White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: A meta‐analysis, systematic review, and recommendations for future study harmonization

Roseborough, Austyn D.; Saad, Lorenzo; Goodman, Maren; Cipriano, Lauren E.; Hachinski, Vladimir; Whitehead, Shawn N.

doi:10.1002/alz.12642

Cited by 35 publications

(31 citation statements)

References 152 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cognitive difficulties present in patients with SCA have been reported to worsen with age. In the general population, white matter hyperintensities appear to be associated with longitudinal intellectual decline, particularly in those with mild cognitive impairment and stroke ( 65 ). Autopsy data are consistent with an effect on myelin secondary to arteriosclerosis and ischemia ( 66 ), associated with decline in perceptual speed, with some evidence of amyloid-β accumulation eventually ( 67 ).…”

Section: Discussionmentioning

confidence: 99%

Quantitative susceptibility mapping (QSM) and R2* of silent cerebral infarcts in sickle cell anemia

et al. 2022

View full text Add to dashboard Cite

Silent cerebral infarction (SCI) is the most commonly reported radiological abnormality in patients with sickle cell anemia (SCA) and is associated with future clinical stroke risk. To date, there have been few histological and quantitative MRI studies of SCI and multiple radiological definitions exist. As a result, the tissue characteristics and composition of SCI remain elusive. The objective of this work was therefore to investigate the composition of segmented SCI lesions using quantitative MRI for R2* and quantitative magnetic susceptibility mapping (QSM). 211 SCI lesions were segmented from 32 participants with SCA and 6 controls. SCI were segmented according to two definitions (FLAIR+/–T1w-based threshold) using a semi-automated pipeline. Magnetic susceptibility (χ) and R2* maps were calculated from a multi-echo gradient echo sequence and mean SCI values were compared to an equivalent region of interest in normal appearing white matter (NAWM). SCI χ and R2* were investigated as a function of SCI definition, patient demographics, anatomical location, and cognition. Compared to NAWM, SCI were significantly less diamagnetic (χ = –0.0067 ppm vs. –0.0153 ppm, p < 0.001) and had significantly lower R2* (16.7 s−1 vs. 19.2 s−1, p < 0.001). SCI definition had a significant effect on the mean SCI χ and R2*, with lesions becoming significantly less diamagnetic and having significantly lower R2* after the application of a more stringent T1w-based threshold. SCI-NAWM R2* decrease was significantly greater in patients with SCA compared with controls (–2.84 s−1 vs. –0.64 s−1, p < 0.0001). No significant association was observed between mean SCI–NAWM χ or R2* differences and subject age, lesion anatomical location, or cognition. The increased χ and decreased R2* in SCI relative to NAWM observed in both patients and controls is indicative of lower myelin or increased water content within the segmented lesions. The significant SCI–NAWM R2* differences observed between SCI in patients with SCA and controls suggests there may be differences in tissue composition relative to NAWM in SCI in the two populations. Quantitative MRI techniques such as QSM and R2* mapping can be used to enhance our understanding of the pathophysiology and composition of SCI in patients with SCA as well as controls.

show abstract

Section: Discussionmentioning

confidence: 99%

Quantitative susceptibility mapping (QSM) and R2* of silent cerebral infarcts in sickle cell anemia

et al. 2022

View full text Add to dashboard Cite

show abstract

“…WMH can negatively impact on executive, memory and global cognitive function, but associations with memory function have been less consistent compared to associations with executive function (for review see 35 ). We found rather equally strong relationships between executive or memory performance, respectively, and WMH in widespread regions comprising temporal, parietal and occipital lobes, corpus callosum and several white matter tracts ( eTable 1 ).…”

Section: Discussionmentioning

confidence: 99%

“…WMH can negatively impact cognitive function, but associations with memory have been less consistent compared to associations with executive function (for review see [48]). With the exception of the external capsule, we found rather substantial evidence for associations between WMH and worse cognitive performance, likewise affecting memory and executive function, and outcomes ( Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

Arterial hypertension and β-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity volume: A cross-sectional study

Bernal

Schreiber

Ostendorf

et al. 2022

Preprint

View full text Add to dashboard Cite

ImportancePosterior white matter hyperintensities (WMH) in subjects across the Alzheimer’s disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology —not just arterial hypertension— impacts WMH, adversely influencing cognition.ObjectiveTo characterise the effects of AD pathology, namely β-amyloid (Aβ) and hypertension on WMH and cognition.DesignCross-sectional and longitudinalSettingMulticentreParticipantsWe analysed data from subjects with normal cognition (NC), subjective cognitive decline (SCD), and mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study. We focused on participants with available magnetic resonance imaging (MRI), cerebrospinal fluid biomarkers, and cognitive and hypertension information. We conducted analyses between 02.2022 and 06.2022.Intervention(s) (for clinical trials) or Exposure(s) (for observational studies)NAMain Outcomes and MeasuresSpatial distribution and volume of MRI WMH in relation to Aß42/40 levels and arterial hypertension. Mediation of the relationship between Aβ positivity and hypertension on cognition by the regional WMH volume.ResultsWe included 355 participants (median age 70.3 [IQR 66.0-74.4] years; 168 female; 121 NC, 154 SCD, 80 MCI). Hypertension and Aβ positivity were positively associated (pFTR<0.05) with WMH volume, with large spatial overlap in the occipital lobes (regression coefficient ± standard error; hypertension: 0.49±0.14; Aβ: 0.41±0.15), parietal lobes (hypertension: 0.62±0.23; Aβ: 0.61±0.24), corona radiata (hypertension: 0.55±0.19; Aβ: 0.61±0.24), optic radiation (hypertension: 0.64±0.19; Aβ: 0.50±0.20) and splenium (hypertension: 0.38±0.13; Aβ: 0.39±0.13). Global and occipital WMH volumes were strongly associated cognitive changes over a three-year period, estimated with preclinical Alzheimer’s cognitive composite 5 (PACC5) (global: 2.18±0.61, pFDR<0.01; occipital: 3.31±0.75, pFDR<0.01), regardless of Aβ and hypertension status. The association between Aβ positivity and baseline cognitive performance (direct-memory: -0.42±0.08, pFDR<0.01; executive: - 0.28±0.28, pFDR<0.01) was partially mediated by WMH in the corona radiata (indirect-memory: -0.04±0.02, pFDR<0.05; executive: -0.04±0.02, pFDR<0.01) and splenium (indirect-memory: -0.02±0.02, pFDR<0.01; executive: -0.04±0.02, pFDR<0.01). Evidence supporting hypertension affected cognition was insufficient (direct-memory: 0.03±0.07, pFDR=0.683; executive: -0.05±0.07, pFDR=0.499; PACC5 change: 0.01±0.02, pFDR =0.588).Conclusions and RelevancePosterior white matter is susceptible to vascular disease and Aβ accumulation. Its deterioration is involved in the association between Aβ and cognitive dysfunction. Posterior WMH could be a promising target to tackle the downstream damage related to the interacting and potentiating effect of these two pathologies.Trial RegistrationGerman Clinical Trials Register (DRKS00007966, 04/05/2015)Key PointsQuestionIs the spatial distribution and volume of cerebral white matter hyperintensities (WMH) related to arterial hypertension, amyloid pathology, and cognition?FindingsIn this cross-sectional and longitudinal cohort study, WMH increased with hypertension and amyloid, with a spatial overlap in occipital and parietal lobes. Amyloid is involved in the relationship between WMH in corona radiata and splenium on cognitive performance. Global, occipital, and frontal WMH were strongly associated cognitive performance and worsening, regardless of hypertension and amyloid status.MeaningPosterior white matter is susceptible to vascular disease and amyloid pathology; its damage plays a role in the effect of amyloid pathology on cognition.

show abstract

“…With these advances will come more detailed insights into the etiopathogenetic origin and neurobehavioral sequelae of white matter damage, and exciting new therapeutic ideas. Among the most promising, but far from exclusive, avenues of study are vascular ( 28 , 85 , 115 ), traumatic ( 64 – 66 ), and inflammatory ( 54 , 116 ) mechanisms, as these processes all impact white matter and can affect humans throughout the lifespan. As investigators pursue better understanding of these and other areas, clinicians will need to consider a host of related questions, including the making of an accurate diagnosis and determining what interventions are indicated, at what age, and at what stage of the disorder or its precursor stage.…”

Section: Future Directionsmentioning

confidence: 99%

White matter dementia then… and now

Filley

2022

Front. Neurol.

View full text Add to dashboard Cite

White matter dementia (WMD) is a concept introduced in 1988 to highlight the importance of white matter pathology in producing cognitive dysfunction and dementia. Whereas gray matter, particularly the cerebral cortex, has been primarily investigated in the dementias, subcortical pathology has long been correlated with cognitive loss, and a corticocentric perspective cannot account for the full range of neurobehavioral disorders. Within the subcortical regions, white matter is prominent, accounting for about half the volume of the adult brain, and many white matter diseases, injuries, and intoxications can produce cognitive dysfunction so severe as to justify the term dementia. Recognition of this novel syndrome relied heavily on the introduction of magnetic resonance imaging (MRI) that permitted in vivo visualization of white matter lesions. Neuropsychological studies clarified the clinical presentation of WMD by identifying a profile dominated by cognitive slowing and executive dysfunction, and a precursor syndrome of mild cognitive dysfunction was proposed to identify early cognitive impairment that may later evolve to WMD. As knowledge advanced, the role of white matter in structural connectivity within distributed neural networks was elucidated. In addition, highlighting the frequent commingling of gray and white matter involvement, white matter pathology was associated with neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy, with potentially transformative clinical implications. In particular, preventive measures and treatments exploiting white matter restoration and plasticity are gaining much attention. Today, WMD has matured into a concept that not only integrates knowledge from across the spectrum of clinical neuroscience, but also informs new investigations into many perplexing disorders and enables a more complete understanding of brain-behavior relationships.

show abstract

White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: A meta‐analysis, systematic review, and recommendations for future study harmonization

Cited by 35 publications

References 152 publications

Quantitative susceptibility mapping (QSM) and R2* of silent cerebral infarcts in sickle cell anemia

Quantitative susceptibility mapping (QSM) and R2* of silent cerebral infarcts in sickle cell anemia

Arterial hypertension and β-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity volume: A cross-sectional study

White matter dementia then… and now

Contact Info

Product

Resources

About