Contrast Clearance Analysis (CCA) to Assess Viable Tumour following Stereotactic Radiosurgery (SRS) to Brain Metastasis in Non-Small Cell Lung Cancer (NSCLC).

BACKGROUND AND OBJECTIVE: Brain metastases are common in lung cancer and increasingly treated using targeted radiotherapy techniques such as stereotactic radiosurgery (SRS). Using MRI, post-SRS changes may be difficult to distinguish from progressive brain metastasis. Contrast clearance analysis (CCA) uses T1-weighted MRI images to assess the clearance of gadolinium and can be thus used to assess vascularity and active tumours. DESIGN AND METHODS: We retrospectively assessed CCAs in 62 patients with non-small cell lung cancer (NSCLC) undergoing 104 CCA scans in a single centre. RESULTS: The initial CCA suggested the aetiology of equivocal changes on standard MRI in 80.6% of patients. In all patients whose initial CCA showed post-SRS changes and who underwent serial CCAs, the initial diagnosis was upheld with the serial imaging. In only two cases of a presumed progressive tumour on the initial CCA, subsequent treatment for radionecrosis was instigated; a retrospective review and re-evaluation of the CCAs show that progression was reported where a thin rim of rapid contrast clearance was seen, and this finding has been subsequently recognised as a feature of post-treatment change on CCAs. The lack of concordance with CCA findings in those who underwent surgical resection was also found to be due to the over-reporting of the thin blue rim as disease in the early cases of CCA use and, in three cases, potentially related to timelines longer than 7 days prior to surgery, both factors being unknown during the early implementation phase of CCA at our centre but subsequently learned. CONCLUSIONS: Our single-centre experience shows CCA to be feasible and useful in patients with NSCLC in cases of diagnostic uncertainty in MRI. It has helped guide treatment in the majority of patients, with subsequent outcomes following the implementation of the treatment based on the results, suggesting correct classification. Recommendations from our experience of the implementation include the careful consideration of the thin rim of the rapid contrast clearance and the timing of the CCA prior to surgery for suspected brain metastasis progression.

Visualisation of lenticulostriate arteries using contrast-enhanced time-of-flight magnetic resonance angiography at 7 Tesla.

7 Tesla-field-strength (7 T) Magnetic Resonance Imaging allows the small perforating arteries in the brain to be visualised, and this modality may allow visualisation of the arterial pathology in cerebral small vessel disease. Most studies have used standard Time-of-Flight (ToF) Magnetic Resonance Angiography (MRA). Whether the use of contrast enhancement improves perforating artery visualisation at 7 T remains unclear. In a prospective study, we compared standard ToF MRA with contrast-enhanced (CE) ToF MRA at 7 T for the visualisation of the lenticulostriate arteries (LSAs). Ten patients with symptomatic lacunar stroke were recruited (mean age, SD, 64 ± 9.9 years). Visualisation was assessed using a visual rating scale administered by two independent expert readers and length of the LSAs visible. Visualisation of the LSAs was improved with CE ToF MRA. The mean Visibility and Sharpness Score was higher for CE ToF MRA over standard ToF MRA (2.55 ± 0.64 vs. 1.75 ± 0.68; P = 0.0008). The mean length of LSA visualised was significantly longer with CE ToF MRA compared to standard ToF MRA (24.4 ± 4.5 vs. 21.9 ± 4.0 mm; P = 0.01). CE ToF MRA offers improved visualisation of the LSAs over standard ToF MRA. The addition of contrast may improve the ability to visualise cerebral small vessel disease arterial pathology.

Cognitive impact of cerebral microbleeds in patients with symptomatic small vessel disease.

BACKGROUND AND AIM: Whether cerebral microbleeds cause cognitive impairment remains uncertain. We analyzed whether cerebral microbleeds are associated with cognitive dysfunction in patients with symptomatic cerebral small vessel disease, and whether this association is independent of other neuroimaging markers of cerebral small vessel disease. METHODS: We analyzed consecutive patients with MRI-confirmed lacunar stroke included in DNA-Lacunar-2 multicenter study. Cerebral microbleeds were graded using the Brain Observer Microbleed Rating Scale (BOMBS). Neuropsychological assessment was performed using the Brief Memory and Executive Test (BMET). We analyzed the association between cerebral microbleeds, BMET, and the following subdomains: executive function/processing speed and orientation/memory. We also searched for an independent association between cerebral microbleeds and vascular cognitive impairment, defined as BMET ≤ 13. RESULTS: Out of 688 included patients, cerebral microbleeds were detected in 192 (27.9%). After adjusting for white matter hyperintensities severity, lacune count, and other confounders, both the presence and the number of cerebral microbleeds were significantly associated with impaired cognitive performance [ß = -13.0; 95% CI = (-25.3, -0.6) and ß = -13.1; 95% CI = (-19.8, -6.4), respectively]. On analysis of specific cognitive domains, associations were present for executive function/processing speed [ß = -5.8; 95% CI = (-9.3, -2.2) and ß = -4.3; 95% CI = (-6.2, -2.4), respectively] but not for orientation/memory [ß = -0.4; 95% CI = (-4.0, 3.2) and ß = -2.1; 95% CI = (-4.0, 0.1), respectively]. We also found an independent association between the presence and the number of cerebral microbleeds and vascular cognitive impairment [adjusted OR = 1.48; 95% CI = (1.01, 2.18) and OR = 1.43; 95% CI = (1.15, 1.79), respectively]. CONCLUSION: In a large cohort of symptomatic cerebral small vessel disease patients, after controlling for other neuroimaging markers of cerebral small vessel disease severity, cerebral microbleeds were associated with cognitive dysfunction. Executive function and processing speed were predominantly impaired. This might suggest a causal role of cerebral microbleeds in determining vascular cognitive impairment.

Prevalence and Risk Factors of Cerebral Microbleeds: An Analysis From the UK Biobank.

OBJECTIVE: To determine the prevalence and risk factors for cerebral microbleeds (CMB) at different locations in a large healthy community population. METHODS: 8159 subjects from UK Biobank with MRI scans suitable for CMB analysis were included. Brain susceptibility weighted imaging (SWI) data was acquired on two identical 3.0 T scanners. The Microbleed Anatomical Rating Scale (MARS) was used to identify definite CMB. Generalized linear models were used to determine independent associations with all CMB and lobar, deep and infratentorial CMB. RESULTS: The mean age at scan was 62.1±7.4 years. One of more definite CMB were detected in 572 (7.0%) of subjects. Of those with CMB 439 (76.7%) had lobar CMB, 103 (18.0%) had deep CMB, and 83 (14.5%) had infratentorial CMB. Age was an independent risk factor for CMB in all locations. ApoE4 and male sex were positively, and higher BMI were negatively associated, with lobar CMB. In contrast, hypertension, smoking and alcohol consumption were associated with deep CMB, but not with lobar CMB. Only age was associated with infratentorial CMB. The associations were unchanged after controlling for WMH lesion volume as a marker of small vessel disease severity. CONCLUSIONS: In this large population based study, the CMB prevalence detected using a low sensitivity and high specificity system was 7%. There were distinct risk factor profiles for CMB in lobar and deep locations consistent with different underlying pathophysiological processes.

Association of common genetic variants with brain microbleeds: A genome-wide association study.

OBJECTIVE: To identify common genetic variants associated with the presence of brain microbleeds (BMBs). METHODS: We performed genome-wide association studies in 11 population-based cohort studies and 3 case-control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs. RESULTS: BMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the APOE region reached genome-wide significance for its association with BMB (lead single nucleotide polymorphism rs769449; odds ratio [OR]any BMB [95% confidence interval (CI)] 1.33 [1.21-1.45]; p = 2.5 × 10-10). APOE ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19-1.50]; p = 1.0 × 10-6) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86-1.25]; p = 0.68). APOE ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB. CONCLUSIONS: Genetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.

Quantifying the Impact of Chronic Ischemic Injury on Clinical Outcomes in Acute Stroke With Machine Learning.

Acute stroke is often superimposed on chronic damage from previous cerebrovascular events. This background will inevitably modulate the impact of acute injury on clinical outcomes to an extent that will depend on the precise anatomical pattern of damage. Previous attempts to quantify such modulation have employed only reductive models that ignore anatomical detail. The combination of automated image processing, large-scale data, and machine learning now enables us to quantify the impact of this with high-dimensional multivariate models sensitive to individual variations in the detailed anatomical pattern. We introduce and validate a new automated chronic lesion segmentation routine for use with non-contrast CT brain scans, combining non-parametric outlier-detection score, Zeta, with an unsupervised 3-dimensional maximum-flow, minimum-cut algorithm. The routine was then applied to a dataset of 1,704 stroke patient scans, obtained at their presentation to a hyper-acute stroke unit (St George's Hospital, London, UK), and used to train a support vector machine (SVM) model to predict between low (0-2) and high (3-6) pre-admission and discharge modified Rankin Scale (mRS) scores, quantifying performance by the area under the receiver operating curve (AUROC). In this single center retrospective observational study, our SVM models were able to differentiate between low (0-2) and high (3-6) pre-admission and discharge mRS scores with an AUROC of 0.77 (95% confidence interval of 0.74-0.79), and 0.76 (0.74-0.78), respectively. The chronic lesion segmentation routine achieved a mean (standard deviation) sensitivity, specificity and Dice similarity coefficient of 0.746 (0.069), 0.999 (0.001), and 0.717 (0.091), respectively. We have demonstrated that machine learning models capable of capturing the high-dimensional features of chronic injuries are able to stratify patients-at the time of presentation-by pre-admission and discharge mRS scores. Our fully automated chronic stroke lesion segmentation routine simplifies this process, and utilizes routinely collected CT head scans, thereby facilitating future large-scale studies to develop supportive clinical decision tools.

Encephalomyelitis with Retinopathy in Common Variable Immunodeficiency (CVID).

Common variable immunodeficiency is the most common primary immunodeficiency and rarely causes neurological manifestations since the introduction of IVIg, but here, the authors present a case of a 31-year-old Afro-Caribbean man who after short non-adherence to his immunoglobulins, develops encephalomyelitis with retinopathy. To the authors' knowledge, this is the first case presented with retinal photographs, OCT, CT, MRI and brain biopsies.

Variation of the apparent diffusion coefficient of skull bone marrow by age group, pubertal status, and gender in a pediatric population.

BACKGROUND: Bone marrow composition varies with stage of development. PURPOSE: To assess differences in apparent diffusion coefficient (ADC) derived from clivus bone marrow in healthy children by age, pubertal status, and gender as a benchmark when monitoring local and systemic treatment-induced effects. MATERIAL AND METHODS: Non-oncological pediatric patients (30 pre-pubertal [15 girls, 15 boys] and 30 post-pubertal [15 girls, 15 boys]) with previous normal magnetic resonance imaging (MRI) of the brain including diffusion-weighted magnetic resonance imaging (DW-MRI; 1.5-T Philips Achieva-Ingenia, b-values 0 and 1000s/mm2) were studied. A 4-6 mm diameter region of interest (ROI), drawn within the clivus on two or three DW-MRI slices, yielded mean and centile ADC values. Pubertal status was recognized from imaging appearances of the pituitary gland and from fusion of the spheno-occipital synchondrosis. Correlations between ADC and age were assessed (Pearson's coefficient). Mann-Whitney U tests compared ADC by age, pubertal status, and gender. RESULTS: Age and ADC were significantly negatively correlated (median ADC r=-0.48, mean ADC r=-0.42, P=0.0001 and 0.0008, respectively) which held true when divided by gender. Mean and median ADC differed significantly before and after puberty for the whole population (P=0.0001 and 0.0001, respectively). There was a left shift of the ADC histogram after puberty with significant differences in centile values. ADC differences before and after puberty remained when divided by gender (girls: P=0.04 and 0.009, respectively; boys: P=0.005 and 0.0002, respectively). CONCLUSION: ADC of clivus bone marrow correlates with age in children. ADC decreases significantly after puberty, likely due to replacement of hypercellular marrow with fat. There are no gender-related differences in clivus bone-marrow ADC before or after puberty.

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.

Safety and Efficacy of Erythrocyte Encapsulated Thymidine Phosphorylase in Mitochondrial Neurogastrointestinal Encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder of nucleoside metabolism that is caused by mutations in the nuclear thymidine phosphorylase gene (TYMP) gene, encoding for the enzyme thymidine phosphorylase. There are currently no approved treatments for MNGIE. The aim of this study was to investigate the safety, tolerability, and efficacy of an enzyme replacement therapy for the treatment of MNGIE. In this single centre study, three adult patients with MNGIE received intravenous escalating doses of erythrocyte encapsulated thymidine phosphorylase (EE-TP; dose range: 4 to 108 U/kg/4 weeks). EE-TP was well tolerated and reductions in the disease-associated plasma metabolites, thymidine, and deoxyuridine were observed in all three patients. Clinical improvements, including weight gain and improved disease scores, were observed in two patients, suggesting that EE-TP is able to reverse some aspects of the disease pathology. Transient, non-serious adverse events were observed in two of the three patients; these did not lead to therapy discontinuation and they were managed with pre-medication prior to infusion of EE-TP. To conclude, enzyme replacement therapy with EE-TP demonstrated biochemical and clinical therapeutic efficacy with an acceptable clinical safety profile.

Reversible Cerebral White Matter Abnormalities in Homocystinuria.

Striking MRI brain changes resembling leukoencephalopathy are rarely seen in classical homocystinuria. Our case suggests that reversible white matter changes (WMC) are linked to elevated plasma methionine levels arising during treatment.A 6-year-old boy with learning difficulties and a normal MRI brain scan was diagnosed with homocystinuria (initial total homocysteine 344 µmol/L and methionine 64 µmol/L). At the age of 6.5 years, he developed superior sagittal sinus (SSS) thrombosis. Antithrombotic and homocysteine-lowering treatments were started. Due to poor dietary compliance and betaine treatment, his methionine level reached 1,285 µmol/L, and left side weakness developed. Repeat MRI scan revealed new confluent WMC in previously myelinated brain areas. Further 3-month treatment with tighter dietary control significantly dropped his methionine level (233 µmol/L) with resolution of his neurological deficit and of radiological changes.We suggest a reversible toxicity from hypermethioninaemia as a possible source of cerebral WMC (secondary to a demyelinating process) in patients with homocystinuria. It highlights the importance of homocysteine-lowering treatment as a prevention and complete resolution of neurological complications. It also demonstrates the need to consider homocystinuria in a differential diagnosis of paediatric leukoencephalopathy.

GLUT-1 deficiency presenting with seizures and reversible leukoencephalopathy on MRI imaging.

Glucose transporter type 1 (GLUT1) deficiency syndrome is a well recognised genetic neurometabolic disorder typically presenting with progressive encephalopathy, acquired microcephaly and drug-resistant epilepsy. Imaging is normal in the majority. Here we describe a 5-month-old boy who presented with motor delay, myoclonic jerks and tonic-clonic seizures. His MRI brain scan revealed confluent symmetrical T2 hyperintense signal abnormality in both anterior frontal lobes and delayed myelination. Neurometabolic screen revealed low CSF glucose and lactate levels. A pathogenic de novo heterozygous mutation in SLC2A1 (c.275+1G > A) confirmed the diagnosis of GLUT1 deficiency. Ketogenic diet resulted in a dramatic termination of his seizures at 72 h. At 15 months, he continued to be seizure free with marked developmental catch up. Repeat imaging revealed a significant resolution of the previously seen changes. This case suggests that GLUT1 deficiency should be considered in the differential diagnosis of infants with suspected genetic leukoencephalopathies with important treatment implications.

Identifying preclinical vascular dementia in symptomatic small vessel disease using MRI.

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.

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.

Location, number and factors associated with cerebral microbleeds in an Italian-British cohort of CADASIL patients.

BACKGROUND AND PURPOSE: The frequency, clinical correlates, and risk factors of cerebral microbleeds (CMB) in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) are still poorly known. We aimed at determining the location and number of CMB and their relationship with clinical manifestations, vascular risk factors, drugs, and other neuroimaging features in CADASIL patients. METHODS: We collected clinical data by means of a structured proforma and centrally evaluated CMB on magnetic resonance gradient echo sequences applying the Microbleed Anatomical Rating Scale in CADASIL patients seen in 2 referral centers in Italy and United Kingdom. RESULTS: We evaluated 125 patients. CMB were present in 34% of patients and their presence was strongly influenced by the age. Twenty-nine percent of the patients had CMB in deep subcortical location, 22% in a lobar location, and 18% in infratentorial regions. After adjustment for age, factors significantly associated with a higher total number of CMB were hemorrhagic stroke, dementia, urge incontinence, and statins use (this latter not confirmed by multivariate analysis). Infratentorial and deep CMB were associated with dementia and urge incontinence, lobar CMB with hemorrhagic stroke, dementia, and statins use. Unexpectedly, patients with migraine, with or without aura, had a lower total, deep, and lobar number of CMB than patients without migraine. DISCUSSION: CMB formation in CADASIL seems to increase with age. History of hemorrhagic stroke, dementia, urge incontinence, and statins use are associated with a higher number of CMB. However, these findings need to be confirmed by longitudinal studies.

Change in multimodal MRI markers predicts dementia risk in cerebral small vessel disease.

OBJECTIVE: To determine whether MRI markers, including diffusion tensor imaging (DTI), can predict cognitive decline and dementia in patients with cerebral small vessel disease (SVD). METHODS: In the prospective St George's Cognition and Neuroimaging in Stroke study, multimodal MRI was performed annually for 3 years and cognitive assessments annually for 5 years in a cohort of 99 patients with SVD, defined as symptomatic lacunar stroke and confluent white matter hyperintensities (WMH). Progression to dementia was determined in all patients. Progression of WMH, brain volume, lacunes, cerebral microbleeds, and a DTI measure (the normalized peak height of the mean diffusivity histogram distribution) as a marker of white matter microstructural damage were determined. RESULTS: Over 5 years of follow-up, 18 patients (18.2%) progressed to dementia. A significant change in all MRI markers, representing deterioration, was observed. The presence of new lacunes, and rate of increase in white matter microstructural damage on DTI, correlated with both decline in executive function and global functioning. Growth of WMH and deterioration of white matter microstructure on DTI predicted progression to dementia. A model including change in MRI variables together with their baseline values correctly classified progression to dementia with a C statistic of 0.85. CONCLUSIONS: This longitudinal prospective study provides evidence that change in MRI measures including DTI, over time durations during which cognitive change is not detectable, predicts cognitive decline and progression to dementia. It supports the use of MRI measures, including DTI, as useful surrogate biomarkers to monitor disease and assess therapeutic interventions.

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).