Christopher J.M. Scott

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.

Magnetic Resonance Imaging in Frontotemporal Dementia Shows Subcortical Atrophy

Background/Aims: The clinical syndrome of the frontotemporal dementias (FTD) overlaps with frontal-subcortical circuit syndromes. We explored the extent to which subcortical atrophy on structural magnetic resonance imaging may indicate a subcortical contribution to the progression of FTD. Methods: This cross-sectional case-control study compared striatal and thalamic gray matter volumes and functional levels from 30 FTD cases and 30 age- and gender-matched controls. Results: The FTD group had significantly more atrophy in all gray matter subcortical regions, correlating with ipsilateral frontocortical atrophy. Subcortical atrophy was also associated with functional disability. Subcortical asymmetry was most marked in subjects with primary progressive aphasia. Conclusion: Subcortical gray matter atrophy may contribute as significantly to symptoms of FTD as cortical atrophy.

Diffusion tensor imaging abnormalities in cognitively impaired multiple sclerosis patients.

BACKGROUND Cognitive impairment can add to the burden of disease in patients with multiple sclerosis (MS). The aim of this study was to assess the relative importance of diffusion tensor imaging (DTI) indices derived from normal appearing white matter (NAWM) and grey matter (NAGM) in determining cognitive dysfunction in MS patients. METHODS Sixty two MS patients [51 female, mean age = 41 (sd = 9.6) years, median expanded disability status scale (EDSS) = 2.5] meeting modified McDonald criteria for MS underwent neuropsychological testing using the Neuropsychological Screening Battery for MS (NSBMS) and magnetic resonance imaging (MRI, 1.5T GE) that included DTI sequences. Total T1 hypointense and T2 hyperintense lesion volumes were obtained using semi-automated software. Lesion volumes were subtracted from whole-brain parenchyma to obtain measures of NAWM and NAGM. Fractional anisotropy (FA) of NAWM and mean diffusivity (MD) of NAGM were obtained. RESULTS Cognitive impairment was present in 11 patients (18%). These patients had higher EDSS scores, were less educated, and were more likely to have secondary progressive MS. They also had higher hypointense (p = 0.001) and hyperintense (p = 0.004) lesion volumes, greater NAWM atrophy (p = 0.007), lower FA of total NAWM (p = 0.003), and higher MD of total NAGM (p = 0.015). Using a logistic regression analysis, and after controlling for demographic and disease-related differences between groups, FA of NAWM emerged as a significant predictor of cognitive impairment adding to the variance derived from lesion and atrophy data. CONCLUSION This study underlies the important role of normal-appearing brain tissue in the pathogenesis of MS-related cognitive impairment.

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.

Lesion Explorer: a video-guided, standardized protocol for accurate and reliable MRI-derived volumetrics in Alzheimer's disease and normal elderly.

Obtaining in vivo human brain tissue volumetrics from MRI is often complicated by various technical and biological issues. These challenges are exacerbated when significant brain atrophy and age-related white matter changes (e.g. Leukoaraiosis) are present. Lesion Explorer (LE) is an accurate and reliable neuroimaging pipeline specifically developed to address such issues commonly observed on MRI of Alzheimers disease and normal elderly. The pipeline is a complex set of semi-automatic procedures which has been previously validated in a series of internal and external reliability tests1,2. However, LEs accuracy and reliability is highly dependent on properly trained manual operators to execute commands, identify distinct anatomical landmarks, and manually edit/verify various computer-generated segmentation outputs. LE can be divided into 3 main components, each requiring a set of commands and manual operations: 1) Brain-Sizer, 2) SABRE, and 3) Lesion-Seg. Brain-Sizers manual operations involve editing of the automatic skull-stripped total intracranial vault (TIV) extraction mask, designation of ventricular cerebrospinal fluid (vCSF), and removal of subtentorial structures. The SABRE component requires checking of image alignment along the anterior and posterior commissure (ACPC) plane, and identification of several anatomical landmarks required for regional parcellation. Finally, the Lesion-Seg component involves manual checking of the automatic lesion segmentation of subcortical hyperintensities (SH) for false positive errors. While on-site training of the LE pipeline is preferable, readily available visual teaching tools with interactive training images are a viable alternative. Developed to ensure a high degree of accuracy and reliability, the following is a step-by-step, video-guided, standardized protocol for LEs manual procedures.

Apathy is not Associated with Basal Ganglia Atrophy in Frontotemporal Dementia

OBJECTIVE To determine whether basal ganglia atrophy, known to be associated with apathy in nondementia populations, was associated with presence of apathy in patients with frontotemporal dementia (FTD). METHODS A cross-sectional case study was conducted at two tertiary dementia care clinics in Toronto, Ontario, Canada. Striatal and thalamic gray matter volumes and apathy measures were collected from 21 subjects with FTD, 6 of whom did not show apathy on the Neuropsychiatric Inventory. RESULTS No significant differences in gray matter volumes were found between apathetic and nonapathetic groups for the striatum or the thalamus. CONCLUSIONS Our findings imply that the etiology of apathy seen in patients with FTD differs from that of patients with apathy after acquired injuries to the basal ganglia. Further study is needed to determine whether posterior thalamic atrophy correlates with apathy in FTD or functional imaging techniques might successfully find a relationship between basal ganglia dysfunction and apathy.

Differentiating between visual hallucination-free dementia with Lewy bodies and corticobasal syndrome on the basis of neuropsychology and perfusion single-photon emission computed tomography.

IntroductionDementia with Lewy bodies (DLB) and Corticobasal Syndrome (CBS) are atypical parkinsonian disorders with fronto-subcortical and posterior cognitive dysfunction as common features. While visual hallucinations are a good predictor of Lewy body pathology and are rare in CBS, they are not exhibited in all cases of DLB. Given the clinical overlap between these disorders, neuropsychological and imaging markers may aid in distinguishing these entities.MethodsProspectively recruited case–control cohorts of CBS (n =31) and visual hallucination-free DLB (n =30), completed neuropsychological and neuropsychiatric measures as well as brain perfusion single-photon emission computed tomography and structural magnetic resonance imaging (MRI). Perfusion data were available for forty-two controls. Behavioural, perfusion, and cortical volume and thickness measures were compared between the groups to identify features that serve to differentiate them.ResultsThe Lewy body with no hallucinations group performed more poorly on measures of episodic memory compared to the corticobasal group, including the delayed and cued recall portions of the California Verbal Learning Test (F (1, 42) =23.1, P <0.001 and F (1, 42) =14.0, P =0.001 respectively) and the delayed visual reproduction of the Wechsler Memory Scale-Revised (F (1, 36) =9.7, P =0.004). The Lewy body group also demonstrated reduced perfusion in the left occipital pole compared to the corticobasal group (F (1,57) =7.4, P =0.009). At autopsy, the Lewy body cases all demonstrated mixed dementia with Lewy bodies, Alzheimer’s disease and small vessel arteriosclerosis, while the corticobasal cases demonstrated classical corticobasal degeneration in five, dementia with agyrophilic grains + corticobasal degeneration + cerebral amyloid angiopathy in one, Progressive Supranuclear Palsy in two, and Frontotemporal Lobar Degeneration-Ubiquitin/TAR DNA-binding protein 43 proteinopathy in one. MRI measures were not significantly different between the patient groups.ConclusionsReduced perfusion in the left occipital region and worse episodic memory performance may help to distinguish between DLB cases who have never manifested with visual hallucinations and CBS at earlier stages of the disease. Development of reliable neuropsychological and imaging markers that improve diagnostic accuracy will become increasingly important as disease modifying therapies become available.