Long-term psychological outcomes following stroke: the OX-CHRONIC study.

BACKGROUND: Stroke survivors rate longer-term (> 2 years) psychological recovery as their top priority, but data on how frequently psychological consequences occur is lacking. Prevalence of cognitive impairment, depression/anxiety, fatigue, apathy and related psychological outcomes, and whether rates are stable in long-term stroke, is unknown. METHODS: N = 105 long-term stroke survivors (M [SD] age = 72.92 [13.01]; M [SD] acute NIH Stroke Severity Score = 7.39 [6.25]; 59.0% Male; M [SD] years post-stroke = 4.57 [2.12]) were recruited (potential N = 208). Participants completed 3 remote assessments, including a comprehensive set of standardized cognitive neuropsychological tests comprising domains of memory, attention, language, and executive function, and questionnaires on emotional distress, fatigue, apathy and other psychological outcomes. Ninety participants were re-assessed one year later. Stability of outcomes was assessed by Cohen's d effect size estimates and percent Minimal Clinically Important Difference changes between time points. RESULTS: On the Montreal Cognitive Assessment 65.3% scored < 26. On the Oxford Cognitive Screen 45.9% had at least one cognitive impairment. Attention (27.1%) and executive function (40%) were most frequently impaired. 23.5% and 22.5% had elevated depression/anxiety respectively. Fatigue (51.4%) and apathy (40.5%) rates remained high, comparable to estimates in the first-year post-stroke. Attention (d = -0.12; 85.8% stable) and depression (d = 0.09, 77.1% stable) were the most stable outcomes. Following alpha-adjustments, only perceptuomotor abilities (d = 0.69; 40.4% decline) and fatigue (d = -0.33; 45.3% decline) worsened over one year. Cognitive impairment, depression/anxiety, fatigue and apathy all correlated with worse quality of life. CONCLUSION: Nearly half of participants > 2 years post-event exhibited psychological difficulties including domains of cognition, mood, and fatigue, which impact long-term quality of life. Stroke is a chronic condition with highly prevalent psychological needs, which require monitoring and intervention development.

Unravelling the complex interactions between self-awareness, cognitive change, and mood at 6-months post-stroke using the Y-shaped model.

We investigated the relationships between cognitive change following stroke, awareness of cognitive impairments, and mood to further understanding of change processes influencing psychological outcomes post-stroke in line with the "Y-shaped" process model. Patients (n = 143; Mage = 73 years, SD = 13.73; 74 males) were assessed at 3-weeks (T1) and 6-months (T2) post-stroke and had completed the Oxford Cognitive Screen (T1 and T2), the Cognitive Failures Questionnaire (CFQ; T2), and the Hospital Anxiety and Depression Scale (HADS; T2). An ANCOVA controlling for disability relating to activities of daily living (ADL) revealed that awareness of cognitive impairment was significantly lower in participants with moderate-severe cognitive impairment. Regression analysis indicated that greater awareness of cognitive impairment and reduced independence in ADL were associated with greater emotional distress at T2. Cognitive improvement was associated with lower emotional distressat T2. Contrary to the awareness hypothesis, moderation analyses suggest that this effect was largest for those most cognitively impaired at T1. Findings emphasize the importance of monitoring stroke patients' capacity to be self-aware when assessing and formulating long-term post-stroke distress and have potential implications for improving long-term emotional status in those most cognitively impaired post-stroke, e.g., through psychoeducation, cognitive rehabilitation, and emotional support.

Accelerated decline in white matter microstructure in subsequently impaired older adults and its relationship with cognitive decline.

Little is known about a longitudinal decline in white matter microstructure and its associations with cognition in preclinical dementia. Longitudinal diffusion tensor imaging and neuropsychological testing were performed in 50 older adults who subsequently developed mild cognitive impairment or dementia (subsequently impaired) and 200 cognitively normal controls. Rates of white matter microstructural decline were compared between groups using voxel-wise linear mixed-effects models. Associations between change in white matter microstructure and cognition were examined. Subsequently impaired individuals had a faster decline in fractional anisotropy in the right inferior fronto-occipital fasciculus and bilateral splenium of the corpus callosum. A decline in right inferior fronto-occipital fasciculus fractional anisotropy was related to a decline in verbal memory, visuospatial ability, processing speed and mini-mental state examination. A decline in bilateral splenium fractional anisotropy was related to a decline in verbal fluency, processing speed and mini-mental state examination. Accelerated regional white matter microstructural decline is evident during the preclinical phase of mild cognitive impairment/dementia and is related to domain-specific cognitive decline.

Default mode network connectivity and cognition in the aging brain: the effects of age, sex, and APOE genotype.

The default mode network (DMN) overlaps with regions showing early Alzheimer's Disease (AD) pathology. Age, sex, and apolipoprotein E ɛ4 are the predominant risk factors for developing AD. How these risk factors interact to influence DMN connectivity and connectivity-cognition relationships before the onset of impairment remains unknown. Here, we examined these issues in 475 cognitively normal adults, targeting total DMN connectivity, its anticorrelated network (acDMN), and the DMN-hippocampal component. There were four main findings. First, in the ɛ3 homozygous group, lower DMN and acDMN connectivity was observed with age. Second, sex and ɛ4 modified the relationship between age and connectivity for the DMN and hippocampus with ɛ4 vs. ɛ3 males showing sustained or higher connectivity with age. Third, in the ɛ3 group, age and sex modified connectivity-cognition relationships with the oldest participants having the most differential patterns due to sex. Fourth, ɛ4 carriers with lower connectivity had poorer cognitive performance. Taken together, our results show the three predominant risk factors for AD interact to influence brain function and function-cognition relationships.

Association of Depression and Anxiety With Cognitive Impairment 6 Months After Stroke.

OBJECTIVE: To investigate the associations between general cognitive impairment and domain-specific cognitive impairment with depression and anxiety at 6 months poststroke. METHODS: Participants were patients with confirmed acute stroke from the OCS-Care Study who were recruited on stroke wards in a multisite study and followed up at a 6-month poststroke assessment. Depression and anxiety symptoms were assessed by the Hospital Anxiety and Depression Scale subscales, with scores greater than 7 indicating possible mood disorders. General cognitive impairment at follow-up was assessed using the Montreal Cognitive Assessment (MoCA); stroke-specific cognitive domain impairments were assessed using the Oxford Cognitive Screen (OCS). Linear regression was used to examine the associations between cognition and depression/anxiety symptoms at 6 months, controlling for acute stroke severity and activities of daily living impairment, age, sex, education, and co-occurring poststroke depression/anxiety. RESULTS: A total of 437 participants (mean age, 69.28 years [SD 12.17], 226 male [51.72%]) were included in analyses. Six-month poststroke depression (n = 115, 26%) was associated with 6-month impairment on the MoCA (ß = 0.96, standard error [SE] 0.31, p = 0.006) and all individual domains assessed by the OCS: spatial attention (ß = 0.67, SE 0.33, p = 0.041), executive function (ß = 1.37, SE 0.47, p = 0.004), language processing (ß = 0.87, SE 0.38, p = 0.028), memory (ß = 0.76, SE 0.37, p = 0.040), number processing (ß = 1.13, SE 0.40, p = 0.005), and praxis (ß = 1.16, SE 0.49, p = 0.028). Poststroke anxiety (n = 133, 30%) was associated with impairment on the MoCA (ß = 1.47, SE 0.42, p = 0.001) and spatial attention (ß = 1.25, SE 0.45, p = 0.006); these associations did not remain significant after controlling for co-occurring poststroke depression. CONCLUSION: Domain-general and domain-specific poststroke cognitive impairment was found to be highly related to depressive symptomatology but not anxiety symptomatology.

Long-term psychological consequences of stroke (OX-CHRONIC): A longitudinal study of cognition in relation to mood and fatigue after stroke: Protocol.

Background: The long-term psychological consequences of stroke and how cognitive problems change over time after the first-year following stroke remain unclear. Particularly, trajectories of domain-specific and domain-general cognitive functions and how cognition interacts with mood, fatigue and quality of life are not well described. Aims: To determine the prevalence, trajectories and wider impact of domain-specific cognitive impairment in long-term stroke survivors, in relation to mood, fatigue and quality of life. Methods: Participants who previously took part in the Oxford Cognitive Screening study, completed the 6-month follow-up with cognitive, mood, fatigue and quality of life assessments and agreed to be contacted for future research will be recruited into OX-CHRONIC. The eligible cohort is between 2- and 9-years post-stroke. Cognition will be assessed with a detailed neuropsychological battery, alongside questionnaire measures of mood, fatigue, activities of daily life and quality of life measures at two timepoints, 1 year apart. Additionally, medical records will be accessed to extract further clinical information about the stroke and patients may opt-in to wear an activity monitor for 1 week to provide fine-grained measures of sleep and activity. The study protocol and study materials were approved by the national ethics committee (REC Ref: 19/SC/0520). Planned outputs: OX-CHRONIC will provide detailed data on the evolving cognitive profiles of stroke survivors over several years post-stroke. Estimates of long-term prevalence as well as the effect of changes in cognitive profiles on mood, fatigue and quality of life will be examined. This study is funded by a Priority Programme Grant from the Stroke Association (SA PPA 18/100032).

Microstructural Neuroimaging of Frailty in Cognitively Normal Older Adults.

Physical frailty is an age-related clinical syndrome that is associated with multiple adverse health outcomes, including cognitive impairment and dementia. Recent studies have shown that frailty is associated with specific volumetric neuroimaging characteristics. Whether brain microstructural characteristics, particularly gray matter, associated with frailty exist and what their spatial distribution is have not been explored. We identified 670 participants of the Baltimore Longitudinal Study of Aging who were aged 60 and older and cognitively normal and who had concurrent data on frailty and regional microstructural neuroimaging markers by diffusion tensor imaging (DTI), including mean diffusivity (MD) of gray matter and fractional anisotropy (FA) of white matter. We identified neuroimaging markers that were associated with frailty status (non-frail, pre-frail, frail) and further examined differences between three groups using multivariate linear regression (non-frail = reference). Models were adjusted for age, sex, race, years of education, body mass index, scanner type, and Apolipoprotein E e4 carrier status. Compared to the non-frail participants, those who were frail had higher MD in the medial frontal cortex, several subcortical regions (putamen, caudate, thalamus), anterior cingulate cortex, and a trend of lower FA in the body of the corpus callosum. Those who were pre-frail also had higher MD in the putamen and a trend of lower FA in the body of the corpus callosum. Our study demonstrates for the first time that the microstructure of both gray and white matter differs by frailty status in cognitively normal older adults. Brain areas were not widespread but mostly localized in frontal and subcortical motor areas and the body of the corpus callosum. Whether changes in brain microstructure precede future frailty development warrants further investigation.

Association of Poorer Hearing With Longitudinal Change in Cerebral White Matter Microstructure.

Importance: There is a dearth of studies that examine the association between poorer hearing and change in cerebral white matter (WM) microstructure. Objective: To examine the association of poorer hearing with baseline and change in WM microstructure among older adults. Design, Setting, and Participants: This was a prospective cohort study that evaluated speech-in-noise, pure-tone audiometry, and WM microstructure, as measured by mean diffusivity (MD) and fractional anisotropy (FA), both of which were evaluated by diffusion tensor imaging (DTI) in 17 WM regions. Data were collected between October 2012 and December 2018 and analyzed between March 2019 and August 2019 with a mean follow-up time of 1.7 years. The study evaluated responses to the Baltimore Longitudinal Study of Aging among 356 cognitively normal adults who had at least 1 hearing assessment and DTI session. Excluded were those with baseline cognitive impairment, stroke, head injuries, Parkinson disease, and/or bipolar disorder. Exposures: Peripheral auditory function was measured by pure-tone average in the better-hearing ear. Central auditory function was measured by signal-to-noise ratio score from a speech-in-noise task and adjusted by pure-tone average. Main Outcomes and Measures: Linear mixed-effects models with random intercepts and slopes were used to examine the association of poorer peripheral and central auditory function with baseline and longitudinal DTI metrics in 17 WM regions, adjusting for baseline characteristics (age, sex, race, hypertension, elevated total cholesterol, and obesity). Results: Of 356 cognitively normal adults included in the study, the mean (SD) age was 73.5 (8.8) years, and 204 (57.3%) were women. There were no baseline associations between hearing and DTI measures. Longitudinally, poorer peripheral hearing was associated with increases in MD in the inferior fronto-occipital fasciculus (ß = 0.025; 95% CI, 0.008-0.042) and the body (ß = 0.050; 95% CI, 0.015-0.085) of the corpus callosum, but there were no associations of peripheral hearing with FA changes in these tracts. Poorer central auditory function was associated with longitudinal MD increases (ß = 0.031; 95% CI, 0.010-0.052) and FA declines (ß = -1.624; 95% CI, -2.511 to -0.738) in the uncinate fasciculus. Conclusions and Relevance: Findings of this cohort study suggest that poorer hearing is related to change in integrity of specific WM regions involved with auditory processing.

Associations between cognitive and brain volume changes in cognitively normal older adults.

Investigation of relationships between age-related changes in regional brain volumes and changes in domain-specific cognition could provide insights into the neural underpinnings of individual differences in cognitive aging. Domain-specific cognition (memory, verbal fluency, visuospatial ability) and tests of executive function and attention (Trail-Making Test Part A and B) and 47 brain volumes of interest (VOIs) were assessed in 836 Baltimore Longitudinal Study of Aging participants with mean follow-up of 4.1 years (maximum 23.1 years). To examine the correlation between changes in domain-specific cognition and changes in brain volumes, we used bivariate linear mixed effects models with unstructured variance-covariance structure to estimate longitudinal trajectories for each variable of interest and correlations among the random effects of these measures. Higher annual rates of memory decline were associated with greater volume loss in 14 VOIs primarily within the temporal and occipital lobes. Verbal fluency decline was associated with greater ventricular enlargement and volume loss in 24 VOIs within the frontal, temporal, and parietal lobes. Decline in visuospatial ability was associated with volume loss in 3 temporal and parietal VOIs. Declines on the attentional test were associated with volume loss in 4 VOIs located within temporal and parietal lobes. Greater declines on the executive function test were associated with greater ventricular enlargement and volume loss in 10 frontal, parietal, and temporal VOIs. Our findings highlight domain-specific patterns of regional brain atrophy that may contribute to individual differences in cognitive aging.

Lasting consequences of concussion on the aging brain: Findings from the Baltimore Longitudinal Study of Aging.

Studies suggest that concussions may be related to increased risk of neurodegenerative diseases, such as Chronic Traumatic Encephalopathy and Alzheimer's Disease. Most neuroimaging studies show effects of concussions in frontal and temporal lobes of the brain, yet the long-term impacts of concussions on the aging brain have not been well studied. We examined neuroimaging data from 51 participants (mean age at first imaging visit=65.1 ± 11.23) in the Baltimore Longitudinal Study of Aging (BLSA) who reported a concussion in their medical history an average of 23 years prior to the first imaging visit, and compared them to 150 participants (mean age at first imaging visit=66.6 ± 10.97) with no history of concussion. Participants underwent serial structural MRI over a mean of 5.17±6.14 years and DTI over a mean of 2.92±2.22 years to measure brain structure, as well as 15O-water PET over a mean of 5.33±2.19 years to measure brain function. A battery of neuropsychological tests was also administered over a mean of 11.62±7.41 years. Analyses of frontal and temporal lobe regions were performed to examine differences in these measures between the concussion and control groups at first imaging visit and in change over time. Compared to those without concussion, participants with a prior concussion had greater brain atrophy in temporal lobe white matter and hippocampus at first imaging visit, which remained stable throughout the follow-up visits. Those with prior concussion also showed differences in white matter microstructure using DTI, including increased radial and axial diffusivity in the fornix/stria terminalis, anterior corona radiata, and superior longitudinal fasciculus at first imaging visit. In 15O-water PET, higher resting cerebral blood flow was seen at first imaging visit in orbitofrontal and lateral temporal regions, and both increases and decreases were seen in prefrontal, cingulate, insular, hippocampal, and ventral temporal regions with longitudinal follow-up. There were no significant differences in neuropsychological performance between groups. Most of the differences observed between the concussed and non-concussed groups were seen at the first imaging visit, suggesting that concussions can produce long-lasting structural and functional alterations in temporal and frontal regions of the brain in older individuals. These results also suggest that many of the reported short-term effects of concussion may still be apparent later in life.

Profiles of Cognitive Change in Preclinical and Prodromal Alzheimer's Disease Using Change-Point Analysis.

BACKGROUND: Alzheimer's disease (AD) is now understood to have a long preclinical phase in which pathology starts to accumulate in the absence of clinical symptoms. Identifying the temporal stages of accelerated cognitive decline in this phase may help in developing more sensitive neuropsychological tools for early screening of preclinical cognitive decline. Change-point analyses are increasingly used to characterize the temporal stages of accelerated cognitive decline in the preclinical stages of AD. However, statistical comparisons of change-points between specific cognitive measures have not been reported. OBJECTIVE: To characterize and compare the temporal stages of accelerated decline in performance on multiple cognitive tests in a sample of participants from the Baltimore Longitudinal Study on Aging (BLSA) who later developed AD. METHODS: 165 older adults (baseline age range: 61.1-91.2) from the BLSA developed AD during follow-up. Linear and non-linear mixed models were fit for 11 cognitive measures to determine change-points in rates of decline before AD diagnosis. Bootstrapping was used to compare the timing of change-points across cognitive measures. RESULTS: Change-points followed by accelerated decline ranged from 15.5 years (Standard Error (S.E.) = 1.72) for Card Rotations to 1.9 years (S.E. = 0.68) for the Trail-Making Test Part A before AD diagnosis. Accelerated decline in Card Rotations occurred significantly earlier than all other measures, including learning and memory measures. CONCLUSION: Results suggest that visuospatial ability, as assessed by Card Rotations, may have the greatest utility as an early predictive tool in identifying preclinical AD.

Predicting Dementia in Cerebral Small Vessel Disease Using an Automatic Diffusion Tensor Image Segmentation Technique.

Background and Purpose- Cerebral small vessel disease (SVD) is the most common cause of vascular cognitive impairment, with a significant proportion of cases going on to develop dementia. We explore the extent to which diffusion tensor image segmentation technique (DSEG; which characterizes microstructural damage across the cerebrum) predicts both degree of cognitive decline and conversion to dementia, and hence may provide a useful prognostic procedure. Methods- Ninety-nine SVD patients (aged 43-89 years) underwent annual magnetic resonance imaging scanning (for 3 years) and cognitive assessment (for 5 years). DSEG-θ was used as a whole-cerebrum measure of SVD severity. Dementia diagnosis was based Diagnostic and Statistical Manual of Mental Disorders V criteria. Cox regression identified which DSEG measures and vascular risk factors were related to increased risk of dementia. Linear discriminant analysis was used to classify groups of stable versus subsequent dementia diagnosis individuals. Results- DSEG-θ was significantly related to decline in executive function and global cognition (P<0.001). Eighteen (18.2%) patients converted to dementia. Baseline DSEG-θ predicted dementia with a balanced classification rate=75.95% and area under the receiver operating characteristic curve=0.839. The best classification model included baseline DSEG-θ, change in DSEG-θ, age, sex, and premorbid intelligence quotient (balanced classification rate of 79.65%; area under the receiver operating characteristic curve=0.903). Conclusions- DSEG is a fully automatic technique that provides an accurate method for assessing brain microstructural damage in SVD from a single imaging modality (diffusion tensor imaging). DSEG-θ is an important tool in identifying SVD patients at increased risk of developing dementia and has potential as a clinical marker of SVD severity.

Apolipoprotein E ε4 allele effects on longitudinal cognitive trajectories are sex and age dependent.

INTRODUCTION: Questions remain about whether apolipoprotein E (APOE)-ε4 effects on cognitive decline are similar in men and women and how APOE-ε4 and age interact to influence decline in different cognitive domains. METHODS: In sex-stratified analyses, baseline age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments). RESULTS: In men, older baseline age was associated with greater effects of APOE-ε4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater APOE-ε4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant APOE-ε4 effects were found for language, visual-spatial ability, or processing speed. DISCUSSION: Results highlight the importance of considering sex and age when assessing APOE-ε4-associated vulnerability to cognitive decline.

Sex differences in the association between amyloid and longitudinal brain volume change in cognitively normal older adults.

OBJECTIVE: Amyloid positivity is a biomarker of AD pathology, yet the associations between amyloid positivity and brain volumetric changes, especially in the hippocampus, are inconsistent. We hypothesize that sex differences in associations may contribute to inconsistent findings among cognitively normal older adults. METHODS: Using linear mixed effects models, we examined the association of amyloid positivity with prospective volumetric changes (mean = 3.3 visits) of parahippocampal gyrus (phg), hippocampus, entorhinal cortex (erc), precuneus, and fusiform gyrus among 171 Baltimore Longitudinal Study of Aging participants aged ≥55 years. Amyloid positivity was defined by a mean 11C-Pittsburgh Compound B (PiB) distribution volume ratio (DVR) cut-off of 1.062. All analyses included age, race, sex, education, APOE e4 carrier status, and two-way interactions of these covariates with time. Two-way interaction between sex and PiB+/- status and three-way interaction of sex and PiB+/- status with time were added to assess whether sex modified associations. RESULTS: PiB+ status was associated with greater volumetric declines in the phg (ß = -0.036, SE = 0.011, p = 0.001) and erc (ß = -0.019, SE = 0.009, p = 0.045). Sex modified the association of PiB+ status and rates of volumetric declines in fusiform (ß = -0.117, SE = 0.049, p = 0.019). PiB+ males had steeper rates of volumetric declines in phg (ß = -0.051, SE = 0.013, p < 0.001) and erc (ß = -0.029, SE = 0.012, p = 0.014) than PiB- males, while there was no difference in rates of volumetric change between PiB+ and PiB- females. CONCLUSIONS: Amyloidosis is a marker of entorhinal and parahippocampal volume loss. Amyloid positivity is a predictor of volume loss in brain regions affected by early AD pathology in men, but not women.

Vascular burden and APOE ε4 are associated with white matter microstructural decline in cognitively normal older adults.

White matter microstructure can be measured with diffusion tensor imaging (DTI). While increasing age is a predictor of white matter (WM) microstructure changes, roles of other possible modifiers, such as cardiovascular risk factors, APOE ε4 allele status and biological sex have not been clarified. We investigated 665 cognitively normal participants from the Baltimore Longitudinal Study of Aging (age 50-95, 56.7% female) with a total of 1384 DTI scans. WM microstructure was assessed by fractional anisotropy (FA) and mean diffusivity (MD). A vascular burden score was defined as the sum of five risk factors (hypertension, obesity, elevated cholesterol, diabetes and smoking status). Linear mixed effects models assessed the association of baseline vascular burden on baseline and on rates of change of FA and MD over a mean follow-up of 3.6 years, while controlling for age, race, and scanner type. We also compared DTI trajectories in APOE ε4 carriers vs. non-carriers and men vs. women. At baseline, higher vascular burden was associated with lower FA and higher MD in many WM structures including association, commissural, and projection fibers. Higher baseline vascular burden was also associated with greater longitudinal decline in FA in the hippocampal part of the cingulum and the fornix (crus)/stria terminalis and splenium of the corpus callosum, and with greater increases in MD in the splenium of the corpus callosum. APOE ε4 carriers did not differ from non-carriers in baseline DTI metrics but had greater decline in FA in the genu and splenium of the corpus callosum. Men had higher FA and lower MD in multiple WM regions at baseline but showed greater increase in MD in the genu of the corpus callosum. Women showed greater decreases over time in FA in the gyrus part of the cingulum, compared to men. Our findings show that modifiable vascular risk factors (1) have a negative impact on white matter microstructure and (2) are associated with faster microstructural deterioration of temporal WM regions and the splenium of the corpus callosum in cognitively normal adults. Reducing vascular burden in aging could modify the rate of WM deterioration and could decrease age-related cognitive decline and impairment.

Lacunar Infarcts, but Not Perivascular Spaces, Are Predictors of Cognitive Decline in Cerebral Small-Vessel Disease.

BACKGROUND AND PURPOSE: Cerebral small-vessel disease is a major cause of cognitive impairment. Perivascular spaces (PvS) occur in small-vessel disease, but their relationship to cognitive impairment remains uncertain. One reason may be difficulty in distinguishing between lacunes and PvS. We determined the relationship between baseline PvS score and PvS volume with change in cognition over a 5-year follow-up. We compared this to the relationship between baseline lacune count and total lacune volume with cognition. In addition, we examined change in PvS volume over time. METHODS: Data from the prospective SCANS study (St Georges Cognition and Neuroimaging in Stroke) of patients with symptomatic lacunar stroke and confluent leukoaraiosis were used (n=121). Multimodal magnetic resonance imaging was performed annually for 3 years and neuropsychological testing annually for 5 years. Lacunes were manually identified and distinguished from PvS. PvS were rated using a validated visual rating scale, and PvS volumes calculated using T1-weighted images. Linear mixed-effect models were used to determine the impact of PvS and lacunes on cognition. RESULTS: Baseline PvS scores or volumes showed no association with cognitive indices. No change was detectable in PvS volumes over the 3 years. In contrast, baseline lacunes associated with all cognitive indices and predicted cognitive decline over the 5-year follow-up. CONCLUSIONS: Although a feature of small-vessel disease, PvS are not a predictor of cognitive decline, in contrast to lacunes. This study highlights the importance of carefully differentiating between lacunes and PvS in studies investigating vascular cognitive impairment.

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

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).

Progression of MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials.

Detecting treatment efficacy using cognitive change in trials of cerebral small vessel disease (SVD) has been challenging, making the use of surrogate markers such as magnetic resonance imaging (MRI) attractive. We determined the sensitivity of MRI to change in SVD and used this information to calculate sample size estimates for a clinical trial. Data from the prospective SCANS (St George's Cognition and Neuroimaging in Stroke) study of patients with symptomatic lacunar stroke and confluent leukoaraiosis was used (n = 121). Ninety-nine subjects returned at one or more time points. Multimodal MRI and neuropsychologic testing was performed annually over 3 years. We evaluated the change in brain volume, T2 white matter hyperintensity (WMH) volume, lacunes, and white matter damage on diffusion tensor imaging (DTI). Over 3 years, change was detectable in all MRI markers but not in cognitive measures. WMH volume and DTI parameters were most sensitive to change and therefore had the smallest sample size estimates. MRI markers, particularly WMH volume and DTI parameters, are more sensitive to SVD progression over short time periods than cognition. These markers could significantly reduce the size of trials to screen treatments for efficacy in SVD, although further validation from longitudinal and intervention studies is required.