Free water: A marker of age-related modifications of the cingulum white matter and its association with cognitive decline

Diffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination increased the ability of conventional DTI measures to detect associations between tissue diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content and mean diffusivity measured along the cingulum were independently associated with changes in verbal fluency. This suggests that both tissue modifications and an increase in interstitial isotropic water would contribute to cognitive decline. These observations reinforce the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.

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Diffusion MRI free water is a sensitive marker of age-related changes in the cingulum

10.1101/867606 ◽

2019 ◽

Author(s):

Manon Edde ◽

Guillaume Theaud ◽

François Rheault ◽

Bixente Dilharreguy ◽

Catherine Helmer ◽

...

Keyword(s):

White Matter ◽

Verbal Fluency ◽

Diffusion Mri ◽

White Matter Hyperintensities ◽

Free Water ◽

Partial Volume ◽

Cingulum Bundle ◽

Partial Volume Effects ◽

Age Related ◽

Water Elimination

AbstractDiffusion MRI is extensively used to investigate changes in white matter microstructure. However, diffusion measures within white matter tissue can be affected by partial volume effects due to cerebrospinal fluid and white matter hyperintensities, especially in the aging brain. In previous aging studies, the cingulum bundle that plays a central role in the architecture of the brain networks supporting cognitive functions has been associated with cognitive deficits. However, most of these studies did not consider the partial volume effects on diffusion measures. The aim of this study was to evaluate the effect of free water elimination on diffusion measures of the cingulum in a group of 68 healthy elderly individuals. We first determined the effect of free water elimination on conventional DTI measures and then examined the effect of free water elimination on verbal fluency performance over 12 years. The cingulum bundle was reconstructed with a tractography pipeline including a white matter hyperintensities mask to limit the negative impact of hyperintensities on fiber tracking algorithms. We observed that free water elimination improved the sensitivity of conventional DTI measures to detect associations between tissue-specific diffusion measures of the cingulum and changes in verbal fluency in older individuals. Moreover, free water content measured along the cingulum was independently strongly associated with changes in verbal fluency. These observations suggest the importance of using free water elimination when studying brain aging and indicate that free water itself could be a relevant marker for age-related cingulum white matter modifications and cognitive decline.

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083 Response to immunosuppressive therapy in cerebral amyloid angiopathy-related inflammation

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-anzan.82 ◽

2018 ◽

Vol 89 (6) ◽

pp. A33.3-A34

Author(s):

Jasmin Tilling ◽

Benjamin Trewin ◽

Stanley Levy

Keyword(s):

White Matter ◽

Cognitive Decline ◽

Cerebral Amyloid Angiopathy ◽

White Matter Hyperintensities ◽

Neurological Deficits ◽

Amyloid Angiopathy ◽

Dramatic Improvement ◽

Age Related ◽

Cerebral Amyloid ◽

The Brain

IntroductionCerebral amyloid angiopathy (CAA) is a common age-related condition characterised by amyloid beta-peptide deposition affecting the medium sized cortical and leptomeningeal arteries, arterioles and capillaries. CAA-related Inflammation (CAA-I) is an increasingly recognised variant of CAA, which is thought to be due to perivascular auto-inflammation in response to amyloid deposition. We describe the clinical course of two cases of probable CAA-I.CasesA 71 year old man presented with new-onset seizures, headaches and subacute cognitive decline. MRI of the brain demonstrated confluent subcortical T2 white matter hyperintensities and cerebral oedema, with predominantly superimposed widespread cortico-subcortical micro-haemorrhages, in keeping with the diagnosis of CAA-I. A course of immunosuppresive therapy was commenced with five days of intravenous methylprednisolone, resulting in marked radiological and clinical improvement within two weeks.A 76 year old female presented with subacute cognitive dysfunction and apraxia, and transient left-sided weakness. MRI scan of the brain initially demonstrated a right temporo-occipital infarct, leading to primary treatment for stroke, but subsequently evolved to reveal diffuse multi-lobar T2 white matter hyperintensities with leptomeningeal involvement. A provisional diagnosis of CAA-I was made and following a poor clinical response to a trial of corticosteroid therapy, treatment with intravenous cyclophosphamide was commenced.ConclusionThese cases emphasise the importance of CAA-I as part of the differential diagnosis in patients presenting with symptoms of subacute cognitive decline, seizures, headaches and focal neurological deficits, given the potential for dramatic improvement with readily accessible immunosuppressive therapies.

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T Cells Actively Infiltrate the White Matter of the Aging Monkey Brain in Relation to Increased Microglial Reactivity and Cognitive Decline

Frontiers in Immunology ◽

10.3389/fimmu.2021.607691 ◽

2021 ◽

Vol 12 ◽

Author(s):

Katelyn V. Batterman ◽

Payton E. Cabrera ◽

Tara L. Moore ◽

Douglas L. Rosene

Keyword(s):

T Cells ◽

T Cell ◽

White Matter ◽

Cognitive Decline ◽

Normal Aging ◽

Cell Infiltration ◽

Cingulum Bundle ◽

T Cell Infiltration ◽

Age Related ◽

Related Increase

Normal aging is characterized by declines in processing speed, learning, memory, and executive function even in the absence of neurodegenerative diseases such as Alzheimer's Disease (AD). In normal aging monkeys and humans, neuronal loss does not account for cognitive impairment. Instead, loss of white matter volume and an accumulation of myelin sheath pathology begins in middle age and is associated with cognitive decline. It is unknown what causes this myelin pathology, but it likely involves increased neuroinflammation in white matter and failures in oligodendrocyte function (maturation and repair). In frontal white matter tracts vulnerable to myelin damage, microglia become chronically reactive and secrete harmful pro-inflammatory cytokines. Despite being in a phagocytic state, these microglia are ineffective at phagocytosing accruing myelin debris, which directly inhibits myelin sheath repair. Here, we asked whether reported age-related increases in pro-inflammatory markers were accompanied by an adaptive immune response involving T cells. We quantified T cells with immunohistochemistry in the brains of 34 cognitively characterized monkeys and found an age-related increase in perivascular T cells that surround CNS vasculature. We found a surprising age-related increase in T cells that infiltrate the white matter parenchyma. In the cingulum bundle the percentage of these parenchymal T cells increased with age relative to those in the perivascular space. In contrast, infiltrating T cells were rarely found in surrounding gray matter regions. We assessed whether T cell infiltration correlated with fibrinogen extravasation from the vasculature as a measure of BBB leakiness and found no correlation, suggesting that T cell infiltration is not a result of passive extravasation. Importantly, the density of T cells in the cingulum bundle correlated with microglial reactivity and with cognitive impairment. This is the first demonstration that T cell infiltration of white matter is associated with cognitive decline in the normal aging monkey.

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White matter hyperintensities associated with small vessel disease impair social cognition beside attention and memory

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17719380 ◽

2017 ◽

Vol 38 (6) ◽

pp. 996-1009 ◽

Cited By ~ 16

Author(s):

Jana Kynast ◽

Leonie Lampe ◽

Tobias Luck ◽

Stefan Frisch ◽

Katrin Arelin ◽

...

Keyword(s):

Social Cognition ◽

White Matter ◽

Cognitive Decline ◽

Cognitive Performance ◽

White Matter Hyperintensities ◽

Community Dwelling ◽

Effect Sizes ◽

Attention And Memory ◽

Age Related ◽

The Impact

Age-related white matter hyperintensities (WMH) are a manifestation of white matter damage seen on magnetic resonance imaging (MRI). They are related to vascular risk factors and cognitive impairment. This study investigated the cognitive profile at different stages of WMH in a large community-dwelling sample; 849 subjects aged 21 to 79 years were classified on the 4-stage Fazekas scale according to hyperintense lesions seen on individual T2-weighted fluid-attenuated inversion recovery MRI scans. The evaluation of cognitive functioning included seven domains of cognitive performance and five domains of subjective impairment, as proposed by the DSM-5. For the first time, the impact of age-related WMH on Theory of Mind was investigated. Differences between Fazekas groups were analyzed non-parametrically and effect sizes were computed. Effect sizes revealed a slight overall cognitive decline in Fazekas groups 1 and 2 relative to healthy subjects. Fazekas group 3 presented substantial decline in social cognition, attention and memory, although characterized by a high inter-individual variability. WMH groups reported subjective cognitive decline. We demonstrate that extensive WMH are associated with specific impairment in attention, memory, social cognition, and subjective cognitive performance. The detailed neuropsychological characterization of WMH offers new therapeutic possibilities for those affected by vascular cognitive decline.

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White matter hyperintensities may be an early marker for age-related cognitive decline in the ADNI cohort

10.1101/2021.09.23.461560 ◽

2021 ◽

Author(s):

Cassandra Morrison ◽

Mahsa Dadar ◽

Sylvia Villeneuve ◽

D. Louis Collins

Keyword(s):

White Matter ◽

Cognitive Decline ◽

White Matter Hyperintensities ◽

White Matter Hyperintensity ◽

Subjective Cognitive Decline ◽

Age Related ◽

Lower Baseline ◽

Age Related Cognitive Decline ◽

Linear Regressions

Background: Previous research suggests that white matter hyperintensities, amyloid, and tau contribute to age-related cognitive decline. It remains unknown as to how these factors relate to one another and how they jointly contribute to cognitive decline in normal aging. This project examines the association between these pathologies and their relationship to cognitive decline. Methods: Cognitively normal older adult data from the Alzheimers Disease Neuroimaging Initiative were examined. Participants were included if they had no subjective cognitive decline, had baseline white matter hyperintensity, CSF AB42/40, CSF pTau181, and cognitive scores. Of the 102 participants included, only 79 had follow-up cognitive scores. Linear regressions examined the influence of white matter hyperintensities, amyloid, and tau on baseline and follow-up cognitive scores. Linear regressions also examined the association of amyloid and tau on white matter hyperintensities and between tau and amyloid. Results: Increased white matter hyperintensity load was associated with lower baseline memory (B= -0.20, p =.046), follow-up executive functioning (B= -0.32, p<.001), and follow-up ADAS-13 (B=2.69, p<.001) scores. White matter hyperintensities were not related to pTau or AB42/40. Lower AB42/40 was associated with increased pTau (p=.025). pTau was not associated with decline in any cognitive score. Lower AB42/40 was associated with lower baseline (p=.015) but not follow-up executive function. Discussion: White matter hyperintensities may be one of the earliest pathologies observed in healthy older adults that contribute to cognitive decline. The inclusion of white matter hyperintensities as an additional marker for early cognitive decline may improve our current understanding of age-related changes.

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Combination of white matter hyperintensities and Aβ burden is related to cognitive composites domain scores in subjective cognitive decline: the FACEHBI cohort

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00877-6 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

G. Ortega ◽

A. Espinosa ◽

M. Alegret ◽

GC. Monté-Rubio ◽

O. Sotolongo-Grau ◽

...

Keyword(s):

White Matter ◽

Cognitive Decline ◽

Cognitive Performance ◽

Sex Education ◽

Associative Memory ◽

White Matter Hyperintensities ◽

Domain Score ◽

Subjective Cognitive Decline ◽

Age Related ◽

Domain Scores

Abstract Background To explore whether the combination of white matter hyperintensities (WMHs) and amyloid-beta (Aβ) deposition is associated with worse cognitive performance on cognitive composites (CCs) domain scores in individuals with subjective cognitive decline (SCD). Methods Two hundred participants from the FACEHBI cohort underwent structural magnetic resonance imaging (MRI), 18F-florbetaben positron emission tomography (FBB-PET), and neuropsychological assessment. WMHs were addressed through the Fazekas scale, the Age-Related White Matter Changes (ARWMC) scale, and the FreeSurfer pipeline. Eight CCs domain scores were created using the principal component analysis (PCA). Age, sex, education, and apolipoprotein E (APOE) were used as adjusting variables. Results Adjusted multiple linear regression models showed that FreeSurfer (B − .245; 95% CI − .1.676, − .393, p = .016) and β burden (SUVR) (B − .180; 95% CI − 2.140, − .292; p = .070) were associated with face–name associative memory CCs domain score, although the latest one was not statistically significant after correction for multiple testing (p = .070). There was non-significant interaction of these two factors on this same CCs domain score (p = .54). However, its cumulative effects on face–name associative performance indicated that those individuals with either higher WMH load or higher Aβ burden showed the worst performance on the face–name associative memory CCs domain score. Conclusions Our results suggest that increased WMH load and increased Aβ are independently associated with poorer episodic memory performance in SCD individuals, indicating a cumulative effect of the combination of these two pathological conditions in promoting lower cognitive performance, an aspect that could help in terms of treatment and prevention.

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