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

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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Metabolic syndrome impact on cognitive composites domain scores and on white matter hyperintensities in subjective cognitive decline: The FACEHBI Cohort

Alzheimer s & Dementia ◽

10.1002/alz.051324 ◽

2021 ◽

Vol 17 (S6) ◽

Author(s):

Gemma Ortega ◽

Ana Espinosa ◽

Montserrat Alegret ◽

Gemma Monté‐Rubio ◽

Oscar Sotolongo‐Grau ◽

...

Keyword(s):

Metabolic Syndrome ◽

White Matter ◽

Cognitive Decline ◽

White Matter Hyperintensities ◽

Subjective Cognitive Decline ◽

Domain Scores

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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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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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Evidence of a Relation Between Hippocampal Volume, White Matter Hyperintensities, and Cognition in Subjective Cognitive Decline and Mild Cognitive Impairment

The Journals of Gerontology Series B ◽

10.1093/geronb/gbz120 ◽

2019 ◽

Vol 75 (7) ◽

pp. 1382-1392 ◽

Cited By ~ 4

Author(s):

Marie Caillaud ◽

Carol Hudon ◽

Benjamin Boller ◽

Simona Brambati ◽

Simon Duchesne ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

White Matter ◽

Episodic Memory ◽

Cognitive Decline ◽

White Matter Hyperintensities ◽

Hippocampal Volume ◽

Subjective Cognitive Decline

Abstract Objective The concepts of mild cognitive impairment (MCI) and subjective cognitive decline (SCD) have been proposed to identify individuals in the early stages of Alzheimer’s disease (AD), or other neurodegenerative diseases. One approach to validate these concepts is to investigate the relationship between pathological brain markers and cognition in those individuals. Method We included 126 participants from the Consortium for the Early Identification of Alzheimer’s disease-Quebec (CIMA-Q) cohort (67 SCD, 29 MCI, and 30 cognitively healthy controls [CH]). All participants underwent a complete cognitive assessment and structural magnetic resonance imaging. Group comparisons were done using cognitive data, and then correlated with hippocampal volumes and white matter hyperintensities (WMHs). Results Significant differences were found between participants with MCI and CH on episodic and executive tasks, but no differences were found when comparing SCD and CH. Scores on episodic memory tests correlated with hippocampal volumes in both MCI and SCD, whereas performance on executive tests correlated with WMH in all of our groups. Discussion As expected, the SCD group was shown to be cognitively healthy on tasks where MCI participants showed impairment. However, SCD’s hippocampal volume related to episodic memory performances, and WMH to executive functions. Thus, SCD represents a valid research concept and should be used, alongside MCI, to better understand the preclinical/prodromal phase of AD.

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White Matter Integrity Underlies the Physical-Cognitive Correlations in Subjective Cognitive Decline

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.700764 ◽

2021 ◽

Vol 13 ◽

Author(s):

Yi-Chia Wei ◽

Chih-Chin Heather Hsu ◽

Wen-Yi Huang ◽

Yao-Liang Chen ◽

Chemin Lin ◽

...

Keyword(s):

Physical Activity ◽

Older Adults ◽

White Matter ◽

Cognitive Decline ◽

Cognitive Performance ◽

Physical Inactivity ◽

Subjective Cognitive Decline ◽

Cognitively Normal ◽

Corona Radiata ◽

Moca Score

Objective: Although previous studies postulated that physical and cognitive decline codeveloped in preclinical dementia, the interconnected relationship among subjective cognitive complaints (SCCs), objective cognitive performance, and physical activity remained hazy. We investigated the mediating roles of physical activity between subjective and objective cognition. Diffusion tensor imaging (DTI) was utilized to test our hypothesis that brain white matter microstructural changes underlie the physical-cognitive decline in subjective cognitive decline (SCD).Methods: We enrolled cognitively normal older adults aged > 50 years in the Community Medicine Research Center of Keelung Chang Gung Memorial Hospital during 2017–2020. Regression models analyzed mediation effects of physical activity between subjective and objective cognition. The self-reported AD8 questionnaire assessed SCCs. The SCD group, defined by AD8 score ≥ 2, further underwent diffusion MRI scans. Those who agreed to record actigraphy also wore the SOMNOwatch™ for 72 h. Spearman's correlation coefficients evaluated the associations of diffusion indices with physical activity and cognitive performance.Results: In 95 cognitively normal older adults, the AD8 score and the Montreal Cognitive Assessment (MoCA) score were mediated partially by the metabolic equivalent of the International Physical Activity Questionnaire-Short Form (IPAQ-SF MET) and fully by the sarcopenia score SARC-F. That is, the relation between SCCs and poorer cognitive performance was mediated by physical inactivity. The DTI analysis of 31 SCD participants found that the MoCA score correlated with mean diffusivity at bilateral inferior cerebellar peduncles and the pyramids segment of right corticospinal tract [p < 0.05, false discovery rate (FDR) corrected]. The IPAQ-SF MET was associated with fractional anisotropy (FA) at the right posterior corona radiata (PCR) (p < 0.05, FDR corrected). In 15 SCD participants who completed actigraphy recording, the patterns of physical activity in terms of intradaily variability and interdaily stability highly correlated with FA of bilateral PCR and left superior corona radiata (p < 0.05, FDR corrected).Conclusions: This study addressed the role of physical activity in preclinical dementia. Physical inactivity mediated the relation between higher SCCs and poorer cognitive performance. The degeneration of specific white matter tracts underlay the co-development process of physical-cognitive decline in SCD.

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White Matter Hyperintensities Relate to Clinical Progression in Subjective Cognitive Decline

Stroke ◽

10.1161/strokeaha.115.009475 ◽

2015 ◽

Vol 46 (9) ◽

pp. 2661-2664 ◽

Cited By ~ 39

Author(s):

Marije R. Benedictus ◽

Argonde C. van Harten ◽

Annebet E. Leeuwis ◽

Teddy Koene ◽

Philip Scheltens ◽

...

Keyword(s):

White Matter ◽

Cognitive Decline ◽

White Matter Hyperintensities ◽

Subjective Cognitive Decline ◽

Clinical Progression

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

PLoS ONE ◽

10.1371/journal.pone.0242696 ◽

2020 ◽

Vol 15 (11) ◽

pp. e0242696

Author(s):

Manon Edde ◽

Guillaume Theaud ◽

François Rheault ◽

Bixente Dilharreguy ◽

Catherine Helmer ◽

...

Keyword(s):

White Matter ◽

Cognitive Decline ◽

Verbal Fluency ◽

White Matter Hyperintensities ◽

Free Water ◽

Partial Volume ◽

Cingulum Bundle ◽

Partial Volume Effects ◽

Age Related ◽

Water Elimination

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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Arterial Stiffness Is Associated with White Matter Disruption and Cognitive Impairment: A Community-Based Cohort Study

Journal of Alzheimer s Disease ◽

10.3233/jad-201424 ◽

2021 ◽

Vol 80 (2) ◽

pp. 567-576

Author(s):

Fei Han ◽

Fei-Fei Zhai ◽

Ming-Li Li ◽

Li-Xin Zhou ◽

Jun Ni ◽

...

Keyword(s):

Cognitive Function ◽

White Matter ◽

Arterial Stiffness ◽

Cognitive Decline ◽

Sex Education ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

White Matter Injury ◽

White Matter Integrity ◽

Cross Sectional

Background: Mechanisms through which arterial stiffness impacts cognitive function are crucial for devising better strategies to prevent cognitive decline. Objective: To examine the associations of arterial stiffness with white matter integrity and cognition in community dwellings, and to investigate whether white matter injury was the intermediate of the associations between arterial stiffness and cognition. Methods: This study was a cross-sectional analysis on 952 subjects (aged 55.5±9.1 years) who underwent diffusion tensor imaging and measurement of brachial-ankle pulse wave velocity (baPWV). Both linear regression and tract-based spatial statistics were used to investigate the association between baPWV and white matter integrity. The association between baPWV and global cognitive function, measured as the mini-mental state examination (MMSE) was evaluated. Mediation analysis was performed to assess the influence of white matter integrity on the association of baPWV with MMSE. Results: Increased baPWV was significantly associated with lower mean global fractional anisotropy (β= –0.118, p < 0.001), higher mean diffusivity (β= 0.161, p < 0.001), axial diffusivity (β= 0.160, p < 0.001), and radial diffusivity (β= 0.147, p < 0.001) after adjustment of age, sex, and hypertension, which were measures having a direct effect on arterial stiffness and white matter integrity. After adjustment of age, sex, education, apolipoprotein E ɛ4, cardiovascular risk factors, and brain atrophy, we found an association of increased baPWV with worse performance on MMSE (β= –0.093, p = 0.011). White matter disruption partially mediated the effect of baPWV on MMSE. Conclusion: Arterial stiffness is associated with white matter disruption and cognitive decline. Reduced white matter integrity partially explained the effect of arterial stiffness on cognition.

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Optimizing Subjective Cognitive Decline to Detect Early Cognitive Dysfunction

Journal of Alzheimer s Disease ◽

10.3233/jad-201322 ◽

2021 ◽

Vol 80 (3) ◽

pp. 1185-1196

Author(s):

Silvia Chapman ◽

Preeti Sunderaraman ◽

Jillian L. Joyce ◽

Martina Azar ◽

Leigh E. Colvin ◽

...

Keyword(s):

Cognitive Decline ◽

Cognitive Dysfunction ◽

Associative Memory ◽

Short Term Memory ◽

Subjective Cognitive Decline ◽

Short Term ◽

Term Memory ◽

Memory Binding ◽

Preclinical Ad ◽

List Learning

Background: The utility of subjective cognitive decline (SCD) as an indicator of preclinical AD is overshadowed by its inconsistent association with objective cognition. Objective: This study examines if manipulations of SCD measurement affect its association with early cognitive dysfunction characteristic of preclinical AD. Methods: Cognitively healthy older adults (n = 110) completed SCD questionnaires that elicited complaints in general, compared to 5 years ago (retrospective SCD) and compared to their peers (age-anchored SCD) in binary and Likert scales. Outcome cognitive tasks included an associative memory task (Face-Name Test), a visual short-term memory binding task (STMB test), and a clinical neuropsychological list learning test (Selective Reminder Test). Results: SCD complaints, when compared to age-matched peers (age-anchored SCD) were endorsed less frequently than complaints compared to 5 years ago (retrospective SCD) (p < 0.01). In demographically adjusted regressions, age-anchored ordinal-rated SCD was associated with short term memory binding (β= –0.22, p = 0.040, CI = –0.45, –0.01), associative memory (β= –0.26, p = 0.018, CI = –0.45, –0.06), and list learning (β= –0.31, p = 0.002, CI = –0.51, –0.12). Retrospective and general ordinal-rated SCD was associated with associative memory (β= –0.25, p = 0.012, CI = –0.44, –0.06; β= –0.29, p = 0.003, CI = –0.47, –0.10) and list learning only (β= –0.25, p = 0.014, CI = –0.45, –0.05; β= –0.28, p = 0.004, CI = –0.48, –0.09). Conclusion: Ordinal age-anchored SCD appears better suited than other SCD measurements to detect early cognitive dysfunction characteristic of preclinical AD.

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