS in BG and CS with BIN1-rs744373, as well as APOE genotypes. We found a significant association of the BIN1-rs744373 polymorphism in the CS subscale (p value = 0.019; OR = 2.564), suggesting that G allele carriers have an increased risk of ePVS in comparison with A allele carriers. In stratified analysis by APOE-ε4 status (carriers vs. non-carriers), these results remained significant only for ε4 carriers (p value = 0.011; OR = 1.429). To our knowledge, the present study is the first suggesting that genetic predisposition for AD is associated with ePVS in CS. These findings provide evidence that underlying biological processes affecting AD may influence CS-ePVS.
Among others, the existence of pathophysiological biomarkers such as cerebrospinal fluid (CSF) Aβ-42, t-tau, and p-tau preceding the onset of Alzheimer's disease (AD) symptomatology have shifted the ...conceptualization of AD as a continuum. In addition, magnetic resonance imaging (MRI) enables the study of structural and functional cross-sectional correlates and longitudinal changes in vivo and, therefore, the combination of CSF data and imaging analyses emerges as a synergistic approach to understand the structural correlates related with specific AD-related biomarkers. In this chapter, we describe the methods used in neuroimaging that will allow researchers to combine data on CSF metabolites with imaging analyses.
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