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Andrew D. MacKinnon

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4 papers

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YNICL Journal 2019 Journal Article

Corrigendum to “Diffusion tensor image segmentation of the cerebrum provides a single measure of cerebral small vessel disease severity related to cognitive change” [Neuroimage: Clinical 16 (2017) 330–342]

Owen A. Williams
Eva A. Zeestraten
Philip Benjamin
Christian Lambert
Andrew J. Lawrence
Andrew D. MacKinnon
Robin G. Morris
Hugh S. Markus

The authors regret that due to a data coding error, cross-sectional effects from linear mixed effects models were stored, presented and interpreted as longitudinal effects (i.e. interactions with the time variable). As a result, the results presented in Tables 5 and 6 [Table presented] do not represent the associations between change in MRI markers and change in executive function (EF) and information processing speed (IPS) but show the baseline associations. The true longitudinal associations are provided in the corrected Tables 5 and 6. The primary difference in the results is that while change in DSEG θ is significantly associated with change in EF and IPS in univariable analyses, it does not remain significant in the multivariable analyses as previously stated. Furthermore, changes in histogram metrics of FA and MD were not associated to EF and only change in FA NPH was significantly associated with IPS, whereas all four metrics were originally reported to be associated with change in EF and IPS. The changes in the results do effect some of the conclusions in the original article. While DSEG θ is a valid measure of cerebral small vessel disease (SVD) and is associated with change in EF and IPS, we must retract the statement that DSEG θ “provides the strongest predictor of cognitive change” as, in the multivariable models, lacunar infarcts and FA NPH were associated with change in EF and IPS respectively. Nevertheless, DSEG θ provides a marker of SVD severity that is related to changes in cognitive performance. The authors would like to apologize for any inconvenience caused by this error.

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YNICL Journal 2018 Journal Article

Identifying preclinical vascular dementia in symptomatic small vessel disease using MRI

Christian Lambert
Eva Zeestraten
Owen Williams
Philip Benjamin
Andrew J. Lawrence
Robin G. Morris
Andrew D. MacKinnon
Thomas R. Barrick

Sporadic cerebral small vessel disease is an important cause of vascular dementia, a syndrome of cognitive impairment together with vascular brain damage. At post-mortem pure vascular dementia is rare, with evidence of co-existing Alzheimer's disease pathology in 95% of cases. This work used MRI to characterize structural abnormalities during the preclinical phase of vascular dementia in symptomatic small vessel disease. 121 subjects were recruited into the St George's Cognition and Neuroimaging in Stroke study and followed up longitudinally for five years. Over this period 22 individuals converted to dementia. Using voxel-based morphometry, we found structural abnormalities present at baseline in those with preclinical dementia, with reduced grey matter density in the left striatum and hippocampus, and more white matter hyperintensities in the frontal white-matter. The lacunar data revealed that some of these abnormalities may be due to lesions within the striatum and centrum semiovale. Using support vector machines, future dementia could be best predicted using hippocampal and striatal Jacobian determinant data, achieving a balanced classification accuracy of 73%. Using cluster ward linkage we identified four anatomical subtypes. Successful predictions were restricted to groups with lower levels of vascular damage. The subgroup that could not be predicted were younger, further from conversion, had the highest levels of vascular damage, with milder cognitive impairment at baseline but more rapid deterioration in processing speed and executive function, consistent with a primary vascular dementia. In contrast, the remaining groups had decreasing levels of vascular damage and increasing memory impairment consistent with progressively more Alzheimer's-like pathology. Voxel-wise rates of hippocampal atrophy supported these distinctions, with the vascular group closely resembling the non-dementing cohort, whereas the Alzheimer's like group demonstrated global hippocampal atrophy. This work reveals distinct anatomical endophenotypes in preclinical vascular dementia, forming a spectrum between vascular and Alzheimer's like pathology. The latter group can be identified using baseline MRI, with 73% converting within 5 years. It was not possible to predict the vascular dominant dementia subgroup, however 19% of negative predictions with high levels of vascular disease would ultimately develop dementia. It may be that techniques more sensitive to white matter damage, such as diffusion weighted imaging, may prove more useful for this vascular dominant subgroup in the future. This work provides a way to accurately stratify patients using a baseline MRI scan, and has utility in future clinical trials designed to slow or prevent the onset of dementia in these high-risk cohorts.

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YNICL Journal 2017 Journal Article

Diffusion tensor image segmentation of the cerebrum provides a single measure of cerebral small vessel disease severity related to cognitive change

Owen A. Williams
Eva A. Zeestraten
Philip Benjamin
Christian Lambert
Andrew J. Lawrence
Andrew D. MacKinnon
Robin G. Morris
Hugh S. Markus

Cerebral small vessel disease (SVD) is the primary cause of vascular cognitive impairment and is associated with decline in executive function (EF) and information processing speed (IPS). Imaging biomarkers are needed that can monitor and identify individuals at risk of severe cognitive decline. Recently there has been interest in combining several magnetic resonance imaging (MRI) markers of SVD into a unitary score to describe disease severity. Here we apply a diffusion tensor image (DTI) segmentation technique (DSEG) to describe SVD related changes in a single unitary score across the whole cerebrum, to investigate its relationship with cognitive change over a three-year period. 98 patients (aged 43–89) with SVD underwent annual MRI scanning and cognitive testing for up to three years. DSEG provides a vector of 16 discrete segments describing brain microstructure of healthy and/or damaged tissue. By calculating the scalar product of each DSEG vector in reference to that of a healthy ageing control we generate an angular measure (DSEG θ) describing the patients' brain tissue microstructural similarity to a disease free model of a healthy ageing brain. Conventional MRI markers of SVD brain change were also assessed including white matter hyperintensities, cerebral atrophy, incident lacunes, cerebral-microbleeds, and white matter microstructural damage measured by DTI histogram parameters. The impact of brain change on cognition was explored using linear mixed-effects models. Post-hoc sample size analysis was used to assess the viability of DSEG θ as a tool for clinical trials. Changes in brain structure described by DSEG θ were related to change in EF and IPS (p <0. 001) and remained significant in multivariate models including other MRI markers of SVD as well as age, gender and premorbid IQ. Of the conventional markers, presence of new lacunes was the only marker to remain a significant predictor of change in EF and IPS in the multivariate models (p =0. 002). Change in DSEG θ was also related to change in all other MRI markers (p <0. 017), suggesting it may be used as a surrogate marker of SVD damage across the cerebrum. Sample size estimates indicated that fewer patients would be required to detect treatment effects using DSEG θ compared to conventional MRI and DTI markers of SVD severity. DSEG θ is a powerful tool for characterising subtle brain change in SVD that has a negative impact on cognition and remains a significant predictor of cognitive change when other MRI markers of brain change are accounted for. DSEG provides an automatic segmentation of the whole cerebrum that is sensitive to a range of SVD related structural changes and successfully predicts cognitive change. Power analysis shows DSEG θ has potential as a monitoring tool in clinical trials. As such it may provide a marker of SVD severity from a single imaging modality (i. e. DTIs).

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YNICL Journal 2014 Journal Article

Strategic lacunes and their relationship to cognitive impairment in cerebral small vessel disease

Philip Benjamin
Andrew J. Lawrence
Christian Lambert
Bhavini Patel
Ai Wern Chung
Andrew D. MacKinnon
Robin G. Morris
Thomas R. Barrick

OBJECTIVES: Lacunes are an important disease feature of cerebral small vessel disease (SVD) but their relationship to cognitive impairment is not fully understood. To investigate this we determined (1) the relationship between lacune count and total lacune volume with cognition, (2) the spatial distribution of lacunes and the cognitive impact of lacune location, and (3) the whole brain anatomical covariance associated with these strategically located regions of lacune damage. METHODS: One hundred and twenty one patients with symptomatic lacunar stroke and radiological leukoaraiosis were recruited and multimodal MRI and neuropsychological data acquired. Lacunes were mapped semi-automatically and their volume calculated. Lacune location was automatically determined by projection onto atlases, including an atlas which segments the thalamus based on its connectivity to the cortex. Lacune locations were correlated with neuropsychological results. Voxel based morphometry was used to create anatomical covariance maps for these 'strategic' regions. RESULTS: Lacune number and lacune volume were positively associated with worse executive function (number p < 0.001; volume p < 0.001) and processing speed (number p < 0.001; volume p < 0.001). Thalamic lacunes, particularly those in regions with connectivity to the prefrontal cortex, were associated with impaired processing speed (Bonferroni corrected p = 0.016). Regions of associated anatomical covariance included the medial prefrontal, orbitofrontal, anterior insular cortex and the striatum. CONCLUSION: Lacunes are important predictors of cognitive impairment in SVD. We highlight the importance of spatial distribution, particularly of anteromedial thalamic lacunes which are associated with impaired information processing speed and may mediate cognitive impairment via disruption of connectivity to the prefrontal cortex.

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