Joel Ramirez

Lesion Explorer: a comprehensive segmentation and parcellation package to obtain regional volumetrics for subcortical hyperintensities and intracranial tissue.

Subcortical hyperintensities (SH) are a commonly observed phenomenon on MRI of the aging brain (Kertesz et al., 1988). Conflicting behavioral, cognitive and pathological associations reported in the literature underline the need to develop an intracranial volumetric analysis technique to elucidate pathophysiological origins of SH in Alzheimers disease (AD), vascular cognitive impairment (VCI) and normal aging (De Leeuw et al., 2001; Mayer and Kier, 1991; Pantoni and Garcia, 1997; Sachdev et al., 2008). The challenge is to develop processing tools that effectively and reliably quantify subcortical small vessel disease in the context of brain tissue compartments. Segmentation and brain region parcellation should account for SH subtypes which are often classified as: periventricular (pvSH) and deep white (dwSH), incidental white matter disease or lacunar infarcts and Virchow-Robin spaces. Lesion Explorer (LE) was developed as the final component of a comprehensive volumetric segmentation and parcellation image processing stream built upon previously published methods (Dade et al., 2004; Kovacevic et al., 2002). Inter-rater and inter-method reliability was accomplished both globally and regionally. Volumetric analysis showed high inter-rater reliability both globally (ICC=.99) and regionally (ICC=.98). Pixel-wise spatial congruence was also high (SI=.97). Whole brain pvSH volumes yielded high inter-rater reliability (ICC=.99). Volumetric analysis against an alternative kNN segmentation revealed high inter-method reliability (ICC=.97). Comparison with visual rating scales showed high significant correlations (ARWMC: r=.86; CHIPS: r=.87). The pipeline yields a comprehensive and reliable individualized volumetric profile for subcortical vasculopathy that includes regionalized (26 brain regions) measures for: GM, WM, sCSF, vCSF, lacunar and non-lacunar pvSH and dwSH.

Visible Virchow-Robin Spaces on Magnetic Resonance Imaging of Alzheimer's Disease Patients and Normal Elderly from the Sunnybrook Dementia Study

BACKGROUND Visible Virchow-Robin spaces (VRS) are commonly used markers for small vessel disease in aging and dementia. OBJECTIVE However, as previous reports were based on subjective visual ratings, the goal of this project was to validate and apply an MRI-based quantitative measure of VRS as a potential neuroimaging biomarker. METHODS A modified version of Lesion Explorer was applied to MRIs from Alzheimers disease patients (AD: n = 203) and normal elderly controls (NC: n = 94). Inter-rater reliability, technique validity, group/gender differences, and correlations with other small vessel disease markers were examined (lacunes and white matter hyperintensities, WMH). RESULTS Inter-rater reliability and spatial congruence was excellent (ICC = 0.99, SI = 0.96), and VRS volumes were highly correlated with established rating scales (CS: ρ = 0.84, p < 0.001; BG: ρ = 0.75, p < 0.001). Compared to NC, AD had significantly greater volumes of WMH (p < 0.01), lacunes (p < 0.001), and VRS in the white matter (p < 0.01), but not in the basal ganglia (n.s.). Compared to women, demented and non-demented men had greater VRS in the white matter (p < 0.001), but not in the basal ganglia (n.s.). Additionally, VRS were correlated with lacunes and WMH, but only in AD (r = 0.3, p < 0.01). CONCLUSION Compared to women, men may be more susceptible to greater volumes of VRS, particularly in the white matter. RESULTS support the hypothesis that VRS in the white matter may be more related to AD-related vascular pathology compared to VRS found in the basal ganglia. Future work using this novel VRS segmentation tool will examine its potential utility as an imaging biomarker of vascular rather than parenchymal amyloid.

Misclassified Tissue Volumes in Alzheimer Disease Patients With White Matter Hyperintensities: Importance of Lesion Segmentation Procedures for Volumetric Analysis

Background and Purpose— MRI-based quantification of gray and white matter volume is common in studies involving elderly patient populations. The aim of the present study was to describe the effects of not accounting for subcortical white matter hyperintensities (WMH) on tissue volumes in Alzheimer Disease patients with varying degrees of WMH (mild: n=19, moderate: n=22, severe: n=18). Methods— An automated tissue segmentation protocol that was optimized for an elderly population, a brain regional parcellation procedure, and a lesion segmentation protocol were applied to measure tissue volumes (whole brain and regional lobar volumes) with and without lesion segmentation to quantify the volume of misclassified tissue. Results— After application of the tissue segmentation protocol and lesion analysis, mean total percentage misclassified volume across all subjects was 2% (17.9 cm3) of whole brain volume (corrected for total intracranial capacity). Mean percentage of misclassified tissue volumes for the severe group was 4.8% of whole brain, which translates to a mean volume 42.2 cm3. Gray matter volume was most overestimated in the severe group, where 6.4% of the total gray matter volume was derived from misclassified WMH. The regional analysis showed that frontal (41%, 7.4 cm3) and inferior parietal (18%, 3.25 cm3) lobes were most affected by tissue misclassification. Conclusion— MRI-based volumetric studies of Alzheimer Disease that do not account for WMH can expect an erroneous inflation of gray or white matter volumes, especially in the frontal and inferior parietal regions. To avoid this source of error, MRI-based volumetric studies in patient populations susceptible to hyperintensities should include a WMH segmentation protocol.

Imaging the Perivascular Space as a Potential Biomarker of Neurovascular and Neurodegenerative Diseases.

Although the brain lacks conventional lymphatic vessels found in peripheral tissue, evidence suggests that the space surrounding the vasculature serves a similar role in the clearance of fluid and metabolic waste from the brain. With aging, neurodegeneration, and cerebrovascular disease, these microscopic perivascular spaces can become enlarged, allowing for visualization and quantification on structural MRI. The purpose of this review is to: (i) describe some of the recent pre-clinical findings from basic science that shed light on the potential neurophysiological mechanisms driving glymphatic and perivascular waste clearance, (ii) review some of the pathobiological etiologies that may lead to MRI-visible enlarged perivascular spaces (ePVS), (iii) describe the possible clinical implications of ePVS, (iv) evaluate existing qualitative and quantitative techniques used for measuring ePVS burden, and (v) propose future avenues of research that may improve our understanding of this potential clinical neuroimaging biomarker for fluid and metabolic waste clearance dysfunction in neurodegenerative and neurovascular diseases.

White matter hyperintensity burden in elderly cohort studies: The Sunnybrook Dementia Study, Alzheimer's Disease Neuroimaging Initiative, and Three-City Study

Given the recent acknowledgement of the complex mixed pathologies that contribute to the clinical expression of dementia, various cohort studies have aimed to examine Alzheimers disease and cerebrovascular disease as comorbid pathologies, with neuroimaging playing a central role in these studies. Using white matter hyperintensities (WMH) as a biomarker of cerebrovascular disease, we compared WMH burden between the Sunnybrook Dementia Study, the Alzheimers Disease Neuroimaging Initiative (ADNI‐1), the Three‐City Study, and various other studies around the world. Based on our findings, it was evident that ADNI‐1 had minimal WMH burden relative to other large studies that examine aging and dementia. This low WMH burden in ADNI‐1 may be considered as both an advantage, representing a relatively “pure” sample with little confounding vasculopathy, and a disadvantage, as it limits generalizability to “real‐world” patient populations with mixed pathologies and to nondemented groups with baseline vascular disease. We explore possible reasons for this distinction, including management of vascular risk factors, gaps in diagnostic criteria, and future directions for clinical research.

Subcortical hyperintensity volumetrics in Alzheimer’s disease and normal elderly in the Sunnybrook Dementia Study: correlations with atrophy, executive function, mental processing speed, and verbal memory

IntroductionSubcortical hyperintensities (SHs) are radiological entities commonly observed on magnetic resonance imaging (MRI) of patients with Alzheimer’s disease (AD) and normal elderly controls. Although the presence of SH is believed to indicate some form of subcortical vasculopathy, pathological heterogeneity, methodological differences, and the contribution of brain atrophy associated with AD pathology have yielded inconsistent results in the literature.MethodsUsing the Lesion Explorer (LE) MRI processing pipeline for SH quantification and brain atrophy, this study examined SH volumes of interest and cognitive function in a sample of patients with AD (n = 265) and normal elderly controls (n = 100) from the Sunnybrook Dementia Study.ResultsCompared with healthy controls, patients with AD were found to have less gray matter, less white matter, and more sulcal and ventricular cerebrospinal fluid (all significant, P <0.0001). Additionally, patients with AD had greater volumes of whole-brain SH (P <0.01), periventricular SH (pvSH) (P <0.01), deep white SH (dwSH) (P <0.05), and lacunar lesions (P <0.0001). In patients with AD, regression analyses revealed a significant association between global atrophy and pvSH (P = 0.02) and ventricular atrophy with whole-brain SH (P <0.0001). Regional volumes of interest revealed significant correlations with medial middle frontal SH volume and executive function (P <0.001) in normal controls but not in patients with AD, global pvSH volume and mental processing speed (P <0.01) in patients with AD, and left temporal SH volume and memory (P <0.01) in patients with AD.ConclusionsThese brain-behavior relationships and correlations with brain atrophy suggest that subtle, yet measurable, signs of small vessel disease may have potential clinical relevance as targets for treatment in Alzheimer’s dementia.

Overlap in frontotemporal atrophy between normal aging and patients with frontotemporal dementias.

Normal aging leads to frontocortical atrophy. The degree to which this complicates the use of frontotemporal atrophy as a diagnostic criterion for the frontotemporal dementias (FTDs) has not been reported. The present case-control study compared frontotemporal volumes delineated with semi-automatic brain region extraction [n=30 controls vs. 16 behavioral variant FTD (bvFTD) vs. 14 primary progressive aphasia]. Logistic regression identified those regions least helpful for distinguishing bvFTD and primary progressive aphasia from controls. Linear regression tested the correlation of duration of illness to atrophy severity. The control group showed high variance in volumes. Controls had right frontal lobe volumes that overlapped considerably with bvFTD volumes, but, as anticipated, the left anterior temporal volumes of interest showed 91% accuracy in distinguishing the aphasic subgroup from controls. Left-sided and not right-sided atrophy in the medial middle frontal region distinguished the bvFTD group from controls. The relegation of structural imaging to a supportive criterion for diagnosis is reasonable in the context of the range of atrophy due to normal aging. While volumetry identified left-sided atrophy as useful for identifying FTD cases, future studies should determine whether clinicians could make these distinctions on viewing routine diagnostic magnetic resonance imaging scans.

Dynamic Progression of White Matter Hyperintensities in Alzheimer's Disease and Normal Aging: Results from the Sunnybrook Dementia Study.

Although white matter hyperintensities (WMH), markers of cerebral small vessel disease (SVD), are believed to generally increase over time, some studies have shown sharp decreases after therapeutic intervention, suggesting that WMH progression may be more dynamic than previously thought. Our primary goal was to examine dynamic progression of WMH in a real-world sample of Alzheimer’s disease (AD) patients and normal elderly (NC), with varying degrees of SVD. WMH volumes from serial magnetic resonance imaging (MRI; mean = 1.8 years) were measured from NC (n = 44) and AD patients (n = 113) with high and low SVD burden. Dynamic progression for each individual was measured using spatial overlap images to assess shrinkage, growth, and stable WMH volumes. Significant group differences were found for shrinkage (p < 0.001), growth (p < 0.001) and stable (p < 0.001) WMH, where the AD high SVD group showed the largest changes relative to low SVD and NC. Our results suggest spatial progression measured at the individual patient level may be more sensitive to the dynamic nature of WMH.

Cholinergic Subcortical Hyperintensities in Alzheimer's Disease Patients from the Sunnybrook Dementia Study: Relationships with Cognitive Dysfunction and Hippocampal Atrophy

BACKGROUND Subcortical hyperintensities within the cholinergic fiber projections (chSH) on MRI are believed to reflect cerebral small vessel disease (SVD) which may adversely impact cognition. Additionally, hippocampal atrophy represents a commonly used biomarker to support the diagnosis of Alzheimers disease (AD). OBJECTIVE To examine potential differences in neuropsychological test performance between AD patients (n = 234) with high and low chSH volumes and whether these differences corresponded to hippocampal atrophy. METHODS A modified version of Lesion Explorer was used to volumetrically quantify chSH severity. The Sunnybrook Hippocampal Volumetry Tool was applied to obtain hippocampal volumes. Composite z-scores to assess executive, memory, and visuospatial functioning were generated from standardized neuropsychological test performance scores. RESULTS Inter-method technique validation demonstrated a high degree of correspondence with the Cholinergic Pathways Hyperintensities Scale (n = 40, ρ = 0.84, p < 0.001). After adjusting for brain atrophy, disease severity, global SH volumes, and demographic variables, multivariate analyses revealed a significant group difference, with the high chSH group demonstrating poorer memory function compared to the low chSH group (p = 0.03). A significant difference was found between low and high chSH groups in total (p < 0.05) and left (p < 0.01) hippocampal volume. CONCLUSION These results suggest degradation of the cholinergic projections due to strategic SVD may independently contribute to memory dysfunction and hippocampal atrophy. Future studies examining subcortical vasculopathy in the cholinergic pathways may have implications on the development of therapeutic strategies for dementia and SVD.

Associations between amyloid β and white matter hyperintensities: A systematic review

This systematic review synthesizes current evidence for associations between cortical amyloid β, visualized on amyloid positron emission tomography imaging, and white matter hyperintensity (WMH) burden on magnetic resonance imaging in healthy elderly adults and individuals with cognitive impairment and dementia.