White matter hyperintensities in Alzheimer's disease: Beyond vascular contribution

Garnier‐Crussard, Antoine; Cotton, François; Krolak‐Salmon, Pierre; Chételat, Gaël

doi:10.1002/alz.13057

Cited by 17 publications

(10 citation statements)

References 69 publications

(155 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been shown that AD patients have more posterior predominant (i.e. parieto-occipital and posterior periventricular) WMH as compared to the normal aging population [ 71 ]. This is why we compared the amount of WMH in the posterior and posterior periventricular regions between AD patients with SEA versus those without to evaluate whether these WMH could potentially contribute to more severe visuospatial deficits in AD patients with SEA.…”

Section: Discussionmentioning

confidence: 99%

Subclinical epileptiform activity in the Alzheimer continuum: association with disease, cognition and detection method

Nous,

Seynaeve,

Feys

et al. 2024

Alz Res Therapy

View full text Add to dashboard Cite

Background Epileptic seizures are an established comorbidity of Alzheimer’s disease (AD). Subclinical epileptiform activity (SEA) as detected by 24-h electroencephalography (EEG) or magneto-encephalography (MEG) has been reported in temporal regions of clinically diagnosed AD patients. Although epileptic activity in AD probably arises in the mesial temporal lobe, electrical activity within this region might not propagate to EEG scalp electrodes and could remain undetected by standard EEG. However, SEA might lead to faster cognitive decline in AD. Aims 1. To estimate the prevalence of SEA and interictal epileptic discharges (IEDs) in a well-defined cohort of participants belonging to the AD continuum, including preclinical AD subjects, as compared with cognitively healthy controls. 2. To evaluate whether long-term-EEG (LTM-EEG), high-density-EEG (hd-EEG) or MEG is superior to detect SEA in AD. 3. To characterise AD patients with SEA based on clinical, neuropsychological and neuroimaging parameters. Methods Subjects (n = 49) belonging to the AD continuum were diagnosed according to the 2011 NIA-AA research criteria, with a high likelihood of underlying AD pathophysiology. Healthy volunteers (n = 24) scored normal on neuropsychological testing and were amyloid negative. None of the participants experienced a seizure before. Subjects underwent LTM-EEG and/or 50-min MEG and/or 50-min hd-EEG to detect IEDs. Results We found an increased prevalence of SEA in AD subjects (31%) as compared to controls (8%) (p = 0.041; Fisher’s exact test), with increasing prevalence over the disease course (50% in dementia, 27% in MCI and 25% in preclinical AD). Although MEG (25%) did not withhold a higher prevalence of SEA in AD as compared to LTM-EEG (19%) and hd-EEG (19%), MEG was significantly superior to detect spikes per 50 min (p = 0.002; Kruskall–Wallis test). AD patients with SEA scored worse on the RBANS visuospatial and attention subset (p = 0.009 and p = 0.05, respectively; Mann–Whitney U test) and had higher left frontal, (left) temporal and (left and right) entorhinal cortex volumes than those without. Conclusion We confirmed that SEA is increased in the AD continuum as compared to controls, with increasing prevalence with AD disease stage. In AD patients, SEA is associated with more severe visuospatial and attention deficits and with increased left frontal, (left) temporal and entorhinal cortex volumes. Trial registration Clinicaltrials.gov, NCT04131491. 12/02/2020.

show abstract

Section: Discussionmentioning

confidence: 99%

Subclinical epileptiform activity in the Alzheimer continuum: association with disease, cognition and detection method

Nous,

Seynaeve,

Feys

et al. 2024

Alz Res Therapy

View full text Add to dashboard Cite

show abstract

“…64 Others argue that WMH are the result of AD-related neurodegeneration, so called Wallerian degeneration. 65,66 We have argued against some of these pathways on the basis of temporality, experimental evidence, and anatomical distribution. 67 The results of this study provide further evidence against these possibilities.…”

Section: Discussionmentioning

confidence: 99%

Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome

Edwards,

Lao,

Alshikho

et al. 2023

Preprint

View full text Add to dashboard Cite

ImportanceBy age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer’s disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hypothesized to be mediated by inflammatory factors.ObjectiveTo examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS.DesignCross sectional analysis of neuroimaging, plasma, and clinical data.SettingParticipants were enrolled in Alzheimer’s Biomarker Consortium – Down Syndrome (ABC-DS), a multisite study of AD in adults with DS.ParticipantsOne hundred eighty-five participants (mean [SD] age=45.2 [9.3] years) with available MRI and plasma biomarker data were included. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI scans and plasma biomarker concentrations of amyloid beta (Aβ42/Aβ40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays.Main Outcomes and MeasuresWe examined the bivariate relationships of WMH, Aβ42/Aβ40, p-tau217, and GFAP with age-residualized NfL across AD diagnostic groups. A series of mediation and path analyses examined causal pathways linking WMH and AD pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis.ResultsThere was a direct and indirect bidirectional effect through GFAP of WMH on p-tau217 concentration, which was associated with NfL concentration in the entire sample. Among cognitively stable participants, WMH was directly and indirectly, through GFAP, associated with p-tau217 concentration, and in those with MCI, there was a direct effect of WMH on p-tau217 and NfL concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia.Conclusions and RelevanceThe findings suggest that among individuals with DS, CVD promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of AD. This work joins an emerging literature that implicates CVD and its interface with neuroinflammation as a core pathological feature of AD in adults with DS.Key PointsQuestionDo white matter hyperintensities, a magnetic resonance imaging marker of small vessel cerebrovascular disease, predict plasma Alzheimer’s biomarker concentrations of amyloid, tau, and neuroinflammatory pathophysiology and downstream neurodegeneration in adults with Down syndrome?FindingsIncreases in white matter hyperintensity volume precede and promote inflammation- and tau-related pathophysiology, directly and indirectly, leading to downstream neurodegeneration.MeaningSmall vessel cerebrovascular disease may contribute to the pathophysiological progression of Alzheimer’s disease in adults with Down syndrome. These findings support the hypothesis that cerebrovascular disease is a core feature of Alzheimer’s disease in adults with Down syndrome.

show abstract

“…Nevertheless, our findings confirmed the robustness of the connectivity pattern of WMH (of presumed vascular origin) to the cortex across different tractography methods and populations. However, it is worth noting that WMH resulting from other pathologies, such as in multiple sclerosis or Alzheimer’s disease, may have different connectivity patterns, 52 , 53 which requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Regional cortical thinning, demyelination and iron loss in cerebral small vessel disease

Jacob

Cai

et al. 2023

Brain

View full text Add to dashboard Cite

The link between white matter hyperintensities (WMH) and cortical thinning is thought to be an important pathway by which WMH contributes to cognitive deficits in cerebral small vessel disease (SVD). However, the mechanism behind this association and the underlying tissue composition abnormalities are unclear. The objective of this study is to determine the association between WMH and cortical thickness, and the in-vivo tissue composition abnormalities in the WMH-connected cortical regions. In this cross-sectional study, we included 213 participants with SVD who underwent standardized protocol including multimodal neuroimaging scans and cognitive assessment (i.e., processing speed, executive function, and memory). We identified the cortex connected to WMH using probabilistic tractography starting from the WMH and defined the WMH-connected regions at three connectivity levels (low, medium, and high connectivity level). We calculated the cortical thickness, myelin and iron of the cortex based on T1-weighted, quantitative R1, R2*, and susceptibility maps. We used diffusion-weighted imaging to estimate the mean diffusivity (MD) of the connecting white matter tracts. We found that cortical thickness, R1, R2*, and susceptibility values in the WMH-connected regions were significantly lower than in the WMH-unconnected regions (all p-corrected<0.001). Linear regression analyses showed that higher MD of the connecting white matter tracts were related to lower thickness (β=-0.30, p-corrected<0.001), R1 (β=-0.26, p-corrected=0.001), R2* (β=-0.32, p-corrected<0.001) and susceptibility values (β=-0.39, p-corrected<0.001) of WMH-connected cortical regions at high connectivity level. In addition, lower scores on processing speed were significantly related to lower cortical thickness (β=0.20, p-corrected=0.030), lower R1 values (β=0.20, p-corrected=0.006), lower R2* values (β=0.29, p-corrected=0.006), and lower susceptibility values (β=0.19, p-corrected=0.024) of the WMH-connected regions at high connectivity level, independent of WMH volumes and the cortical measures of WMH-unconnected regions. Together, our study demonstrated that the microstructural integrity of white matter tracts passing through WMH is related to the regional cortical abnormalities as measured by thickness, R1, R2* and susceptibility values in the connected cortical regions. These findings are indicative of cortical thinning, demyelination and iron loss in the cortex, which is most likely through the disruption of the connecting white matter tracts and may contribute to processing speed impairment in SVD, a key clinical feature of SVD. These findings may have implications for finding intervention targets for the treatment of cognitive impairment in SVD by preventing secondary degeneration.

show abstract

White matter hyperintensities in Alzheimer's disease: Beyond vascular contribution

Cited by 17 publications

References 69 publications

Subclinical epileptiform activity in the Alzheimer continuum: association with disease, cognition and detection method

Subclinical epileptiform activity in the Alzheimer continuum: association with disease, cognition and detection method

Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome

Regional cortical thinning, demyelination and iron loss in cerebral small vessel disease

Contact Info

Product

Resources

About