Background
We classified non‐demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and ...imaging profiles.
Materials and methods
From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut‐offs of 1000 pg/mL for amyloid beta (Aß)1‐42 and 27 pg/mL for p‐tau181 were validated using Gaussian mixture models. Given strong correlation of p‐tau and t‐tau (R2 = 0.98, P < 0.001), neurodegeneration was defined by age‐adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages.
Results
Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A–T–N–, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non‐Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T–N– compared to A–T–N– (P < 0.001).
Discussion
In non‐demented individuals along the AD continuum, p‐tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.
OBJECTIVETo develop and evaluate a model for staging cortical amyloid deposition using PET with high generalizability.
METHODSThree thousand twenty-seven individuals (1,763 cognitively unimpaired CU, ...658 impaired, 467 with Alzheimer disease AD dementia, 111 with non-AD dementia, and 28 with missing diagnosis) from 6 cohorts (European Medical Information Framework for AD, Alzheimerʼs and Family, Alzheimerʼs Biomarkers in Daily Practice, Amsterdam Dementia Cohort, Open Access Series of Imaging Studies OASIS-3, Alzheimer’s Disease Neuroimaging Initiative ADNI) who underwent amyloid PET were retrospectively included; 1,049 individuals had follow-up scans. With application of dataset-specific cutoffs to global standard uptake value ratio (SUVr) values from 27 regions, single-tracer and pooled multitracer regional rankings were constructed from the frequency of abnormality across 400 CU individuals (100 per tracer). The pooled multitracer ranking was used to create a staging model consisting of 4 clusters of regions because it displayed a high and consistent correlation with each single-tracer ranking. Relationships between amyloid stage, clinical variables, and longitudinal cognitive decline were investigated.
RESULTSSUVr abnormality was most frequently observed in cingulate, followed by orbitofrontal, precuneal, and insular cortices and then the associative, temporal, and occipital regions. Abnormal amyloid levels based on binary global SUVr classification were observed in 1.0%, 5.5%, 17.9%, 90.0%, and 100.0% of individuals in stage 0 to 4, respectively. Baseline stage predicted decline in Mini-Mental State Examination (MMSE) score (ADNIn = 867, F = 67.37, p < 0.001; OASISn = 475, F = 9.12, p < 0.001) and faster progression toward an MMSE score ≤25 (ADNIn = 787, hazard ratio HRstage1 2.00, HRstage2 3.53, HRstage3 4.55, HRstage4 9.91, p < 0.001; OASISn = 469, HRstage4 4.80, p < 0.001).
CONCLUSIONThe pooled multitracer staging model successfully classified the level of amyloid burden in >3,000 individuals across cohorts and radiotracers and detects preglobal amyloid burden and distinct risk profiles of cognitive decline within globally amyloid-positive individuals.
Background
Cross‐sectional diffusion tensor imaging (DTI) studies report white matter (WM) microstructural alterations, mainly involving fornix and corpus callosum (CC), in symptomatic stages of ...Alzheimer’s Disease (AD). Exploring these changes longitudinally in relation to preclinical and prodromal AD pathology is essential to track disease progression.
We investigated trajectories of WM alterations in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort and their relationship with AD biomarkers.
Method
EPAD inclusion criteria were age>50 years and Clinical Dementia Rating≤0.5. We selected participants with baseline CSF samples, and longitudinal DTI scans. After defining AT groups(Ingala et al. 2021), A‐T+ participants were excluded (final N = 283).
MRI acquisition and preprocessing was previously described(Lorenzini et al. 2022). We extracted fractional anisotropy (FA) in 14 regions(Mori et al. 2005) from DTI as a marker of WM integrity. Site harmonization of MRI‐derived data was performed with ComBat toolbox(Fortin et al. 2018).
Age‐ and sex‐corrected linear mixed models with random intercepts on participants were used to estimate time‐effect on MRI‐derived phenotypes, and their interaction with AT status. Results were corrected for multiple testing.
Result
At baseline, A+T‐ participants showed lower FA in body/columns (ß = ‐0.04, p<0.01) and crus of fornix (ß = ‐0.01, p = 0.04), and in splenium (ß = ‐0.007, p = 0.04) and body of CC (ß = ‐0.01, p = 0.03) compared to A‐T‐. In the whole group, FA decreased over time in splenium (ß = ‐0.003, p<0.01), body (ß = ‐0.002, p<0.01) and genu of CC (ß = ‐0.009, p<0.01), body/columns (ß = ‐0.004, p<0.01) and crus of fornix (ß = ‐0.005, p<0.01), and inferior longitudinal fasciculus (ß = ‐0.007, p<0.01). Compared to A‐T‐, A+T+ participants showed steeper FA reduction in superior (Interaction:ß = ‐0.004, p = 0.03) and anterior corona radiata (Interaction:ß = ‐0.006, p = 0.02).
Conclusion
Our results suggest that WM integrity in key AD regions may degenerate early in the AD continuum, showing greater impairment over short‐time intervals in individuals with higher AD‐specific pathological burden.
Background
Cross‐sectional diffusion tensor imaging (DTI) studies report white matter (WM) microstructural alterations, mainly involving fornix and corpus callosum (CC), in symptomatic stages of ...Alzheimer’s Disease (AD). Exploring these changes longitudinally in relation to preclinical and prodromal AD pathology is essential to track disease progression. We investigated trajectories of WM alterations in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort and their relationship with AD biomarkers.
Method
EPAD inclusion criteria were age>50 years and Clinical Dementia Rating = 0.5. We selected participants with baseline CSF samples, and longitudinal DTI scans. After defining AT groups(Ingala et al. 2021), A‐T+ participants were excluded (final N = 283). MRI acquisition and preprocessing was previously described(Lorenzini et al. 2022). We extracted fractional anisotropy (FA) in 14 regions(Mori et al. 2005) from DTI as a marker of WM integrity. Site harmonization of MRI‐derived data was performed with ComBat toolbox(Fortin et al. 2018). Age‐ and sex‐corrected linear mixed models with random intercepts on participants were used to estimate time‐effect on MRI‐derived phenotypes, and their interaction with AT status. Results were corrected for multiple testing.
Result
At baseline, A+T‐ participants showed lower FA in body/columns (ß = ‐0.04, p<0.01) and crus of fornix (ß = ‐0.01, p = 0.04), and in splenium (ß = ‐0.007, p = 0.04) and body of CC (ß = ‐0.01, p = 0.03) compared to A‐T‐. In the whole group, FA decreased over time in splenium (ß = ‐0.003, p<0.01), body (ß = ‐0.002, p<0.01) and genu of CC (ß = ‐0.009, p<0.01), body/columns (ß = ‐0.004, p<0.01) and crus of fornix (ß = ‐0.005, p<0.01), and inferior longitudinal fasciculus (ß = ‐0.007, p<0.01). Compared to A‐T‐, A+T+ participants showed steeper FA reduction in superior (Interaction:ß = ‐0.004, p = 0.03) and anterior corona radiata (Interaction:ß = ‐0.006, p = 0.02).
Conclusion
Our results suggest that WM integrity in key AD regions may degenerate early in the AD continuum, showing greater impairment over short‐time intervals in individuals with higher AD‐specific pathological burden.
Objectives
Neurodegeneration in suspected Alzheimer’s disease can be determined using visual rating or quantitative volumetric assessments. We examined the feasibility of volumetric measurements of ...gray matter (GMV) and hippocampal volume (HCV) and compared their diagnostic performance with visual rating scales in academic and non-academic memory clinics.
Materials and methods
We included 231 patients attending local memory clinics (LMC) in the Netherlands and 501 of the academic Amsterdam Dementia Cohort (ADC). MRI scans were acquired using local protocols, including a T1-weighted sequence. Quantification of GMV and HCV was performed using FSL and FreeSurfer. Medial temporal atrophy and global atrophy were assessed with visual rating scales. ROC curves were derived to determine which measure discriminated best between cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer’s dementia (AD).
Results
Patients attending LMC (age 70.9 ± 8.9 years; 47% females; 19% CN; 34% MCI; 47% AD) were older, had more cerebrovascular pathology, and had lower GMV and HCV compared to those of the ADC (age 64.9 ± 8.2 years; 42% females; 35% CN, 43% MCI, 22% AD). While visual ratings were feasible in > 95% of scans in both cohorts, quantification was achieved in 94–98% of ADC, but only 68–85% of LMC scans, depending on the software. Visual ratings and volumetric outcomes performed similarly in discriminating CN vs AD in both cohorts.
Conclusion
In clinical settings, quantification of GM and hippocampal atrophy currently fails in up to one-third of scans, probably due to lack of standardized acquisition protocols. Diagnostic accuracy is similar for volumetric measures and visual rating scales, making the latter suited for clinical practice.
Summary statement
In a real-life clinical setting, volumetric assessment of MRI scans in dementia patients may require acquisition protocol optimization and does not outperform visual rating scales.
Key Points
•
In a real-life clinical setting, the diagnostic performance of visual rating scales is similar to that of automatic volumetric quantification and may be sufficient to distinguish Alzheimer’s disease groups
.
•
Volumetric assessment of gray matter and hippocampal volumes from MRI scans of patients attending non-academic memory clinics fails in up to 32% of cases
.
•
Clinical MR acquisition protocols should be optimized to improve the output of quantitative software for segmentation of Alzheimer’s disease–specific outcomes
.
Aging-related cognitive decline can be accelerated by a combination of genetic factors, cardiovascular and cerebrovascular dysfunction, and amyloid-β burden. Whereas cerebral blood flow (CBF) has ...been studied as a potential early biomarker of cognitive decline, its normal variability in healthy elderly is less known. In this study, we investigated the contribution of genetic, vascular, and amyloid-β components of CBF in a cognitively unimpaired (CU) population of monozygotic older twins. We included 134 participants who underwent arterial spin labeling (ASL) MRI and 18Fflutemetamol amyloid-PET imaging at baseline and after a four-year follow-up. Generalized estimating equations were used to investigate the associations of amyloid burden and white matter hyperintensities with CBF. We showed that, in CU individuals, CBF: 1) has a genetic component, as within-pair similarities in CBF values were moderate and significant (ICC > 0.40); 2) is negatively associated with cerebrovascular damage; and 3) is positively associated with the interaction between cardiovascular risk scores and early amyloid-β burden, which may reflect a vascular compensatory response of CBF to early amyloid-β accumulation. These findings encourage future studies to account for multiple interactions with CBF in disease trajectory analyses.
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.
Abstract
Background
Little is known about the genetic factors and downstream molecular pathways determining individual variability in fluid and imaging biomarkers associated with Alzheimer’s ...disease(AD). We studied polygenic risk scores (PRS) and pathway‐specific PRS in relationship with AD fluid and imaging biomarkers, in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort.
Method
EPAD inclusion criteria were age>50 and Clinical Dementia Rating≤0.5 (n = 1886,
Table 1
). AD‐PRS was based on 85 previously identified loci, including and excluding APOE (PRS
APOE
, PRS
noAPOE
)1. Using gene‐variant and variant‐pathway mapping2, six pathway‐specific PRSnoAPOE were identified:1) immune‐activation, 2) signal‐transduction, 3) inflammatory‐response, 4) migration, 5) amyloid‐production, and 6) clearance. Linear models were used to assess the relationship of all PRS with fluid AD biomarkers, including Aβ1‐42, p‐Tau181, and t‐tau; and several imaging biomarkers, including hippocampal volume, global and lobar white matter hyperintensities (WMH) volumes, fractional anisotropy (FA) in 14 regions of interest from diffusion tensor imaging, and 10 resting‐state network connectivity from functional MRI. Models were adjusted for age, sex, site, and multiple comparisons.
Result
Models’ coefficients are reported in
Table 2
. PRSAPOE was significantly associated with decreased Aβ1‐42, and increased p‐Tau181 and t‐Tau. PRS
noAPOE
showed a weaker, but still significant, negative association with Aβ1‐42 levels, and a significant positive association with p‐Tau181 and t‐Tau. Aβ1‐42 was only significantly associated with the migration, amyloid, and clearance pathways, while all pathways were significantly positively associated with p‐Tau181 and t‐Tau.
Hippocampal volume was only significantly associated with PRS
APOE
. Regarding WMH load, PRS
APOE
showed a positive association with global, frontal periventricular, and parietal deep lobes. Furthermore, the clearance pathway was related to WMH load in all regions, most strongly in periventricular areas.
Only the migration pathway was related to increases in FA in the splenium, body, and genu of the corpus callosum. Only the PRS
APOE
was related to reduced functional connectivity (FC) in the default mode, control, and visual networks.
Conclusion
We show that genetic risk beyond APOE facilitates the manifestation of AD related pathologies. Moreover, clearance and migration pathways were associated with neuroimaging measures of white matter integrity, while FC and hippocampal volume were associated with overall AD genetic risk.
Background
The role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.
Method
We ...included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aβ1‐42; CSVD indices (visual assessment for perivascular spaces PVS in the basal ganglia BG and centrum‐semiovale CS, periventricular and deep white matter hyperintensities WMHs, presence of lobar or deep cerebral microbleeds CMBs, and lacunes, and quantification of global and lobar WMH volumes) and Aβ1‐42 and p‐Tau181, including an interaction between CSVD indices and Aβ1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.
Result
Higher FRS scores were associated with lower CSF Aβ1‐42 (β = ‐0.18; p<0.001) and higher P‐tau181 (β = 0.21; p<0.001). Aβ1‐42 was negatively associated with all CSVD markers (all p<0.001; Figure‐2).
We found stronger association between Aβ1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction<0.005) scores, and higher regional WMH (all p‐interactions<0.005) volumes.
Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aβ1‐42 (indirect effect: β = ‐0.03; p<0.001). Aβ1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aβ1‐42 on P‐tau181 levels (β = ‐0.14; p<0.001) and HCV (β = 0.06; p<0.05), and of P‐tau181 levels onto HCV (β = ‐0.05; p<0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: β = 0.36; p < 0.05) and HCV (indirect effect: β = ‐0.24; p < 0.05) through Aβ1‐42 was observed.
Conclusion
Expression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.
Background
The role of cardiovascular risk factors and cerebral small vessel disease (CSVD) on the sequences of Alzheimer’s Disease (AD) pathological events remains to be determined.
Method
We ...included 1592 non‐demented participants from EPAD‐LCS (Table‐1). Linear models were used to study associations between the Framingham score (FRS) and CSF‐Aß1‐42; CSVD indices (visual assessment for perivascular spaces PVS in the basal ganglia BG and centrum‐semiovale CS, periventricular and deep white matter hyperintensities WMHs, presence of lobar or deep cerebral microbleeds CMBs, and lacunes, and quantification of global and lobar WMH volumes) and Aß1‐42 and p‐Tau181, including an interaction between CSVD indices and Aß1‐42 for the latter. Hippocampal volumes (HCV) were quantified using LEAP. Structural equation models (SEM) were used to assess the association between clinical variables as described in Figure‐1. Models were corrected for age, sex, site and multiple comparisons.
Result
Higher FRS scores were associated with lower CSF Aß1‐42 (ß = ‐0.18; p<0.001) and higher P‐tau181 (ß = 0.21; p<0.001). Aß1‐42 was negatively associated with all CSVD markers (all p<0.001; Figure‐2). We found stronger association between Aß1‐42 and P‐tau181 in participants with higher Fazekas deep and periventricular (p‐interaction<0.005) scores, and higher regional WMH (all p‐interactions<0.005) volumes. Using SEM, the CSVD‐burden latent factor fully mediated the association between FRS and Aß1‐42 (indirect effect: ß = ‐0.03; p<0.001). Aß1‐42 did not significantly predict the CSVD‐burden latent factor. We observed a significant direct effect of Aß1‐42 on P‐tau181 levels (ß = ‐0.14; p<0.001) and HCV (ß = 0.06; p<0.05), and of P‐tau181 levels onto HCV (ß = ‐0.05; p<0.05). A significant indirect, but not direct, effect of the latent factor on both P‐tau181 (indirect effect: ß = 0.36; p < 0.05) and HCV (indirect effect: ß = ‐0.24; p < 0.05) through Aß1‐42 was observed.
Conclusion
Expression of cerebrovascular pathology fully mediates the effects of vascular risk factors on amyloid and accelerates manifestation of downstream biomarkers in the preclinical phases of AD, stressing the importance of vascular‐protective treatments.
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