Correlations in post-mortem imaging-histopathology studies of sporadic human cerebral small vessel disease: A systematic review.

AIMS: Sporadic human cerebral small vessel disease (SVD) commonly causes stroke and dementia but its pathogenesis is poorly understood. There are recognised neuroimaging and histopathological features. However, relatively few studies have examined the relationship between the radiological and pathological correlates of SVD; better correlation would promote greater insight into the underlying biological changes. METHODS: We performed a systematic review to collate and appraise the information derived from studies that correlated histological with neuroimaging-defined SVD lesions. We searched for studies describing post-mortem imaging and histological tissue examination in adults, extracted data from published studies, categorised the information and compiled this narrative. RESULTS: We identified 38 relevant studies, including at least 1146 subjects, 342 of these with SVD: 29 studies focussed on neuroradiological white matter lesions (WML), six on microinfarcts and three on dilated perivascular spaces (PVS) and lacunes. The histopathology terminology was diverse with few robust definitions. Reporting and methodology varied widely between studies, precluding formal meta-analysis. PVS and 'oedema' were frequent findings in WML, being described in at least 94 and 18 radiological WML, respectively, in addition to myelin pallor. Histopathological changes extended beyond the radiological lesion margins in at least 33 radiological WML. At least 43 radiological lesions not seen pathologically and at least 178 histological lesions were not identified on imaging. CONCLUSIONS: Histopathological assessment of human SVD is hindered by inconsistent methodological approaches and unstandardised definitions. The data from this systematic review will help to develop standardised definitions to promote consistency in human SVD research.

Factors associated with cognitive impairment before intracerebral haemorrhage: community-based neuropathological study.

Little is known about whether clinical, radiological or neuropathological features are associated with cognitive impairment before intracerebral haemorrhage. We conducted a community-based cohort study of 125 adults with intracerebral haemorrhage (lobar n = 71, non-lobar n = 54) with consent to brain autopsy. We compared small vessel disease biomarkers on diagnostic CT head and neuropathological findings including neurofibrillary tangles and amyloid plaques in adults without cognitive impairment versus cognitive impairment without dementia versus dementia before intracerebral haemorrhage, stratified by lobar and non-lobar intracerebral haemorrhage. In non-lobar intracerebral haemorrhage, severe cortical atrophy was less common in those without cognitive impairment (8/36, 22%) and cognitive impairment without dementia (0/9, 0%) versus dementia (5/9, 56%); P = 0.008. Irrespective of intracerebral haemorrhage location, adults without cognitive impairment had milder neurofibrillary tangle pathology measured by median Braak stage (lobar intracerebral haemorrhage: no cognitive impairment 2 [interquartile range, 2-3] versus cognitive impairment without dementia 4 [2-6] versus dementia 5.5 [4-6]; P = 0.004; non-lobar intracerebral haemorrhage: no cognitive impairment 2 [1-2] versus cognitive impairment without dementia 2 [1-2] versus dementia 5 [3-6]; P < 0.001). Irrespective of intracerebral haemorrhage location, adults without cognitive impairment had milder amyloid plaque pathology measured by median Thal stage (lobar intracerebral haemorrhage: no cognitive impairment 2 [1-2] versus cognitive impairment without dementia 2 [2-3] versus dementia 2.5 [2-3.5]; P = 0.033; non-lobar intracerebral haemorrhage: no cognitive impairment 1 [0-1] versus cognitive impairment without dementia 0 [0-2] versus dementia 3 [2-3]; P = 0.002). Our findings suggest that irrespective of intracerebral haemorrhage location, adults with cognitive impairment before an intracerebral haemorrhage have more Alzheimer's disease neuropathologic change.

A new approach for measuring the work and quality of histopathology reporting.

AIMS: Cancer datasets drive report quality, but require more work to inform compliant reports. The aim of this study was to correlate the number of words with measures of quality, to examine the impact of the drive for improved quality on the workload of histopathology reporting over time. METHODS AND RESULTS: We examined the first 10 reports of colon, breast, renal, lung and ovarian carcinoma, melanoma resection, nodal lymphoma appendicitis and seborrhoeic keratosis (SK) issued in 1991, 2001 and 2011. Correlations were analysed using Pearson's partial correlation coefficients. Word count increased significantly over time for most specimen types examined. Word count almost always correlated with units of information, indicating that the word count was a good measure of the amount of information contained within the reports; this correlation was preserved following correction for the effect of time. A good correlation with compliance with cancer datasets was also observed, but was weakened or lost following correction for the increase in word count and units of information that occurred between time points. CONCLUSIONS: These data indicate that word count could potentially be used as a measure of information content if its integrity and usefulness are continuously validated. Further prospective studies are required to assess and validate this approach.

A protocol for precise comparisons of small vessel disease lesions between ex vivo magnetic resonance imaging and histopathology.

RATIONALE: Neuroimaging and clinical studies have defined human sporadic cerebral small vessel disease but the pathophysiology remains relatively poorly understood. To develop effective therapies and preventative strategies, we must better understand the heterogeneity and development of small vessel disease at a cellular level. HYPOTHESIS: Small vessel disease lesions as seen on neuroimaging have specific neuropathological correlates. METHODS AND DESIGN: Standard histological samples are taken from strategic areas of the brain typically affected by small vessel disease, in cases with a range of disease from mild to severe and controls. Tissue is formalin fixed, scanned using 7-tesla magnetic resonance imaging and processed for histology. Histological slides are digitalized then registered with the corresponding magnetic resonance image. Small vessel disease burden is assessed and lesions are precisely identified on the ex vivo imaging and microscopy independently then compared. The tissue can be interrogated using multiple magnetic resonance sequences and histological methods targeting the gliovascular unit. STUDY OUTCOMES: The primary outcome is identifying and defining the cellular characteristics of small vessel disease lesions compared to imaging. Secondary outcomes are related to obtaining information about abnormalities of protein expression in the gliovascular unit, defining groups of small vessel disease severity in our cohorts for future analysis and developing a reliable, reproducible protocol for accurate radiological-histological lesion comparison, which can be applied to other neurological diseases in the future. DISCUSSION: Comprehensive, precise pathological-radiological-clinical correlations in small vessel disease will provide greater insight into associations and pathophysiology underlying magnetic resonance imaging findings in normal- and abnormal-appearing tissue, ex vivo and in vivo.

Early Contrast Enhancement: A novel magnetic resonance imaging biomarker of pleural malignancy.

INTRODUCTION: Pleural Malignancy (PM) is often occult on subjective radiological assessment. We sought to define a novel, semi-objective Magnetic Resonance Imaging (MRI) biomarker of PM, targeted to increased tumour microvessel density (MVD) and applicable to minimal pleural thickening. MATERIALS AND METHODS: 60 consecutive patients with suspected PM underwent contrast-enhanced 3-T MRI then pleural biopsy. In 58/60, parietal pleura signal intensity (SI) was measured in multiple regions of interest (ROI) at multiple time-points, generating ROI SI/time curves and Mean SI gradient (MSIG: SI increment/time). The diagnostic performance of Early Contrast Enhancement (ECE; which was defined as a SI peak in at least one ROI at or before 4.5 min) was compared with subjective MRI and Computed Tomography (CT) morphology results. MSIG was correlated against tumour MVD (based on Factor VIII immunostain) in 31 patients with Mesothelioma. RESULTS: 71% (41/58) patients had PM. Pleural thickening was <10 mm in 49/58 (84%). ECE sensitivity was 83% (95% CI 61-94%), specificity 83% (95% CI 68-91%), positive predictive value 68% (95% CI 47-84%), negative predictive value 92% (78-97%). ECE performance was similar or superior to subjective CT and MRI. MSIG correlated with MVD (r = 0.4258, p = .02). DISCUSSION: ECE is a semi-objective, perfusion-based biomarker of PM, measurable in minimal pleural thickening. Further studies are warranted.

The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage associated with cerebral amyloid angiopathy: model development and diagnostic test accuracy study.

BACKGROUND: Identification of lobar spontaneous intracerebral haemorrhage associated with cerebral amyloid angiopathy (CAA) is important because it is associated with a higher risk of recurrent intracerebral haemorrhage than arteriolosclerosis-associated intracerebral haemorrhage. We aimed to develop a prediction model for the identification of CAA-associated lobar intracerebral haemorrhage using CT features and genotype. METHODS: We identified adults with first-ever intracerebral haemorrhage diagnosed by CT, who died and underwent research autopsy as part of the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study, a prospective, population-based, inception cohort. We determined APOE genotype and radiologists rated CT imaging appearances. Radiologists were not aware of clinical, genetic, and histopathological features. A neuropathologist rated brain tissue for small vessel diseases, including CAA, and was masked to clinical, radiographic, and genetic features. We used CT and APOE genotype data in a logistic regression model, which we internally validated using bootstrapping, to predict the risk of CAA-associated lobar intracerebral haemorrhage, derive diagnostic criteria, and estimate diagnostic accuracy. FINDINGS: Among 110 adults (median age 83 years [IQR 76-87], 49 [45%] men) included in the LINCHPIN study between June 1, 2010 and Feb 10, 2016, intracerebral haemorrhage was lobar in 62 (56%) participants, deep in 41 (37%), and infratentorial in seven (6%). Of the 62 participants with lobar intracerebral haemorrhage, 36 (58%) were associated with moderate or severe CAA compared with 26 (42%) that were associated with absent or mild CAA, and were independently associated with subarachnoid haemorrhage (32 [89%] of 36 vs 11 [42%] of 26; p=0·014), intracerebral haemorrhage with finger-like projections (14 [39%] of 36 vs 0; p=0·043), and APOE ɛ4 possession (18 [50%] of 36 vs 2 [8%] of 26; p=0·0020). A prediction model for CAA-associated lobar intracerebral haemorrhage using these three variables had excellent discrimination (c statistic 0·92, 95% CI 0·86-0·98), confirmed by internal validation. For the rule-out criteria, neither subarachnoid haemorrhage nor APOE ɛ4 possession had 100% sensitivity (95% CI 88-100). For the rule-in criteria, subarachnoid haemorrhage and either APOE ɛ4 possession or finger-like projections had 96% specificity (95% CI 78-100). INTERPRETATION: The CT and APOE genotype prediction model for CAA-associated lobar intracerebral haemorrhage shows excellent discrimination in this cohort, but requires external validation. The Edinburgh rule-in and rule-out diagnostic criteria might inform prognostic and therapeutic decisions that depend on identification of CAA-associated lobar intracerebral haemorrhage. FUNDING: UK Medical Research Council, The Stroke Association, and The Wellcome Trust.